Search

The purpose of this report is to describe the efficacy of sacubitril/valsartan in 5 hemodialysis patients with hypertension, including a patient with heart failure with reduced ejection fraction (HFrEF) and a patient with preserved ejection fraction (HFpEF) focused on the functional changes in the heart. We switched from angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) to sacubitril/valsartan and compared blood pressure post dialysis, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels and the findings of echocardiography for a period of 6 months. A month after the initiation of sacubitril/valsartan, there was improvement of symptoms and blood pressure post-dialysis, the NT-pro-BNP levels decreased from 23,132.2 ± 16,561.3 pg/mL to 8327 ± 3334.3 pg/mL, and the echocardiography findings showed a decrease in the left atrial dimension from 37.7 ± 5.7 mm to 33 ± 4.9 mm and an increase in the left ventricular ejection fraction from 58.2 ± 16.9% to 66.4 ± 15.0%. These results were sustained for up to 6 months. Also, blood pressure post-dialysis changed from 164 ± 11/77 mmHg to 150 ± 13/72 mmHg over the 6-month period. There were no side effects, such as hyperkalemia and lymphoedema. In conclusion, 5 patients had hypertension, including 2 patients with heart failure. Sacubitril/valsartan improved blood pressure post-dialysis, heart failure symptoms, NT-pro- BNP, the left atrial dimension, the left ventricular ejection fraction, and E/e', E/A found via echocardiography for a 6-months period. Treatment with sacubitril/valsartan was effective in hemodialysis patients in the cardiac function., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

This study investigated whether sacubitril/valsartan or valsartan are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in two experimental models of pre-hypertension induced by continuous light (24 hours/day) exposure or by chronic lactacystin treatment, and how this potential protection interferes with the renin-angiotensin-aldosterone system (RAAS). Nine groups of three-month-old male Wistar rats were treated for six weeks as follows: untreated controls (C), sacubitril/valsartan (ARNI), valsartan (Val), continuous light (24), continuous light plus sacubitril/valsartan (24+ARNI) or valsartan (24+Val), lactacystin (Lact), lactacystin plus sacubitil/valsartan (Lact+ARNI) or plus valsartan (Lact+Val). Both the 24 and Lact groups developed a mild but significant systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, as well as LV systolic and diastolic dysfunction. Yet, no changes in serum renin-angiotensin were observed either in the 24 or Lact groups, though aldosterone was increased in the Lact group compared to the controls. In both models, sacubitril/valsartan and valsartan reduced elevated SBP, LV hypertrophy and fibrosis and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan and valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7 in the 24 and Lact groups and reduced aldosterone in the Lact group. We conclude that both continuous light exposure and lactacystin treatment induced normal-to-low serum renin-angiotensin models of pre-hypertension, whereas aldosterone was increased in lactacystin-induced pre-hypertension. The protection by ARNI or valsartan in the hypertensive heart in either model was related to the Ang II blockade and the protective Ang 1-7, while in lactacystin-induced pre-hypertension this protection seems to be additionally related to the reduced aldosterone level., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Candesartan is a common angiotensin-II receptor-1 blocker used for patients with cardiovascular and renal diseases. Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of blood pressure (BP), and also a major receptor for coronaviruses. To determine whether and how candesartan upregulates ACE2, we examined BP and ACE2 in multi-organs from male and female C57BL/6J mice treated with candesartan (1 mg/kg, i.p.) for 7 days. Relative to the vehicle, candesartan lowered BP more in males than females; ACE2 protein abundances were increased in kidneys, not lungs, hearts, aorta, liver, spleen, brain, or serum, only from males. Ace2-mRNA was similar in kidneys. Candesartan also decreased BP in normal, hypertensive, and nephrotic male rats. The renal ACE2 was increased by the drug in normal and nephrotic male rats but not spontaneously hypertensive ones. In male mouse kidneys, ACE2 was distributed at sodium-hydrogen-exchanger-3 positive proximal-convoluted-tubules; ACE2-ubiquitination was decreased by candesartan, accompanied with increased ubiquitin-specific-protease-48 (USP48). In candesartan-treated mouse renal proximal-convoluted-tubule cells, ACE2 abundances and activities were increased while ACE2-ubiquitination and colocalization with lysosomal and proteosomal markers were decreased. The silence of USP48 by siRNA caused a reduction of ACE2 in the cells. Thus, the sex-differential ACE2 upregulation by candesartan in kidney from males may be due to the decreased ACE2-ubiquitination, associated with USP48, and consequent degradation in lysosomes and proteosomes. This is a novel mechanism and may shed light on candesartan-like-drug choice in men and women prone to coronavirus infections., (© 2024 Federation of American Societies for Experimental Biology.)

Vascular cognitive impairment (VCI) is claimed as the second most common type of dementia after Alzheimer's disease (AD), in which hypertension is a critical inducer. Currently, hypertension-induced cognitive impairment lacks clinical treatments. Irbesartan is a long-acting angiotensin receptor antagonist with promising antihypertensive properties. Our research will focus on the potential function of Irbesartan on hypertension-induced cognitive impairment. Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were orally dosed with normal saline or 20 mg/kg/day Irbesartan for 14 consecutive days, with 4 groups divided shown as below: WKY, Irbesartan, SHR, SHR+ Irbesartan. Firstly, the markedly increased systolic blood pressure observed in SHR rats was signally repressed by Irbesartan on Day 7 and 14 post-dosing. Moreover, notably decreased time of exploring the novel object in the object recognition task (ORT) test, elevated escape latency, and reduced time in the target quadrant in the Morris water maze (MWM) test were observed in SHR rats, which were prominently reversed by Irbesartan. Furthermore, the declined superoxide dismutase (SOD) activity, elevated malondialdehyde (MDA) level, increased cyclin-dependent kinase-5 (CDK5) activity, and enhanced protein level of p35/p25, p-Tau (pSer 214 )/Tau46, and brain-derived neurotrophic factor (BDNF) were memorably rescued by Irbesartan. Lastly, the activity of cAMP/cAMP response element binding protein (CREB) signaling in the hippocampus of SHR rats was markedly repressed, accompanied by an upregulation of phosphodiesterase 4B (PDE4B), which was observably rescued by Irbesartan. Collectively, Irbesartan protected against the hypertension-induced cognitive impairment in SHR rats by regulating the cAMP/CREB signaling.

There lacks real-world study with a large sample size assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM-AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM-AML (20/5 mg) tablet were analyzed in the current prospective, single-arm, multi-center, real-world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was -10.8 ± 0.4/-6.6 ± 0.3 mmHg at W4 and -12.7 ± 0.5/-7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home-measured SeSBP and SeDBP decreased from W1 to W8 (both p < .001). Besides, patients' and physicians' satisfaction were elevated at W8 compared with W0 (both p < .001). The medication possession rate was 94.8% from baseline to W4 and 91.3% from baseline to W8. The most common drug-related adverse events were nervous system disorders (4.6%), vascular disorders (2.6%), and general disorders and administration site conditions (2.3%) by system organ class, which were generally mild and manageable. In conclusion, OM-AML tablet is one of the best antihypertensive agents in patients with essential hypertension., (© 2023 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Quantum pharmacology introduces theoretical models to describe the possibility of ultra-high dilutions to produce biological effects, which may help to explain the placebo effect observed in hypertensive clinical trials. To determine this within physiology and to evaluate novel ARBs, we tested the ability of known angiotensin II receptor blockers (ARBs) (candesartan and telmisartan) used to treat hypertension and other cardiovascular diseases, as well as novel ARBs (benzimidazole- N -biphenyl tetrazole (ACC519T), benzimidazole- bis - N , N '-biphenyl tetrazole (ACC519T(2)) and 4-butyl-N,N0-bis[[20-2Htetrazol-5-yl)biphenyl-4-yl]methyl)imidazolium bromide (BV6(K + ) 2 ), and nirmatrelvir (the active ingredient in Paxlovid) to modulate vascular contraction in iliac rings from healthy male New Zealand White rabbits in responses to various vasopressors (angiotensin A, angiotensin II and phenylephrine). Additionally, the hemodynamic effect of ACC519T and telmisartan on mean arterial pressure in conscious rabbits was determined, while the ex vivo ability of BV6(K + ) 2 to activate angiotensin-converting enzyme-2 (ACE2) was also investigated. We show that commercially available and novel ARBs can modulate contraction responses at ultra-high dilutions to different vasopressors. ACC519T produced a dose-dependent reduction in rabbit mean arterial pressure while BV6(K + ) 2 significantly increased ACE2 metabolism. The ability of ARBs to inhibit contraction responses even at ultra-low concentrations provides evidence of the existence of quantum pharmacology. Furthermore, the ability of ACC519T and BV6(K + ) 2 to modulate blood pressure and ACE2 activity, respectively, indicates their therapeutic potential against hypertension.

This study evaluated the effect of sacubtril/valsartan on cardiac remodeling, molecular and cellular adaptations in experimental (rat) model of hypertension-induced hypertrophic cardiomyopathy. Thirty Wistar Kyoto rats, 10 healthy (control) and 20 rats with confirmed hypertension-induced hypertrophic cardiomyopathy (HpCM), were used for this study. The HpCM group was further subdivided into untreated and sacubitril/valsartan-treated groups. Myocardial structure and function were assessed using echocardiography, Langendorff's isolated heart experiment, blood sampling and qualitative polymerase chain reaction. Echocardiographic examinations revealed protective effects of sacubitril/valsartan by improving left ventricular internal diameter in systole and diastole and fractional shortening. Additionally, sacubitril/valsartan treatment decreased systolic and diastolic blood pressures in comparison with untreated hypertensive rats. Moreover, sacubitril/valsartan treatment reduced oxidative stress and apoptosis (reduced expression of Bax and Cas9 genes) compared to untreated rats. There was a regular histomorphology of cardiomyocytes, interstitium, and blood vessels in treated rats compared to untreated HpCM rats which expressed hypertrophic cardiomyocytes, with polymorphic nuclei, prominent nucleoli and moderately dilated interstitium. In experimental model of hypertension-induced hypertrophic cardiomyopathy, sacubitril/valsartan treatment led to improved cardiac structure, haemodynamic performance, and reduced oxidative stress and apoptosis. Sacubitril/valsartan thus presents as a potential therapeutic strategy resulted in hypertension-induced hypertrophic cardiomyopathy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: Sacubitril/valsartan (Sac/Val, LCZ696), the world's first angiotensin receptor-neprilysin inhibitor (ARNi), has been widely used in the treatment of heart failure. However, the use of Sac/Val in the treatment of atrial fibrillation (AF), especially AF with hypertension, has been less reported. We investigated the effect of Sac/Val on atrial remodeling and hypertension-related AF., Methods: The AF induction rate and electrophysiological characteristics of spontaneously hypertensive rats (SHRs) treated with Sac/Val or Val were detected by rapid atrial pacing and electrical mapping/optical mapping. The whole-cell patch-clamp and Western blot were used to observe electrical/structural remodeling of atrial myocytes/tissue of rats and atrium-derived HL-1 cells cultured under 40 mmHg in vitro., Results: Sac/Val was superior to Val in reducing blood pressure, myocardial hypertrophy and susceptibility of AF in SHRs. The shorten action potentials duration (APD), decreased L type calcium channel current (I Ca,L ) and Cav1.2, increased ultrarapid delayed rectified potassium current (I kur ) and Kv1.5 in atrial myocytes/tissue of SHRs could be better improved by Sac/Val, as well as the levels of atrial fibrosis. While the protein expression of angiotensin-converting enzyme-1 (ACE-1), angiotensin, angiotensin II type I AT1 receptor (AT1R) and neprilysin (NEP) were increased, which could be more effective ameliorated by Sac/Val than Val. Furthermore, Val + Sacubitrilat (LBQ657) (an active NEP inhibitor) was also superior to LBQ657 or Val in improving the electrical and structural remodeling of HL-1 cells through inhibiting NEP., Conclusion: Sac/Val can improve atrial structural and electrical remodeling induced by hypertension and reduce the AF susceptibility by inhibiting RAS and NEP. The above effects of Sac/Val were superior to Val alone., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: There is little information on the pharmacokinetics and pharmacodynamics of sacubitril/valsartan (SV) in patients undergoing peritoneal dialysis (PD) complicated with hypertension or heart failure (HF). This study was designed to evaluate the pharmacokinetics and pharmacodynamics of SV in PD patients with complications of hypertension or HF., Methods: This was an open-label and cross-sectional study investigating PD patients diagnosed with hypertension or New York Heart Association Class II-IV HF. The concentrations of valsartan, sacubitril and sacubitrilat (LBQ657) were measured by ultra-performance liquid chromatography tandem mass spectrometry in plasma, urine and peritoneal dialysate samples. Pharmacodynamics were evaluated by comparing changes in mean sitting systolic blood pressure (msSBP), mean sitting diastolic blood pressure (msDBP), mean sitting heart rate, N-terminal-pro B-type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF)., Results: Forty patients with PD were enrolled including 27 (67.5%) patients with hypertension, 4 (10%) patients with HF and 9 (22.5%) patients with both hypertension and HF. This study included three treatment cohorts: 50 mg twice daily (BID), 100 mg once daily and 100 mg BID. The plasma maximum drug concentrations in the 100 mg BID group were 1995 ± 1499 ng/mL for valsartan, 171 ± 148 ng/mL for sacubitril and 13 686 ± 7418 ng/mL for LBQ657. The 24-h recovery rate of LBQ657 was 3.77% in urine and 2.23% in peritoneal dialysate. After taking SV, msSBP and msDBP decreased by 19.25 ± 10.32 mmHg and 10.10 ± 8.00 mmHg from baseline, respectively. NT-proBNP decreased by 1436.50 (0.00-18 198.00) from baseline, while LVEF increased by 5.00 (-0.25 to 9.25) from baseline after SV treatment., Conclusions: PD and residual renal function contributed only to a minor degree to the elimination of LBQ657. Additionally, a dose of 100 mg BID SV is safe and effective in patients with PD with complications of hypertension or HF., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Hypertension is the most common cause of left ventricular hypertrophy, contributing to heart failure progression. Candesartan (Cand) is an angiotensin receptor antagonist widely used for hypertension treatment. Structural modifications were previously performed by our group using Zinc (ZnCand) as a strategy for improving its pharmacological properties. The measurements showed that ZnCand exerts a stronger interaction with the angiotensin II receptor, type 1 (AT 1 receptor), reducing oxidative stress and intracellular calcium flux, a mechanism implied in cell contraction. These results were accompanied by the reduction of the contractile capacity of mesangial cells. In vivo experiments showed that the complex causes a significant decrease in systolic blood pressure after 8 weeks of treatment in spontaneously hypertensive rats (SHR). The reduction of heart hypertrophy was evidenced by echocardiography, the histologic cross-sectional area of cardiomyocytes, collagen content, the B-type natriuretic peptide (BNP) marker and connective tissue growth factor (CTGF) and the matrix metalloproteinase 2 (MMP-2) expression. Besides, the complex restored the redox status. In this study, we demonstrated that the complexation with Zn(II) improves the antihypertensive and cardiac effects of the parental drug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Chronopharmacology of arterial hypertension impacts the long-term cardiovascular risk of hypertensive subjects. Therefore, clinical and computational studies have proposed optimizing antihypertensive medications' dosing time (Ta). However, the causes and mechanisms underlying the Ta-dependency antihypertensive effect have not been elucidated. Here we propose using a Ta- dependent effect model to understand and predict the antihypertensive effect of valsartan and aspirin throughout the day in subjects with grade I or II essential hypertension. The model based on physiological regulation mechanisms includes a periodic function for each parameter that changes significantly after treatment. Circadian variations of parameters depending on the dosing time allowed the determination of regulation mechanisms dependent on the circadian rhythm that were most relevant for the action of each drug. In the case of valsartan, it is the regulation of vasodilation and systemic vascular resistance. In the case of aspirin, the antithrombotic effect generates changes in the sensitivity of systemic vascular resistance and heart rate to changes in physical activity. Dosing time-dependent models predict a more significant effect on systemic vascular resistance and blood pressure when administering valsartan or aspirin at bedtime. However, circadian dependence on the regulation mechanisms showed different sensitivity of their circadian parameters and shapes of functions, presenting different phase shifts and amplitude. Therefore, different mechanisms of action and pharmacokinetic properties of each drug can generate different profiles of Ta-dependence of antihypertensive effect and optimal dosing times., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cortés-Ríos and Rodriguez-Fernandez.)

There is increasing awareness of seasonal variation in blood pressure (BP). In the present analysis, we investigated seasonal variation in the antihypertensive treatment effect of the irbesartan/hydrochlorothiazide combination in patients with stage 2 and 3 hypertension. The study participants were hypertensive patients enrolled in a 12-week therapeutic study. Antihypertensive treatment was initiated with irbesartan/hydrochlorothiazide 150/12.5 mg/day, with possible uptitration to 300/12.5 mg/day and 300/25 mg/day at 4 and 8 weeks of follow-up, respectively. The month of treatment commencement was classified as spring/summer (May to August) and autumn/winter (September to December). Of the 501 enrolled patients, 313 and 188 commenced antihypertensive treatment in spring/summer and autumn/winter, respectively. The mean changes in systolic/diastolic BP at 8 and 12 weeks of follow-up were greater in patients who commenced treatment in autumn/winter (-32.3/-16.5 and -34.2/-16.7 mmHg, respectively) than those who commenced treatment in spring/summer (-28.4/-13.9 and -27.1/-12.8 mmHg, respectively), with a between-season difference of 3.9 (95% confidence interval [CI], 1.4-6.4, P = 0.002)/2.6 (95% CI, 0.9-4.2, P = 0.002) mmHg and 7.0 (95% CI, 4.7-9.3, P < 0.0001)/3.9 (95% CI, 2.4-5.4, P < 0.0001) mmHg, respectively. Further subgroup analyses according to several baseline characteristics showed a greater between-season difference in the changes in systolic BP in patients aged ≥55 years than in those <55 years (n = 255, 12.6 mmHg vs. n = 246, 6.9 mmHg, P = 0.02), especially in patients who did not use antihypertensive medication at baseline (n = 94, 15.4 mmHg vs. n = 132, 5.4 mmHg, P = 0.006). In conclusion, there is indeed seasonality in the antihypertensive treatment effect, with a greater BP reduction in patients who commenced treatment in cold than warm seasons., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Nebivolol has a dual mechanism of action, exerting a moderate b- blockade effect and reducing peripheral arterial resistance, as a result, the antihypertensive effect of nebivolol may be higher than that of a potent vasodilator CCB such as amlodipine., Aim: The study evaluated the effect of two nebivolol/valsartan on 24 hour ambulatory blood pressure versus amlodipine/valsartan in grade II or III hypertension patients or having uncontrolled BP despite treatment. Ambulatory blood pressure monitoring is a powerful method to monitor the changes in blood pressure over the 24 hour., Materials and Methods: A total of 74 from 90 patients continued the study. Fourty patients received amlodipine 10 mg/valsartan 160 mg (group I), and thirty-four patients received nebivolol 5 mg/ valsartan 160 mg (group II). Peripheral blood pressure readings were measured at randomization at 6 and 12 weeks. Ambulatory blood pressure was measured at randomization and 12 weeks., Results: Both drug combinations showed high efficacy in reducing peripheral and 24 hour ambulatory BP. There was no statistically significant difference between the groups in lowering peripheral systolic and diastolic blood pressure at 6 and 12 weeks. Furthermore, both groups failed to show any significant difference in reducing 24 hour SBP and DBP. Regarding day SBP, the blood pressure dropped by -5.63 ± 14.87 in group I and -6.25 ± 11.59 in group II (p = 0.844). Also, group I reduced the day DBP average by -2.53 ± 9.83 and group II by -3.61 ± 9.78 (p = 0.640). In addition, both drug combinations had no statistically significant difference in lowering night SBP and DBP average., Conclusion: Both treatment groups reached the target ambulatory blood pressure, and there was no statistically significant difference between both groups as a regard reduction in all ambulatory blood pressure readings., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

High fructose intake has been implicated in obesity and metabolic syndrome, which are related to increased cardiovascular mortality. However, few studies have experimentally examined the role of renin-angiotensin system blockers and calcium channel blockers (CCB) in obesity. We investigated the effects of valsartan (an angiotensin II receptor blocker) and amlodipine (a CCB) on lipolysis through the potential mechanism of PU.1 inhibition. We observed that high fructose concentrations significantly increased adipose size and triglyceride, monoacylglycerol lipase, adipose triglyceride lipase, and stearoyl-CoA desaturase-1 (SCD1), activating transcription factor 3 and PU.1 levels in adipocytes in vitro. Subsequently, PU.1 inhibitor treatment was able to reduce triglyceride, SCD1, and PU.1 levels. In addition, elevated levels of triglyceride and PU.1, stimulated by a high fructose concentration, decreased with valsartan and amlodipine treatment. Overall, these findings suggest that high fructose concentrations cause triacylglycerol storage in adipocytes through PU.1-mediated activation. Furthermore, valsartan and amlodipine treatment reduced triacylglycerol storage in adipocytes by inhibiting PU.1 activation in high fructose concentrations in vitro. Thus, the benefits of valsartan and amlodipine in lipolysis may be through PU.1 inhibition in fructose-induced adiposity, and PU.1 inhibition might have a potential therapeutic role in lipolysis in fructose-induced obesity.

Background: Sacubitril/Valsartan, a dual inhibitor of the neprilysin and angiotensin receptor, exerts cardioprotective effects in heart failure. Little is known on the impact of Sacubitril/Valsartan in hypertensive patients early post myocardial infarction., Methods: Spontaneously hypertensive rats (SHR) were pretreated by daily angiotensin receptor blocker (ARB; 30 mg/kg intraperitoneally), Sacubitril/Valsartan (ARNI; 60 mg/kg intraperitoneally) or the same dosage of physiological saline for 1 week. Then each group underwent myocardial infarction induction and received the same treatment for another week. The blood pressure and cardiac function were evaluated prior to sacrifice. We performed histological and molecular evaluation of fibrosis in vivo and in vitro., Results: The blood pressure was comparable between three groups both 1 week prior to and post myocardial infarction. ARNI and ARB restore the decreased ejection fraction (57.3 ± 7.6 vs. 42.9 ± 5.2%, P < 0.05; 54.3 ± 6.9 vs. 42.9 ± 5.2%, P < 0.01, respectively) and fractional shortening (31.6 ± 5.4 vs. 22.1 ± 3.1%, P < 0.05; 29.4 ± 4.5 vs. 22.1 ± 3.1%, P < 0.05, respectively) post myocardial infarction. The infarct size and collagen deposition were also significantly mitigated in ARNI and ARB groups. In addition, ARNI and ARB treatment reduced the expression of cardiac remodeling-related factors, such as Bnp, α-SMA, Vimentin, and Col1a1 (all P < 0.05 vs. MI group). Finally, ARNI and ARB decreased the expression of α-SMA in cardiac fibroblasts treated with Ang II., Conclusion: In conclusion, pretreatment with ARNI maintained cardiac function and reduced myocardial fibrosis in myocardial infarction, probably prior to any anti-hypertensive effect., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Angiotensin receptor-neprilysin inhibitors have multiple beneficial effects on the cardiovascular system. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to effectively reduce ambulatory 24-h blood pressure in patients with hypertension, and improvements in many aspects of hemodynamic function have also been reported. Overall hemodynamic effects on arterial stiffness and nocturnal blood pressure play an important role in the pathogenesis of hypertensive heart disease. Therefore, these could represent mechanistic targets underlying the effects of angiotensin receptor-neprilysin inhibitors on the continuum of cardiovascular disease from hypertension to heart failure. Other potential mechanisms include reductions in circulating volume and sympathetic activity, both of which contribute to the protection against target organ damage and positive changes in cardiac biomarkers seen during angiotensin receptor-neprilysin inhibitor therapy. The mechanisms of action and beneficial effects of angiotensin receptor-neprilysin inhibitors are complementary to those of a number of other treatment options for hypertension, suggesting the possibility of additive or even synergistic benefits. Based on available data, there are a number of patient groups who will benefit from antihypertensive treatment with an angiotensin receptor-neprilysin inhibitor, including those with salt-sensitive hypertension, structural hypertension, resistant hypertension, and hypertension in the presence of heart failure. Overall, angiotensin receptor-neprilysin inhibitors regulate blood pressure and pulse pressure via multiple mechanisms and provide cardiovascular protection. This provides an option for effective intervention early in the vicious cycle of elevated blood pressure and central pressures with progression toward heart failure that should help to address the growing worldwide heart failure epidemic., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Although amlodipine is recommended as the first-line therapy for the treatment of hypertension, its use is limited by its potential side effects. S-amlodipine is expected to be able to minimize side effects of amlodipine with a similar antihypertensive effect by removing the malicious R-chiral form. However, sustainable blood pressure control with S-amlodipine has not been well established yet. The purpose of the current study was to evaluate ambulatory blood pressure (ABP) profiles before and after a 12-week treatment of S-amlodipine. Patients received once-daily S-amlodipine 2.5 or 5 mg. ABP during 24 hr and office blood pressure were measured at baseline and after the 12-week treatment. Primary endpoints were changes of systolic and diastolic 24 hr ABP. After 12-week S-amlodipine treatment, mean systolic ABP (-15.1 ± 16.2 mmHg, p < .001) and diastolic ABP (-8.9 ± 9.8 mmHg, p < .001) were decreased significantly. Both daytime and night-time mean systolic BP and diastolic BP were also significantly decreased after the 12-week treatment. Global trough-to-peak ratio and smoothness index after 12-week S-amlodipine treatment were .75 and .79 for SBP and .65 and .61 for DBP, respectively. Age ≥65 years (hazard ratio [HR]: 3.13; 95% confidence interval [CI]: 1.67-14.3) and nonalcohol drinking (HR: 3.09; 95% CI: 1.34-7.17) were independent clinical factors for target ABP achievement. Adverse drug reactions (ADR) were developed in 16 (6.4%) patients, including two (.8%) cases of peripheral edema. In conclusion, this study demonstrated the efficacy and safety of S-amlodipine in patients with uncontrolled essential hypertension., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Aim: To assess the influence of the therapy of arterial hypertension with azilsartan medoxomil on the renal function in overweight or obese patients with concomitant metabolic disorders., Materials and Methods: An international multicenter observational nonintervention prospective study included 1945 patients, taking azilsartan medoxomil in accordance with approved prescribing information. The observation period reached 6 months., Results: In patients with an initial glomerular filtration rate (GFR)60 ml/min/1.73 m2 or 60 ml/min/1.73 m2 mean change in systolic blood pressure after 6 months of therapy reached -32.511.1 and -30.413.6 mmHg, correspondingly, while the change in diastolic blood pressure was -13.78.8 and -14.29.4 mmHg, respectively. No decrease in renal function was observed. Moreover, in patients with an initial GFR60 ml/min/1.73 m2 GFR increased significantly (p0.001)., Conclusion: Azilsartan medoxomil, prescribed as monotherapy or in free combinations, provided an effective control of blood pressure in patients with arterial hypertension with both normal or moderately reduced and initially significantly reduced renal function. High efficacy and acceptability of the drug was associated with a beneficial effect on renal function, which allows to consider azilsartan medoxomil as the drug of choice for the treatment of hypertension in patients with concomitant metabolic disorders.

Background High-fructose diet (HFr) induces hypertension and renal damage. However, it has been unknown whether the HFr-induced hypertension and renal damage are exaggerated in subjects with salt sensitivity. We tested impacts of HFr in Dahl salt-sensitive (DS) and salt-resistant (DR) rats. Methods and Results Male DS and DR rats were fed control diet or HFr (60% fructose) with normal-salt content. After 12 weeks, plasma and urinary parameters, renal histological characteristics, and renal expression of renin-angiotensin system components were examined. Furthermore, effects of renin-angiotensin system inhibitors were also examined in DS rats fed the HFr. HFr elevated blood pressure in DS rats but not in DR rats. HFr increased urinary albumin and liver type fatty acid binding protein excretions in both rats, but the excretions were exaggerated in DS rats. HFr increased plasma lipids and uric acid in both rats, whereas HFr increased creatinine clearance in DS rats but not DR rats. Although HFr decreased plasma renin activity in DS rats, HFr-induced glomerular injury, afferent arteriolar thickening, and renal interstitial fibrosis were exaggerated in DS rats. HFr increased renal expression of angiotensinogen, renin, (pro)renin receptor, angiotensin-converting enzyme, and angiotensin II type 1 receptor in DS rat, whereas HFr increased only angiotensin-converting enzyme expression and decreased renin and angiotensin II type 1 receptor expressions in DR rats. Enalapril and candesartan attenuated the HFr-induced hypertension, albuminuria, glomerular hyperfiltration, and renal damage in DS rats. Conclusion HFr-induced hypertension and renal damage are exaggerated in DS rats via renal renin-angiotensin system activation, which can be controlled by renin-angiotensin system inhibitors.

Angiotensin-receptor blockers are often considered insufficiently efficacious in reducing blood pressure. However, newer angiotensin-receptor blockers may be more effective than the older ones. A network meta-analysis was performed to compare the efficacy of various angiotensin-receptor blockers in reducing office and ambulatory blood pressure in hypertensive patients. Relevant literature was searched from English and Chinese databases for randomized controlled trials involving angiotensin-receptor blockers in hypertension. Efficacy variables included systolic and diastolic blood pressure either in the office or on ambulatory blood pressure monitoring. Absolute blood pressure reductions at 6-12 weeks of treatment and their credible intervals were reported. A total of 34 publications provided adequate data for analysis (n = 14 859). In 28 studies on office systolic blood pressure (n = 12 731), against the common comparator valsartan 80 mg, the differences in systolic blood pressure were in favor of azilsartan medoxomil (20-80 mg), irbesartan (300 mg), olmesartan (20-40 mg), telmisartan (80 mg), and valsartan (160-320 mg), but not candesartan (8-16 mg), losartan (50-100 mg), irbesartan (150 mg), olmesartan (10 mg), and telmisartan (40 mg). The ranking plot shows that azilsartan medoxomil 80 mg had a possibility of 99% being the best in the class. Similar results were observed for office diastolic blood pressure and from 13 studies for 24-hour ambulatory systolic and diastolic blood pressure. In conclusion, angiotensin-receptor blockers had different blood pressure lowering efficacy. The newest angiotensin-receptor blocker azilsartan medoxomil at the dose of 80 mg seemed to be most efficacious in reducing both systolic and diastolic blood pressure in the office and on ambulatory measurement., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Hypertension is a worldwide epidemic that continues to grow, with a subset of patients responding poorly to current treatment available. This is especially relevant in Asia, which constitutes 61% of the global population. Hypertension in Asia is a unique entity that is often salt-sensitive, nocturnal, and systolic predominant. Sacubitril/valsartan is a first-in-class angiotensin receptor neprilysin inhibitor that was first used in heart failure with reduced ejection fraction. Sacubitril inhibits neprilysin, a metallopeptidase that degrades natriuretic peptides (NPs). NPs exert sympatholytic, diuretic, natriuretic, vasodilatory, and insulin-sensitizing effects mostly via cyclic guanosine monophosphate (cGMP)-mediated pathways. As an antihypertensive agent, sacubitril/valsartan has outperformed angiotensin II receptor type 1 blockers (ARBs), with additional reductions of office systolic blood pressures ranging between 5 and 7 mmHg, in multiple studies in Asia and around the globe. The drug was well tolerated even in the elderly or those with chronic kidney disease. Its mechanisms of actions are particularly attractive for treatment of hypertension in Asia. Sacubitril/valsartan offers a novel, dual class, single-molecule property that may be considered as first-line antihypertensive therapy. Further investigations are needed to validate its safety for long-term use and to explore other potentials such as in the management of insulin resistance and obesity, which often coexist with hypertension in Asia., (© 2020 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

We tested our hypothesis that, in hypertensive patients with higher nocturnal home systolic blood pressure (HSBP) at baseline, a valsartan/cilnidipine (80/10 mg) combination would reduce nocturnal HSBP more markedly than a valsartan/hydrochlorothiazide (80/12.5 mg) combination. Patients measured their nocturnal HSBP over three nights prior to study randomization and at the end of treatment. Sixty-three and 66 patients comprised the valsartan/cilnidipine and valsartan/hydrochlorothiazide groups; their respective baseline nocturnal HSBP values were 124.3 ± 15.6 and 125.8 ± 15.2 mm Hg (P = .597). Nocturnal HSBPs were significantly reduced from baseline in both groups. Although the valsartan/hydrochlorothiazide group exhibited a significantly greater reduction in nocturnal HSBP compared to the valsartan/cilnidipine group (-5.0 vs. -10.0 mm Hg, P = .035), interaction between the treatment groups and the baseline nocturnal HSBP levels for the changes in nocturnal HSBP after the treatment periods was significant (P = .047). The BP-lowering effect of valsartan/cilnidipine was more dependent on baseline nocturnal HSBP than that of valsartan/hydrochlorothiazide., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

We examined the effects of a fixed-dose single-pill combination of cilnidipine (10 mg), an L-/N-type calcium channel blocker, and valsartan (80 mg) (SPC of Cil/Val) on the day-by-day variability of morning home systolic blood pressure (MHSBP) in 616 patients with treated hypertension for 12 months as a sub-analysis of the HOPE-Combi survey, multicentral, post-marketing, and prospective observational survey. The SPC of Cil/Val was administrated once a day in the morning. The SPC of Cil/Val decreased the standard deviation (SD, from 6.3 ± 4.8 to 5.1 ± 3.8 mmHg, p < .01), coefficient of variation (from 4.3 ± 3.2 to 3.8 ± 2.9%, p < .05), average real variability (ARV, from 7.9 ± 6.6 to 6.3 ± 5.1 mmHg, p < .01), and the difference between maximum and minimum (MMD, from 11.9 ± 9.2 to 9.7 ± 7.2 mmHg, p < .01) of MHSBP. The variability of MHSBP increased with age; however, this was not increased in patients ≥70 years at the baseline. In elderly patients (≥70 years, N = 283), the SPC of Cil/Val decreased the SD (from 6.9 ± 5.6 to 5.6 ± 4.4 mmHg, p < .01), ARV (from 8.6 ± 7.7 to 6.9 ± 5.7 mmHg, p < .05), and MMD (from 13.2 ± 10.7 to 10.7 ± 8.3 mmHg, p < .01) of MHSBP at 12 months; the reduction in these MHSBP variability parameters was comparable to that in adults <70 years. These results suggest that the SPC of Cil/Val is effective in reducing day-by-day variability of MHSBP in elderly patients., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Angiotensin (1-7) production increases during AT1R (angiotensin type-1 receptor) blockade. The contribution of Ang (1-7) (angiotensin [1-7]) and its receptor (MasR) to the favorable effect of angiotensin receptor blockers on remodeling and function of resistance arteries remains unclear. We sought to determine whether MasR contributes to the improvement of vascular structure and function during chronic AT1R blockade. Spontaneously hypertensive rats were treated with Ang (1-7) or olmesartan ± MasR antagonist A-779, or vehicle, for 14 days. Blood pressure was measured by tail cuff methodology. Mesenteric arteries were dissected and mounted on a pressurized micromyograph to evaluate media-to-lumen ratio (M/L) and endothelial function. Expression of MasR and eNOS (endothelial nitric oxide synthase) was evaluated by immunoblotting, plasma nitrate by colorimetric assay, and reactive oxygen species production by dihydroethidium staining. Independently of blood pressure, olmesartan significantly reduced M/L and improved NO bioavailability, A-779 prevented these effects. Likewise, Ang (1-7) significantly reduced M/L and NO bioavailability. MasR expression was significantly increased by Ang (1-7) as well as by olmesartan, and it was blunted in the presence of A-779. Both Ang (1-7) and olmesartan increased eNOS expression and plasma nitrite which were reduced by A-779. Superoxide generation was attenuated by olmesartan and Ang (1-7) and was blunted in the presence of A-779. These MasR-mediated actions were independent of AT2R activation since olmesartan and Ang (1-7) increased MasR expression and reduced M/L in Ang II (angiotensin II)-infused AT2R knockout mice, independently of blood pressure control. A-779 prevented these effects. Hence, MasR activation may contribute to the favorable effects of AT1R antagonism on NO bioavailability and microvascular remodeling, independently of AT2R activation and blood pressure control.

Angiotensin receptor blockers (ARBs) plus calcium channel blockers (CCBs) are a widely used combination therapy for hypertensive patients. In order to determine which combination was better as the next-step therapy for standard-dose combination of ARBs and CCBs, a combination with high-dose CCBs or a triple combination with diuretics, the authors conducted a prospective, randomized, open-label trial to determine which of the following combination is better as the next-step treatment: a combination with high-dose CCBs or a triple combination with diuretics. Hypertensive outpatients who did not achieve their target blood pressure (BP) with usual dosages of ARBs and amlodipine 5 mg were randomly assigned to treatment with irbesartan 100 mg/amlodipine 10 mg (Group 1: n = 48) or indapamide 1 mg in addition to ARBs plus amlodipine 5 mg (Group 2: n = 46). The primary end point was changes in the systolic BP (SBP) and diastolic BP (DBP) after the 12-week treatment period, while secondary end points were changes in BP after the 24-week treatment period and laboratory values. At 12 weeks, the SBP/DBP significantly decreased from 152.1/83.4 mm Hg to 131.5/76.1 mm Hg in Group 1 and 153.9/82.1 mm Hg to 132.7/75.9 mm Hg in Group 2. Although both groups produced a similar efficacy in reducing the SBP/DBP (-19.2/-9.2 mm Hg in Group 1 and -21.6/-8.8 mm Hg in Group 2; SBP P = .378, DBP P = .825), high-dose CCBs combined with ARBs controlled hypertension without elevation of serum uric acid. These results will provide new evidence for selecting optimal combination therapies for uncontrolled hypertensive patients., (©2020 Wiley Periodicals LLC.)

Uridine 5'-triphosphate (UTP) has an important role as an extracellular signaling molecule that regulates inflammation, angiogenesis, and vascular tone. While chronic hypertension has been shown to promote alterations in arterial vascular tone regulation, carotid artery responses to UTP under hypertensive conditions have remained unclear. The present study investigated carotid artery responses to UTP in spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats (WKY). Accordingly, our results found that although UTP promotes concentration-dependent relaxation in isolated carotid artery segments from both SHR and WKY after pretreatment with phenylephrine, SHR exhibited significantly lower arterial relaxation responses compared with WKY. Moreover, UTP-induced relaxation was substantially reduced by endothelial denudation and by the nitric oxide (NO) synthase inhibitor N G -nitro-L-arginine in both SHR and WKY. The difference in UTP-induced relaxation between both groups was abolished by the selective P2Y 2 receptor antagonist AR-C118925XX and the cyclooxygenase (COX) inhibitor indomethacin but not by the thromboxane-prostanoid receptor antagonist SQ29548. Furthermore, we detected the release of PGE 2 , PGF 2α , and PGI 2 in the carotid arteries of SHR and WKY, both at baseline and in response to UTP. UTP administration also increased TXA 2 levels in WKY but not SHR. Overall, our results suggest that UTP-induced relaxation in carotid arteries is impaired in SHR perhaps due to impaired P2Y 2 receptor signaling, reductions in endothelial NO, and increases in the levels of COX-derived vasoconstrictor prostanoids.

Background: Hypertension is a disease with significant clinical and socio-economic consequences. The reduction in cardiovascular mortality and morbidity in patients treated for hypertension is directly related to the magnitude of blood pressure reduction. Diuretics have proven useful for the prevention of cardiovascular complications in addition to a long history of safety and efficacy. The main aim for this meta-analysis is to compare the efficacy of the combination of angiotensin receptor blocker (ARB) and chlorthalidone (CTLD) to the combination of ARB and hydrochlorothiazide (HCTZ) in patients with hypertension., Methods: A comprehensive literature search was conducted through electronic databases PubMed, MEDLINE, Scopus, PsyInfo, Cochrane, eLIBRARY.ru, http://ClinicalTrials.gov and http://www.clinicaltrialsregister.eu in July 2020 to identify studies that investigate the effect of the combination of angiotensin receptor blocker with chlorthalidone or hydrochlorothiazide on the systolic and diastolic blood pressure in patients with hypertension. Changes in systolic and diastolic blood pressure (BP) expressed as a weighted mean difference (WMD) were our primary outcomes. The random-effects method was chosen as the primary analysis and results were presented with a 95% confidence interval (CI). Sensitivity analysis was performed and bias was assessed., Results: Our search returned 2745 titles. Of them, 51 full-text articles remained to be subjected to assessment. Comparisons of ARB/HCTZ versus ARB showed changes in BP of -6.89 (-8.09, -5.69) mmHg for systolic BP and - 3.67 (-4.15, -3.19) mmHg for diastolic BP. For the ARB/CTLD versus ARB/HCTZ comparison changes were - 6.30 (-7.30, -5.29) mmHg for systolic BP and - 3.57 (-4.17, 2.98) mmHg for diastolic BP., Conclusion: Our analysis suggests a small but significant favor for CTLD in blood pressure control when compared to HCTZ. We believe it should be considered as a valuable alternative for HCTZ and an option for fixed dose combinations with an ARB although further research is required.

Background: Real-world data on the effectiveness of antihypertensive drugs (AHDs) in India is limited. The present study aims to provide updated evidence regarding the effectiveness of olmesartan as monotherapy or in combination with other AHDs in Indian patients with essential hypertension., Methods: Electronic medical record data of adult patients who were diagnosed with essential hypertension (≥140/90 mmHg) and were prescribed olmesartan as mono- or add-on therapy were retrospectively analyzed. Patients were classified based on the number of AHD classes prescribed on initiation of olmesartan. Change in systolic and diastolic blood pressure (SBP and DBP) from baseline was the primary endpoint. Secondary endpoint was evaluation of proportion of patients who achieved treatment goals as per 2018 European Society of Cardiology/European Society of Hypertension guidelines. Readings were obtained before initiating olmesartan and after at least a month of therapy with olmesartan., Results: Among the 459 included patients, majority were on olmesartan monotherapy or olmesartan+1AHD (91.7%). Mean (95% confidence interval [CI]) change in olmesartan monotherapy group was: SBP (-13.4 [-15.7, -11.1] mmHg) and DBP (-8.3 [-9.5, -7.1] mmHg) and mean (95% CI) change in olmesartan+1AHD group was: SBP (-11.7 [-15.1, -8.3] mmHg) and DBP (-6.6 [-8.3, -4.9] mmHg) (P<0.001 for all). SBP and DBP goals were achieved by 40.4% and 50.3% of patients on olmesartan monotherapy and by 36.1% and 46.2% of patients on olmesartan+1AHD. Among patients with comorbid diabetes, mean (95% CI) change in olmesartan monotherapy group was: SBP (-15.5 [-18.6, -12.4] mmHg) and DBP (-8.7 [-10.2, -7.2] mmHg) and mean (95% CI) change in olmesartan+1AHD group was: SBP (-13.5 [-18.3, -8.7] mmHg) and DBP (-7.6 [-9.8, -5.4] mmHg) (P<0.001 for all). SBP and DBP goals were achieved by 38.5% and 49.4% of patients on olmesartan monotherapy and by 31.7% and 42.9% of patients on olmesartan+1AHD., Conclusion: Olmesartan prescribed as mono- or add-on therapy during routine clinical practice significantly reduced blood pressure in Indian patients with essential hypertension as well as in patients with comorbid diabetes., (© Journal of the Association of Physicians of India 2011.)

Objective: To compare the potential beneficial effects of the angiotensin converting enzyme inhibitor (ACEI) benazepril and the angiotensin II receptor 1 blocker (ARB) irbesartan on vaginal vascular remodeling and fibrosis in female spontaneously hypertensive rats (SHRs)., Methods: Twelve-week-old female SHRs were treated with irbesartan or benazepril for 12 weeks. Vaginal renin angiotensin system (RAS) components were detected by polymerase chain reaction and western blot and vaginal α-smooth muscle actin (α-SMA), endothelial nitric oxide synthase (eNOS), and collagen III (Col III) were analyzed by western blot. Vaginal tissue sections were examined by hematoxylin and eosin staining, Masson trichrome staining, and immunohistochemical analysis of α-SMA and Col III., Results: Irbesartan and benazepril had different impacts on vaginal RAS components. Both agents decreased vaginal α-SMA and Col III and increased eNOS expression in SHR. The wall/lumen thickness ratio of vaginal arterioles was similarly decreased following irbesartan and benazepril treatment. Both drugs also decreased collagen deposition in SHRs. There was no difference in vaginal vascular remodeling or fibrosis between the two groups., Conclusions: Irbesartan and benazepril have different effects on vaginal RAS expression but similar positive effects against vaginal vascular remodeling and fibrosis.

Objective: The current study was planned to formulate, characterize and evaluate the pharmacokinetics, and pharmacodynamics of a novel 'NanoFDC' comprising hydrochlorothiazide, candesartan (CNDT) and amlodipine., Methodology: The candidate drugs were loaded in poly(DL-lactide-co-glycolide) by emulsion-diffusion-evaporation method. The formulations were evaluated for their size, morphology, drug loading and in-vitro release individually. Repeat dose pharmacokinetic and pharmacodynamic study of the nano-fixed dose combination (FDC) was done in dexamethasone-induced animal model., Results: The entrapment efficiencies ranged from 44 ± 2.1, 32.2 ± 4 and 40.5 ± 2.6% for amlodipine, hydrochlorothiazide and CNDT, respectively. The nanoparticles ranged in size from 164 to 215 nm. In-vitro release profile of the nanoformulation showed unto 90% release by day 7 in simulated gastric fluid and simulated intestinal fluid, respectively. In pharmacokinetic analysis a sustained-release for 7 days was observed in nano-FDC group. Once weekly oral dosing of nano-FDC of amlodipine, CNDT and hydrochlorothiazide provided adequate antihypertensive effect which was not statistically different from daily dosing of free drugs in dexamethasone-induced animal model., Conclusion: Once weekly oral dosing of nano-FDC of amlodipine, CNDT and hydrochlorothiazide provided adequate antihypertensive effect and was not statistically different from daily dosing of free drugs in dexamethasone-induced animal model. This study provides proof of concept of feasibility of once weekly dosing of a nano-FDC comprising three antihypertensive drugs, which can lead to significant improvement in patient adherence to therapy.

Leptomeningeal anastomoses (LMAs) are pial collaterals that perfuse the penumbra and important for stroke outcome. We previously showed LMAs from SHRs (spontaneously hypertensive rats) were vasoconstricted compared with normotensive Wistar rats. Here, we investigated mechanisms by which hypertension causes LMA vasoconstriction. SHRs were treated with the ACE (angiotensin-converting enzyme) inhibitor captopril, an Ang II (angiotensin II)-independent antihypertensive agent hydralazine, or vehicle for 5 weeks in drinking water (n=8/group). A group of Wistar rats (n=8) had regular drinking water served as controls. Blood pressure was measured twice weekly by tail-cuff. LMAs were isolated and studied under pressurized conditions. Vasoreactivity of LMAs, including myogenic responses, reactivity to Rho-kinase inhibitor Y-27632, and nitric oxide were measured. Both captopril and hydralazine lowered blood pressure in SHRs similar to Wistar. However, only captopril normalized LMA increased tone compared with untreated SHRs (15±2% versus 50±3%; P <0.01) that was similar to Wistar (16±2%) but not hydralazine (38±6%; P >0.05). Vasodilatory response of LMAs to Y-27632 was impaired in SHRs compared with Wistar (28±3% versus 81±4%; P <0.01) that was restored by captopril (84±5%; P <0.01) and partially hydralazine (59±4%). LMAs from all groups constricted similarly to NOS (NO synthase) inhibition; however, the vasodilatory response of LMAs to the nitric oxide donor sodium nitroprusside was impaired in SHRs compared with Wistar rats (29±4% versus 80±2%; P <0.01) that was restored by captopril (84±4%; P <0.01), not hydralazine (38±8%; P >0.05). These results suggest that ACE inhibition during chronic hypertension reversed vascular dysfunction and hyperconstriction of LMAs that could improve stroke outcome by increasing collateral perfusion.

Introduction: Essential hypertension is a significant risk factor for cardiovascular disease, renal disease, and mortality with increasing prevalence. Despite the availability of various antihypertensive agents, hypertension is still poorly controlled. Therefore, new chemical compounds with antihypertensive efficacy need to be developed. The dual angiotensin II receptor-neprilysin inhibitor LCZ696 is a single molecule synthesized by co-crystallization of valsartan and the neprilysin inhibitor prodrug sacubitril (1:1 molar ratio)., Areas Covered: This review includes an overview of hypertension and the current pharmacotherapy. The authors summarize the LCZ696 drug chemistry, pharmacodynamics, pharmacokinetics, metabolism, randomized control trials (RCTs), and safety concerns. Databases searched included PubMed, Google Scholar, Embase, and ClinicalTrials.gov., Expert Opinion: LCZ696 is effective in hypertension treatment. Short-term RCTs have shown that the highest doses of LCZ696 (200 and 400 mg [q.d.]) were more effective at lowering office and ambulatory blood pressure than angiotensin II receptor blockers (ARB) alone while having a similar tolerability profile. The effects of LCZ696 on hypertensive organ damage are only sparsely investigated and so far no studies have established the impact of LCZ696 on cardiovascular event rates. Future studies should focus on the comparison of LCZ696 and combination therapies already in use such as ARB and calcium channel blockers.

Background: It is unclear whether generics are as safe as brand-name drugs in cardiology. For public health surveillance purposes, we evaluated if switching from the brand-name losartan, valsartan, or candesartan impacted the occurrence of the following outcomes: emergency room (ER) consultations, hospitalizations, or death., Study Design: This was a retrospective cohort study., Methods: This study was conducted in the Quebec Integrated Chronic Disease Surveillance System, including healthcare administrative data of the population of Quebec, Canada. We included brand-name users of losartan, valsartan, or candesartan aged ≥ 66 years who had undergone ≥ 30 days of stable treatment on the brand-name drug prior to cohort entry (substitution time-distribution matching was used to prevent immortal time bias). Outcomes up to 1 year were compared between groups using multivariable Cox proportional hazards regression models (validity assumptions were verified)., Results: In our cohorts (losartan, n =15,783; valsartan, n =16,907; candesartan, n =26,178), mean age was 76-78 years, 59-66% were female, 90-92% had hypertension, and 13-15% had heart failure. Validity assumptions were violated for losartan only. For patients switched to generic valsartan, the hazard ratio (95% confidence interval) was 1.07 (0.99-1.14) for ER consultation, 1.26 (1.14-1.39) for hospitalization, and 1.01 (0.61-1.67) for death. The corresponding rates for candesartan were 1.00 (0.95-1.05), 0.96 (0.89-1.03), and 0.57 (0.37-0.88), respectively., Conclusions: We observed an increased risk of hospitalizations for patients switched to generic valsartan, and a decreased risk of death for patients switched to generic candesartan, compared with those who continued taking the brand-name drug. The differences between generic and brand-name drugs may lead to some differences in public health outcomes, but this safety signal must be further studied using other cohorts and settings.

Objectives: Combined angiotensin receptor--neprilysin inhibition (ARNI) reduces glomerulosclerosis better than single angiotensin receptor blockade (ARB) in diabetic, hypertensive rats. The renoprotective mechanism remains unknown, but may depend on superior blood pressure control, improved renal hemodynamics, suppressed renal inflammation or prevention of podocyte loss., Methods: To address this, TGR(mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic for 12 weeks and treated with vehicle (n = 10), valsartan (ARB; n = 7) or sacubitril/valsartan (ARNI; n = 8) for the final 3 weeks. Arterial pressure was measured via radiotelemetry., Results: Sacubitril/valsartan lowered mean arterial pressure by -50 ± 4 mmHg and valsartan by -43 ± 4 mmHg (P = 0.3). Both treatments lowered albuminuria, but only sacubitril/valsartan maintained high urinary atrial natriuretic peptide, improved glycemic control and protected podocyte integrity, reflected by increased nephrin expression and suppression of transient receptor potential canonical 6 and regulator of calcineurin 1. This resulted in markedly reduced glomerulosclerosis (P < 0.05 vs. control and valsartan). Despite higher effective renal plasma flow and glomerular filtration rates, sacubitril/valsartan did neither improve filtration fraction nor renal immune cell infiltration., Conclusion: Sacubitril/valsartan offers drug-class-specific renoprotection in a preclinical model of diabetes and hypertension. Renoprotection is unrelated to antihypertensive efficacy, renal hemodynamics or inflammation, but may be related to protective effects of natriuretic peptides on podocyte integrity.

The home blood pressure (BP) control by a single-pill combination of cilnidipine (an L-/N-type calcium channel blocker; CCB) and valsartan (HOPE-Combi) survey is a multicenter, post-marketing, prospective observational study of a single-pill combination of cilnidipine 10 mg and valsartan 80 mg (SPC of Cil/Val) in patients with uncontrolled hypertension. We examined the effects of the SPC of Cil/Val on morning home systolic BP (MHSBP) and morning home pulse pressure (MHPP) of 1036 patients with hypertension over 12 months. MHSBP decreased by 14.0 mm Hg (P < .01), and MHPP decreased by 6.6 mm Hg (P < .01). Moreover, morning home pulse rate (MHPR) decreased by 2.1 bpm (P < .01). A more progressive and greater decrease in MHSBP (-17.2 vs -10.3 mm Hg, P < .01) and MHPP (-7.6 vs -4.9 mm Hg, P < .01) was observed in patients with higher MHPR (≥70 bpm) than in those with lower MHPR (<70 bpm) over the treatment period. In particular, in patients with a wide MHPP (≥70 mm Hg), the difference in the MHPP reduction was greater in patients with higher MHPR than in those with lower MHPR (-17.9 vs -13.6 mm Hg, P < .01). These results suggested that the SPC of Cil/Val, which possesses the unique sympatholytic characteristics of an L-/N-type CCB, was particularly effective in patients with uncontrolled hypertension and sympathetic hyperactivity., (© 2019 Wiley Periodicals, Inc.)

Background: Hypertension is a major cause of death and morbidity worldwide and is increasing in prevalence. The Renin-angiotensin system (RAS) is the most common mechanism involved in the pathophysiology of hypertension. Understanding the mechanism of the pathophysiologic processes will help direct potential therapeutic strategies to treat hypertension and improve cardiac function. Recently, a novel drug LCZ696 containing both an angiotensin receptor blocker valsartan and a neprilysin inhibitor (AHU377) has shown a promising effect on the treatment of hypertension. However, the effects of LCZ696 on the expression of main components of RAS, namely, angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), angiotensin II type 1 receptor (AT1 R), angiotensin II type 2 receptor (AT2 R), and angiotensin (1-7) receptor/Mas receptor (MasR) remain unclear. The aim of the present study was to evaluate the effects of LCZ696 on the protective arms of RAS in the cardiac tissue when compared with valsartan under the equal inhibition of AT1 R. We hypothesized that the superior effects of LCZ696 may contribute to its greater effect on the RAS than valsartan., Materials and Methods: Sixteen-week-old female spontaneously hypertensive rats (SHRs) were used in this study. Wistar-Kyoto (WKY) rats were used as controls. All rats were randomly divided into LCZ696 (n = 10), valsartan (n = 10), SHR (n = 10), and WKY (n = 10) groups under a 12-hour dark and 12-hour light cycle and provided with regular chow diet and water. The tail-cuff method was performed to measure blood pressure. Cardiac function was assessed by echocardiography., Results: The blood pressure value was lower in LCZ696 than valsartan in SHR after 12 weeks of treatment. Further, LCZ696 inhibits the ACE and AT1 R protein expression in the cardiac of SHR and significantly upregulate the protective axis of RAS components, including ACE2, MasR, and AT2 R. Left ventricular AT2 R messenger RNA (mRNA) expression was higher in the LCZ696+SHR group compared with valsartan. In addition, real-time polymerase chain reaction analysis revealed that LCZ696 enhanced the mRNA expression of antihypertensive components AT2 R, ACE2, and MasR and decreased the expression of AT1 R. However, only AT2 R and ACE2 mRNA expressions have a statistical difference between the LCZ696 and valsartan groups. No difference was observed in the mRNA expression of ACE and MasR. The stronger positive signal of transforming growth factor β in the left ventricle was inhibited in each administrated group compared with SHR groups., Conclusions: LCZ696 ameliorates the vasoconstrictor axis of the RAS AT1 R and stimulate the protective arm effectors, ACE2 and AT2 R, as well as reverses the compensatory upregulation of neuronal nitric oxide synthase and endothelial nitric oxide synthase in SHR. These findings suggest the mechanistic insight of the cardiac-protective and greater hypotensive effects of LCZ696.

Intestinal pathophysiological alterations have recently been revealed to be implicated in the pathogenesis of hypertension, necessitating further investigations to better understand the intestinal effects of anti-hypertensive drugs. The current study thus investigated the pharmacological implications of a commonly used first-line angiotensin II type 1 receptor blocker, candesartan cilexetil, on the intestinal barrier impairment and gut dysbiosis in spontaneously hypertensive rats (SHRs). The results revealed that candesartan treatment protected against ileal and colonic pathologies and increased the intestinal expression of genes encoding tight junction proteins such as cingulin, occludin and tight junction protein 1 in SHRs. Serum level of lipopolysaccharides-binding protein was increased in candesartan-treated SHRs, supporting the notion that candesartan treatment provided protection against hypertension-associated impairment of intestinal barrier. Candesartan treatment also increased the amount of fecal short-chain fatty acids (SCFAs) including acetic acid, propionic acid, and butyric acid in SHRs. Fecal 16S rDNA sequencing further revealed that candesartan treatment normalized hypertension-altered ratio of Firmicutes to Bacteroidetes in SHRs. Most notably, candesartan treatment counteracted hypertension-associated diminishment of lactic acid-producing genus Lactobacillus. Taken together, the current study demonstrates for the first time that candesartan treatment alleviates hypertension-associated pathophysiological alterations in the gut, increases microbial production of SCFAs and preserves gut Lactobacillus under hypertensive conditions, which sheds novel light on the pharmacological implications of candesartan in the treatment of hypertension., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: We hypothesized that renin-angiotensin system and neprilysin (NEP) inhibition can modulate the nociceptive parameters on hypertensive rats. The aim of this study is to assess the preventive and therapeutic effects of ramipril and sacubitril on the pain hypersensitivities, and their interaction mechanisms with high blood pressure., Methods: Antinociceptive effects of ramipril and sacubitril were compared with those of diclofenac. Threshold of pain assesments were recorded before drugs administration. After a 18 days treatment, normotensive and dexamethasone-induced hypertensive rats were evaluated on thermal hyperalgesia and mechanical allodynia tests. Blood pressure of rats were verified by mean arterial pressure measurement., Results: Hypertensive rats showed significantly high pain threshold on thermal plantar test compared to that of normotensives. Among hypertensive rats, pain hypersensitivity was lowest in diclofenac group, followed by sacubitril group, while ramipril caused increased thermal and mechanical hypersensitivities., Conclusion: We found that NEP inhibition may play a role in nociception in hypertensive rats. NEP inhibitors may be suitable choice for the management of hypertension and pain because of their therapeutic and preventive effects on nociception and arterial blood pressure., (Copyright © 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Hypertensive transgenic (mRen2)27 rats exhibit impaired baroreflex sensitivity (BRS) for control of heart rate (HR). Intracerebroventricular infusion of Ang-(1-7) improves indices of vagal BRS independent of lowering mean arterial pressure (MAP), whereas AT1 receptor blockade normalizes MAP and indices of sympathetic tone without correcting the vagal BRS. Scavenging cellular reactive oxygen species (ROS) with tempol in brain fails to correct either hypertension or sympathovagal balance in these animals, despite reports that mitochondrial ROS contributes to Ang II-infusion hypertension. To examine effects of a putative preferential mitochondrial ROS scavenger in the brain of (mRen2)27 rats, ICV infusions of Mito-TEMPO (3.2 μg/2.5 μL/h) were compared with artificial cerebrospinal fluid (aCSF; 2.5 μL/h) and combination AT1 receptor antagonist candesartan (CAN: 4 μg/2.5 μL/h) plus Ang-(1-7) (0.1 μg/2.5 μL/h) treatment. MAP was lower after CAN + Ang-(1-7) treatment, and both vagal and sympathetic components of BRS and sympathovagal balance were improved. By contrast, Mito-TEMPO improved sympathetic components of BRS and tended to improve overall sympathovagal balance but failed to alter MAP in this model of hypertension. Although further studies are required to determine whether Mito-TEMPO or CAN + Ang-(1-7) treatment at the doses used altered mitochondrial ROS, optimal therapeutic benefits are achieved by shifting the balance from Ang II toward Ang-(1-7) in this model of chronic RAS-dependent hypertension.

Background: Augmented sympathetic nerve activity (SNA) and renin-angiotensin-aldosterone system (RAAS) activity are involved in the pathogenesis of hypertension (HT) accompanied by chronic kidney disease (CKD). Oxidative stress in the hypothalamus increases SNA in HT. Administration of an angiotensin ΙΙ receptor blocker (olmesartan; OLM) or renal denervation (RDN) exerts an antihypertensive effect in HT with CKD; however, the precise mechanisms of the combination therapy are not fully elucidated. In the present study, we examined whether combination therapy with OLM and RDN reduces both SNA by decreasing oxidative stress in the hypothalamus and RAAS activity in hypertensive mice with CKD., Methods and Results: In 5/6-nephrectomized ICR-mice (Nx-mice) at 4-weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased, accompanied by increased SNA and albuminuria compared with control-mice. Nx-mice were orally administered OLM, vehicle, or underwent RDN during OLM administration, and divided into Nx-OLM, Nx-VEH, and Nx-OLM/RDN groups, respectively. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH at 8-weeks after treatment, SBP was significantly decreased and both SNA and oxidative stress levels in the hypothalamus were significantly suppressed, without worsened creatinine clearance. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH, albuminuria was also suppressed, and the heart per body weight was decreased. In Nx-OLM/RDN, but not in Nx-OLM, the plasma aldosterone concentration was significantly decreased compared with Nx-VEH., Conclusion: These findings suggest that combination therapy with OLM/RDN has antihypertensive effects in association with suppressing SNA by reducing oxidative stress in the hypothalamus and the plasma aldosterone concentration in hypertensive mice with CKD.

BACKGROUND : We hypothesized that the 5-oxo-1,2,4-oxadiazole moiety of azilsartan (AZL), which represents a small difference in the molecular structures of AZL and candesartan (CAN) [angiotensin II type 1 receptor (AT 1 R) blockers], may be responsible for the molecular effects of AZL. METHODS : We examined the binding affinities of AZL and CAN to AT 1 R, along with their ability to block receptor activity. A competition binding study, inositol phosphate (IP) production assay and extracellular signal-regulated kinase (ERK) assay were performed using wild-type (WT) and mutants AT 1 R-transfected cells. RESULTS : The binding affinities of CAN and AZL were reduced by > 5-fold for Y35F, W84F, R167K, K199Q and I288A compared with WT. In addition, AZL showed a > 5-fold reduction in its binding affinity to V108A. CAN and AZL exhibited > 20-fold and > 100-fold reductions in binding affinity to R167K, respectively. The loss of binding affinity of AZL to R167K was greater than that of CAN. CAN-7H exhibited a > 10-fold reduction in binding affinity to R167K compared with CAN. On the other hand, the binding affinity of AZL-7H to R167K was comparable to that of AZL. While 10 -6 M CAN and CAN-7H partly blocked Ang II-induced IP production in R167K, 10 -6 M AZL and AZL-7H did not. In addition, 10 -6 M CAN, but not 10 -6 M AZL, partly blocked Ang II-induced ERK activation in R167K. CONCLUSIONS : The interaction between 5-oxo-1,2,4-oxadiazole in AZL and Arg 167 in the AT1R appears to be more important than the interaction between the tetrazole ring in CAN and Arg 167 .

Introduction: Obesity is becoming one of the leading risk factors of coronary heart disease, hypertension, cerebrovascular disease. Despite the presence of a large number of antihypertensive agents and scientific substantiation of antihypertensive treatment principles it would be wrong to assume that the problem is completely solved. Development of endothelial dysfunction is one of the key pathogenic mechanisms in hypertension. This process is proven to have contributed by immune inflammation activation which is mediated by pro-inflammatory cytokines and oxidative stress., Aims: To investigate the additional benefits of the combined antihypertensive therapy with lacidipine and candesartan on the basis of studying their antioxidant properties, impact on endothelial function and pro-inflammatory cytokines activity in hypertensive patients with overweight and obesity., Methods: A combination of a calcium channel blocker and angiotensin receptor blocker (lacidipine 2 mg, 4 mg, and candesartan 4mg, 8mg, 16mg) was prescribed to 30 patients with essential hypertension of grades 1-3, 30 to 65 years old (mean age - 54.7 ± 5.8 years), who previously have not been receiving regular antihypertensive therapy., Results: During the course of combined antihypertensive therapy with lacidipine and candesartan, a significant reduction in i-NOS activity, TNF-α to its type I soluble receptor ratio (TNF- α/sTNF-αRI), and oxidative stress marker - 8-iso-PgF2α has been observed. Activity of e-NOS, levels of SOD and catalase, in contrast, have increased by the end of observation period., Conclusion: The improvement of endothelial function due to lower level of oxidative stress and a significant decrease of immune activation has been observed in hypertensive patients with overweight and obesity under the influence of combined antihypertensive therapy with lacidipine and candesartan.

Growing evidence suggests that renin angiotensin system (RAS) modulators support cognitive function in various animal models. However, little is known about their long-term effects on the brain structure in aged hypertensive animals with chronic cerebral hypoperfusion as well as which specific domains of cognition are most affected. Therefore, in the current study we examined the effects of Candesartan and Compound 21 (C21) (RAS modulators) on aspects of cognition known to diminish with advanced age and accelerate with hypertension and vascular disease. Outcome measures for sensorimotor and cognitive function were performed using a sequence of tests, all blindly conducted and assessed at baseline and after 4 and 8 weeks of chronic hypoxic hypoperfusion and treatment. Magnetic resonance imaging (MRI) was performed at the end of the 8 week study period followed by animal sacrifice and tissue collection. Both Candesartan and C21 effectively preserved cognitive function and prevented progression of vascular cognitive impairment (VCI) but only candesartan prevented loss of brain volume in aged hypertensive animals. Collectively, our findings demonstrate that delayed administration of RAS modulators effectively preserve cognitive function and prevent the development / progression of VCI in aged hypertensive animals with chronic cerebral hypoperfusion., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Hypertension is one of the major risk factors for central nervous system (CNS) disorders like stroke and Alzheimer's disease (AD). On the other hand, CNS diseases like AD have been associated with gliosis and impaired neurogenesis. Further, renin angiotensin system (RAS) is intricately associated with hypertension; however, the accumulating evidences suggest that over-activity of RAS may perpetuate the brain inflammation related with AD. Therefore, in the present study, we examined the effect of hypertension and RAS on glial (astrocytes and microglia) activation and hippocampal neurogenesis in a rat model of chronic hypertension. We used Candesartan [angiotensin type 1 receptor (AT1R) blocker (ARB)] both at a low dose (0.1 mg/kg) and anti-hypertensive dose (2 mg/kg) to explore whether their effect on astrocyte and microglial activation, neuroinflammation, and neurogenesis is blood pressure (BP) dependent or independent. Our data revealed that hypertension induces robust microglial and astrocyte activation, neuroinflammation, and cripples hippocampal neurogenesis. Importantly, AT1R blockade by Candesartan, even at low dose (0.1 mg/kg), prevented astrocyte and microglial activation and neuroinflammation in the brain of hypertensive rats. Mechanistically, AT1R blockade prevented the activation of NADPH oxidase, reactive oxygen species (ROS) generation, suppression of MAP kinase and NFкB signaling. Importantly, we, for the first time to our knowledge, provided the evidence that AT1R blockade by activating Wnt/β-catenin signaling, promotes neurogenesis during hypertensive state. We conclude that AT1R blockade prevents astrocyte and microglial activation and improves hippocampal neurogenesis in hypertensive state, independent of BP lowering action.

Introduction: Fimasartan is the ninth and latest Angiotensin Receptor Blockers for the treatment of hypertension. Fimasartan is a derivative of losartan in which the imidazole ring has been replaced. It provides a selective type 1 angiotensin II receptor antagonist effect with noncompetitive, in surmountable binding. Fimasartan is rapidly absorbed following oral administration with an oral bioavailability of 18.6 ± 7.2%. Fimasartan is relatively stable in terms of metabolism and more than 90% of circulating fimasartan moieties in the plasma are in the parent form; fecal elimination and biliary excretion are the predominant elimination pathways of fimasartan. Areas covered: We reviewed data from clinical trials that investigated safety and efficacy of fimasartan in hypertension. Expert opinion: Fimasartan proved good efficacy in blood pressure reduction. In large clinical studies,fimasartan showed an excellent safety profile and when combined with hydrochlorothiazide oram lodipine, it showed a better effect on controlling blood pressure than monotherapy. Fimasartan 60-120 mg once daily has also shown an antihypertensive effect over 24-h. Moreover, preclinical studies demonstrated organ-protecting effects of fimasartan. These results make fimasartan an attractive candidate for the treatment of hypertension. However, it remains to test the benefit of using fimasartan on clinical outcomes.

Increased activation of the renin-angiotensin system is involved in the onset and progression of cardiometabolic diseases, while natriuretic peptides (NP) may exert protective effects. We have recently demonstrated that sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, which blocks the angiotensin II type-1 receptor and augments natriuretic peptide levels, improved peripheral insulin sensitivity in obese hypertensive patients. Here, we investigated the effects of sacubitril/valsartan (400 mg QD) treatment for 8 weeks on the abdominal subcutaneous adipose tissue (AT) phenotype compared to the metabolically neutral comparator amlodipine (10 mg QD) in 70 obese hypertensive patients. Abdominal subcutaneous AT biopsies were collected before and after intervention to determine the AT transcriptome and expression of proteins involved in lipolysis, NP signaling and mitochondrial oxidative metabolism. Both sacubitril/valsartan and amlodipine treatment did not significantly induce AT transcriptional changes in pathways related to lipolysis, NP signaling and oxidative metabolism. Furthermore, protein expression of adipose triglyceride lipase (ATGL) (P time*group  = 0.195), hormone-sensitive lipase (HSL) (P time*group  = 0.458), HSL-ser660 phosphorylation (P time*group  = 0.340), NP receptor-A (NPRA) (P time*group  = 0.829) and OXPHOS complexes (P time*group  = 0.964) remained unchanged. In conclusion, sacubitril/valsartan treatment for 8 weeks did not alter the abdominal subcutaneous AT transcriptome and expression of proteins involved in lipolysis, NP signaling and oxidative metabolism in obese hypertensive patients.

Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open-label, three-period, single sequence study, patients with mild-to-moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and C max of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (-5/-4/-4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470., (© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure (HF). Inhibition of extracellular signal-regulated kinases (ERK) efficaciously suppressed angiotensin II (ANG II)-induced cardiomyocyte hypertrophy and apoptosis by blocking insulin-like growth factor II receptor (IGF-IIR) signaling. However, the detailed mechanism by which ANG II induces ERK-mediated IGF-IIR signaling remains elusive. Here, we found that ANG II activated ERK to upregulate IGF-IIR expression via the angiotensin II type I receptor (AT 1 R). ERK activation subsequently phosphorylates HSF1 at serine 307, leading to a secondary phosphorylation by glycogen synthase kinase III (GSK3) at serine 303. Moreover, we found that ANG II mediated ERK/GSK3-induced IGF-IIR protein stability by downregulating the E3 ubiquitin ligase of IGF-IIR RING finger protein CXXVI (RNF126). The expression of RNF126 decreased following ANG II-induced HSF1 S303 phosphorylation, resulting in IGF-IIR protein stability and increased cardiomyocyte injury. Inhibition of GSK3 significantly alleviated ANG II-induced cardiac hypertrophy in vivo and in vitro. Taken together, these results suggest that HSF1 phosphorylation stabilizes IGF-IIR protein stability by downregulating RNF126 during cardiac hypertrophy. ANG II activates ERK/GSK3 to phosphorylate HSF1, resulting in RNF126 degradation, which stabilizes IGF-IIR protein expression and eventually results in cardiac hypertrophy. HSF1 could be a valuable therapeutic target for cardiac diseases among hypertensive patients., (© 2017 Wiley Periodicals, Inc.)