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This article discusses the case of a 74-year-old female with a history of hypertension who presented to the emergency department with severe abdominal pain. The patient was found to have an acute intramural hematoma of the descending thoracic aorta and bilateral renal artery stenosis. The patient underwent percutaneous renal artery revascularization, which resulted in improved blood pressure control and renal function. The article highlights the importance of recognizing and treating renal artery stenosis in patients with hypertension to prevent complications and preserve renal function. [Extracted from the article]

The article discusses the importance of accurate identification of primary aldosteronism (PA) and the use of adrenal vein sampling (AVS) as the test of choice for identifying surgical candidates. AVS is a technically challenging procedure that relies on experienced interventional radiologists. The article proposes the use of the relative aldosterone secretion index (RASI) as a ratio of aldosterone/cortisol to salvage partially successful AVS studies. However, the study acknowledges potential bias sources and suggests using more stringent RASI criteria and considering other predictors of lateralized PA before pursuing surgery. [Extracted from the article]

Renovascular disease is a major causal factor for secondary hypertension and renal ischemic disease. However, several prospective, randomized trials for atherosclerotic disease failed to demonstrate that renal revascularization is more effective than medical therapy for most patients. These results have greatly reduced the generalized diagnostic workup and use of renal revascularization. Most guidelines and review articles emphasize the limited average improvement and fail to identify those clinical populations that do benefit from revascularization. On the basis of the clinical experience of hypertension centers, specialists have continued selective revascularization, albeit without a summary statement by a major, multidisciplinary, national organization that identifies specific populations that may benefit. In this scientific statement for health care professionals and the public-at-large, we review the strengths and weaknesses of randomized trials in revascularization and highlight (1) when referral for consideration of diagnostic workup and therapy may be warranted, (2) the evidence/rationale for these selective scenarios, (3) interventional and surgical techniques for effective revascularization, and (4) areas of research with unmet need. [ABSTRACT FROM AUTHOR]

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Primary aldosteronism is a frequent cause of resistant hypertension and is associated with an increased risk of developing diabetes mellitus. Aldosterone impairs insulin secretion in isolated islets, and insulin secretion is increased in aldosterone synthase-deficient mice. We hypothesized that treatment for primary aldosteronism increases insulin secretion and insulin sensitivity in humans. We conducted a prospective cohort study in patients with primary aldosteronism, with assessment of glucose metabolism before and 3 to 12 months after treatment. Participants underwent treatment for primary aldosteronism with adrenalectomy or a mineralocorticoid receptor antagonist at the discretion of their treating physician. We assessed insulin secretion and insulin sensitivity by hyperglycemic and hyperinsulinemic-euglycemic clamps, respectively, on 2 study days after a 5-day standardized diet. After treatment, the C-peptide and insulin response during the hyperglycemic clamp increased compared with pretreatment (ΔC-peptide at 90-120 minutes +530.5±384.1 pmol/L, P=0.004; Δinsulin 90-120 minutes +183.0±122.6, P=0.004). During hyperinsulinemic-euglycemic clamps, insulin sensitivity decreased after treatment (insulin sensitivity index 30.7±6.2 versus 18.5±4.7 nmol·kg-1·min-1·pmol-1·L; P=0.02). Insulin clearance decreased after treatment (872.8±207.6 versus 632.3±178.6 mL/min; P=0.03), and disposition index was unchanged. We conclude that the insulin response to glucose increases and insulin clearance decreases after treatment for primary aldosteronism, and these effects were not due to alterations in creatinine clearance or plasma cortisol. These studies may provide further insight into the mechanism of increased diabetes mellitus risk in primary aldosteronism. [ABSTRACT FROM AUTHOR]

A 62-year-old woman with a history of well-controlled hypertension was urgently referred to the Vanderbilt Hypertension Clinic for evaluation of worsening hypertension with increasing blood pressure lability. We considered that tizanidine rebound hypertension could be a cause of rebound hypertension in this patient, similar to clonidine withdrawal hypertension. Fluvoxamine potently inhibits CYP1A2 and has been shown to increase tizanidine drug exposure by 33-fold (determined by drug concentration area under-the-curve), one of the largest drug interactions ever described.[11], [12] Ciprofloxacin increases tizanidine drug exposure by 10-fold. Whereas in the guideline, we were very careful to point out the problem with clonidine withdrawal and not to use clonidine before surgery because you might precipitate a hypertensive crisis during the surgery, we did not highlight the blood pressure side effects of muscle relaxant drugs. [Extracted from the article]

Somatic mutations have been identified in aldosterone-producing adenomas (APAs) in genes that include KCNJ5, ATP1A1, ATP2B3, and CACNA1D. Based on independent studies, there appears to be racial differences in the prevalence of somatic KCNJ5 mutations, particularly between East Asians and Europeans. Despite the high cardiovascular disease mortality of blacks, there have been no studies focusing on somatic mutations in APAs in this population. In the present study, we investigated genetic characteristics of APAs in blacks using a CYP11B2 (aldosterone synthase) immunohistochemistry-guided next-generation sequencing approach. The adrenal glands with adrenocortical adenomas from 79 black patients with primary aldosteronism were studied. Seventy-three tumors from 69 adrenal glands were confirmed to be APAs by CYP11B2 immunohistochemistry. Sixty-five of 73 APAs (89%) had somatic mutations in aldosterone-driver genes. Somatic CACNA1D mutations were the most prevalent genetic alteration (42%), followed by KCNJ5 (34%), ATP1A1 (8%), and ATP2B3 mutations (4%). CACNA1D mutations were more often observed in APAs from males than those from females (55% versus 29%, P=0.033), whereas KCNJ5 mutations were more prevalent in APAs from females compared with those from males (57% versus 13%, P<0.001). No somatic mutations in aldosterone-driver genes were identified in tumors without CYP11B2 expression. In conclusion, 89% of APAs in blacks harbor aldosterone-driving mutations, and unlike Europeans and East Asians, the most frequently mutated aldosterone-driver gene was CACNA1D. Determination of racial differences in the prevalence of aldosterone-driver gene mutations may facilitate the development of personalized medicines for patients with primary aldosteronism. [ABSTRACT FROM AUTHOR]

Observational studies in primary hyperaldosteronism suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiological relationship between the renin--angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without primary hyperaldosteronism. PTH was measured before and after study (1) low-dose angiotensin II (Ang II) infusion (1 ng/kg per minute) and captopril administration (25 mgx1); study (2) high-dose Ang II infusion (3 ng/kg per minute); study (3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg per hour) and vehicle; and study (4) blinded randomization to spironolactone (50 mg/daily) or placebo for 6 weeks. Infusion of Ang II at 1 ng/kg per minute acutely increased aldosterone (+148%) and PTH (+10.3%), whereas Ang II at 3 ng/kg per minute induced larger incremental changes in aldosterone (+241%) and PTH (+36%; P<0.01). Captopril acutely decreased aldosterone (-12%) and PTH (-9.7%; P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy during 6 weeks modestly lowered PTH when compared with placebo (P<0.05). In vitro studies revealed the presence of Ang II type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism: the acute modulation of PTH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme inhibition potentiates basal and bradykinin-stimulated tissue-type plasminogen activator (t-PA) release to a greater extent in women than in men. This study tested the hypothesis that 17beta-estradiol enhances the effect of angiotensin-converting enzyme inhibition on t-PA release in young postmenopausal women. We conducted a double-blind, prospective, crossover study in 14 young postmenopausal women (mean age 48.2+/-2.3 years) who were randomized to receive 17beta-estradiol (1 mg/d) or matching placebo for 4 weeks. At the end of each treatment period, we measured the effect of intraarterial infusion of bradykinin, methacholine, and nitroprusside on forearm blood flow and net t-PA release, before and during intraarterial enalaprilat (0.33 microg/min/100 mL forearm volume). 17Beta-estradiol significantly reduced baseline venous plasminogen activator inhibitor-1 antigen (4.4+/-1.4 versus 10.4+/-2.5 ng/mL, P=0.001) and t-PA antigen (5.5+/-0.6 versus 7.5+/-1.3 ng/mL, P=0.022) compared with placebo. 17Beta-estradiol increased basal forearm vascular release of active t-PA compared with placebo (1.2+/-0.3 IU/mL/min versus 0.4+/-0.1 IU/mL/min respectively, P=0.032), without increasing t-PA antigen release (P=0.761). Enalaprilat significantly increased basal net t-PA antigen release (from -0.8+/-1.0 to 3.2+/-1.2 ng/min/100 mL, P=0.012), but not the release of active t-PA, during either placebo or 17beta-estradiol. Enalaprilat potentiated bradykinin-stimulated vasodilation and t-PA antigen and activity release similarly during placebo and 17beta-estradiol treatment. 17Beta-estradiol treatment does not alter the effect of angiotensin-converting enzyme inhibition on basal t-PA antigen or on bradykinin-stimulated t-PA antigen or activity release. 17Beta-estradiol increases basal release of active t-PA in young postmenopausal women, consistent with enhanced vascular fibrinolytic function. [ABSTRACT FROM AUTHOR]

The article discusses a study which tested the hypothesis that the bradykinin receptor 2 polymorphism affects vascular responses to the peptide bradykinin. There are two bradykinin receptors, bradykinin 1 and bradykinin 2. Genotyping and statistical analysis were the methods of research to test this hypothesis. The bradykinin receptor 2 polymorphism influences bradykinin type 2 receptor-mediated blood vessel dilation during angiotensin-converting enzyme inhibition.

Sodium reabsorption in the distal nephron is tightly regulated in part by epithelial sodium channel (ENaC) and sodium chloride cotransporter (NCC), although non-invasive measure of these proteins in humans has not previously been feasible. We recently analyzed the urinary exosomal proteome and identified candidate targets for quantification of ENaC and NCC using targeted mass spectrometry.To test the hypothesis that urinary exosomal ENaC and NCC are altered during renin-angiotensin-aldosterone system activation, we activated the endogenous RAAS using a low sodium diet (LS) in two separate studies. We provided 8 subjects LS diet (10mmol/day for 7days) to assess urinary protein excretion at 7 days (study 1) and longitudinally over the course of 1 week (study 2). Daily 24-hour urine was collected to monitor sodium balance, and spot urine samples were obtained each morning on days 0, 2, 4, and 6 of LS diet. Urinary exosomal ENaC-α, ENaC-γ, and NCC peptides were analyzed using targeted multiple-reaction-monitoring analysis quantified with stable-isotope peptide standards, and results were normalized to urine creatinine concentration.In study 1, urinary ENaCγ increased after 8 days of LS diet (Figure A). In study 2, urinary exosomal ENaCγ (Figure B) and NCC peptides (Figure C) increased in a time-dependent manner during LS diet. These measures of urinary sodium channel expression may provide further insight into distal sodium reabsorption in human hypertension. [ABSTRACT FROM AUTHOR]

Chronic administration of the PDE5 inhibitor sildenafil citrate improves insulin sensitivity in high fat-fed mice. A small study in patients with metabolic syndrome found that one-month treatment with tadalafil with or without ACE inhibition improves disposition index (DI) and β-cell function, as measured by IVGTT. We report the results of a randomized, double-blind, placebo-controlled study of the effect of 3-month treatment with sildenafil (25mg t.i.d.) on insulin sensitivity and secretion assessed using hyperglycemic clamps in individuals with impaired fasting glucose and/or impaired glucose tolerance. Among 51 subjects randomized, 21 subjects completed sildenafil treatment [8 men, 2 black Americans, body mass index (BMI) 35.7±6.8 Kg/m2], and 21 completed placebo treatment (8 men, 6 black Americans, BMI 36.4±6.6 Kg/m2). There was no significant difference in acute- or late-phase glucose-stimulated insulin secretion (GSIS) between groups. In contrast, insulin sensitivity index (ISI) and DI were significantly higher in the sildenafil group (Figure, adjusted means and 95% CI after controlling for baseline measurements and BMI, ∗P<0.05). Sildenafil did not significantly affect blood pressure or heart rate compared to placebo. These data suggest that pharmacological strategies to increase cGMP enhance insulin sensitivity. Additional studies are needed to determine whether PDE5 inhibition prevents incident diabetes in high risk populations. [ABSTRACT FROM AUTHOR]

Renin-angiotensin-aldosterone system blockade reduces the incidence of type 2 diabetes in clinical trials. We previously demonstrated that aldosterone impairs insulin secretion via a direct beta-cell effect in mice. To test the hypothesis that aldosterone and the mineralocorticoid receptor contribute to impaired insulin secretion in humans, we enrolled subjects with metabolic syndrome treated with hydrochlorothiazide (HCTZ) 12.5 mg daily for 4 weeks (baseline) followed by either Spironolactone 25 mg daily (SPL, n=16) versus Aliskiren 150 mg daily (ALI, n=19) for 4 weeks. We assessed insulin secretion and sensitivity using hyperglycemic clamps during sodium controlled diet (160 mmol Na).During HCTZ alone, plasma aldosterone correlated inversely with the initial insulin response and disposition index (Figure A), but not with insulin sensitivity index. Plasma aldosterone decreased during aliskiren (-1.5±0.78 ng/dL) and increased during spironolactone treatment (+4.0±0.8 ng/dL; p<0.001 between treatment). Blood pressure, serum potassium, and insulin sensitivity index were unchanged. The acute insulin response increased compared to baseline during SPL compared to ALI (+11.6±7.9 vs -10.7±7.7 μU/mL; p=0.048), whereas insulin sensitivity index was unchanged.We conclude that aldosterone is inversely associated with the initial phase insulin secretory response, the earliest detectable change in impaired glucose tolerance. Treatment with spironolactone could improve glucose homeostasis by restoring insulin secretion in subjects with metabolic syndrome. [ABSTRACT FROM AUTHOR]

Epoxyeicosatrienoic acids (EETs) are products of CYP450 epoxygenase and are degraded to DHETs by soluble epoxide hydrolase (sEH). Their natriuretic and vasodilatory actions oppose those of mineralocorticoids, but the effect of aldosterone on EET metabolism has not been investigated. To test the hypothesis that aldosterone impairs EET metabolism via altered production or degradation, we treated wild type C57Bl6J mice with aldosterone (50 μg/kg/d) or vehicle ± the mineralocorticoid receptor (MR) antagonist RU-28318 during high sodium intake for 2 weeks. Aldosterone decreased plasma (Fig A ; -29%, 4.4±0.6 vs. 3.1±0.4 ng/ml, control vs. aldosterone) and pancreatic EETs (Fig B ;-43%, 112±15 vs. 64±15 ng/mg tissue, control vs. aldosterone) but not hepatic or kidney EETs. MR antagonism prevented this effect of aldosterone on plasma EETs. The urinary DHET/EET ratio markedly increased, suggesting increased renal sEH activity. Because both aldosterone and EETs affect insulin secretion, we further assessed CYP epoxygenase expression within the pancreas. We detected Cyp2c44 and sEH (Ephx2) mRNA in isolated murine islets, and immunohistochemistry demonstrated CYP2C expression in beta-cells. Aldosterone decreased protein expression of CYP2C epoxygenase within whole pancreas, and ex vivo aldosterone treatment decreased Cyp2c and increased sEH mRNA expression within isolated islets. These data demonstrate that aldosterone decreases CYP2C expression and EET production in vivo. We propose that the renin-angiotensin-aldosterone system interacts with the CYP450 epoxygenase system to alter blood pressure and glucose homeostasis via EET metabolism. [ABSTRACT FROM AUTHOR]

Epoxyeicosatrienoic acids (EETs) induce vasodilation via activation of calcium-sensitive potassium channels and smooth muscle cell hyperpolarization. Soluble epoxide hydrolase (sEH) hydrolyzes EETs to less biologically active metabolites. The variant Gln287 of EPHX2 encodes for a sEH enzyme with reduced hydrolase activity. In murine models of type 2 diabetes, inhibition of sEH or EPHX2 deletion results in improved insulin sensitivity. In humans, forearm blood flow is significantly increased in Gln287 variant allele carriers. Given that insulin sensitivity is influenced by vascular perfusion, we hypothesized that insulin sensitivity would be increased in Gln287-carriers compared with wild-type individuals. Insulin secretion and sensitivity were assessed in 63 volunteers (43 with metabolic syndrome, 34 females, 42.5 ± 13 years old, 15 black Americans) during hyperglycemic clamps. Statistical analyses were adjusted for BMI. Plasma total- (r=0.63, p=0.007), 14-15- (r=0.62, p=0.008), and 11-12- (r=0.57, p=0.02) EET concentrations correlated with insulin sensitivity. There was no effect of genotype on insulin secretion (not shown). In individuals without metabolic syndrome, insulin sensitivity was significantly increased in Gln287 variant carriers compared with wild-type individuals (Fig. A). Insulin sensitivity was decreased in individuals with the metabolic syndrome, but also trended higher in Gln287 variant carriers when compared with wild-type individuals (Fig. B). Taken together, these results suggest that the loss-of-function Gln287 variant of EPHX2 is associated with increased insulin sensitivity. [ABSTRACT FROM AUTHOR]

Renin-angiotensin-aldosterone system (RAAS) activation worsens insulin resistance, and aldosterone impairs insulin secretion via a direct beta-cell effect in mice. To test the hypothesis that the endogenous RAAS contributes to impaired insulin secretion and contributes to impaired glucose tolerance in humans, we assessed glucose homeostasis in 37 subjects with metabolic syndrome (18 Female; 29 white/7 African American; age 45.6±1.8 years). After washout of anti-hypertensive medications, glucose tolerance was characterized as normal glucose tolerance (NGT, n=21), impaired glucose tolerance (IGT, n=11), or type 2 diabetes (T2DM, n=5). Baseline body mass index, body fat percentage, age, plasma renin activity (PRA) and aldosterone were similar among glucose tolerance groups.We then provided hydrochlorothiazide 12.5mg daily for one month and conducted hyperglycemic clamps on a controlled diet (Na 160, K 80 mEq/d). Potassium was supplemented to similarly maintain serum K+ ≥3.8 (3.90±0.2 NGT, 3.82±0.2 IGT, and 3.86±0.2 mEq/L T2DM). During HCTZ, plasma aldosterone and PRA increased to a greater extent in subjects with IGT compared to NGT or T2DM groups (Figures a, b). Plasma aldosterone-renin ratio was similar among groups. Insulin sensitivity index was similar among groups (5.63±2.8 NGT, 7.27±5.4 IGT, and 4.13±3.7 in T2DM; P=0.29). The acute insulin response (AIR) to glucose was significantly impaired in IGT and T2DM subjects (figure c). The AIR correlated inversely with aldosterone (figure d) but not PRA.HCTZ treatment activates the RAAS to a greater extent in subjects with IGT, and the aldosterone response specifically correlates with impaired insulin secretion. [ABSTRACT FROM AUTHOR]