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Background: Lactate is a commonly used biomarker for sepsis, although it has limitations in certain cases, suggesting the need for novel biomarkers. We evaluated the diagnostic accuracy of plasma renin concentration and renin activity for mortality and kidney outcomes in patients with sepsis with hypoperfusion or hypotension. Methods: This was a multicenter, prospective, observational study of 117 patients with septic shock treated at three tertiary emergency departments between September 2021 and October 2022. The accuracy of renin activity, renin, and lactate concentrations in predicting 28-day mortality, acute kidney injury (AKI), and renal replacement requirement was assessed using the area under the ROC curve (AUC) analysis. Results: The AUCs of initial renin activity, renin, and lactate concentrations for predicting 28-day mortality were 0.66 (95% confidence interval [CI], 0.55–0.77), 0.63 (95% CI, 0.52–0.75), and 0.65 (95% CI, 0.53–0.77), respectively, and those at 24 hrs were 0.74 (95% CI, 0.62–0.86), 0.70 (95% CI, 0.56–0.83), and 0.67 (95% CI, 0.54–0.79). Renin concentrations and renin activity outperformed initial lactate concentrations in predicting AKI within 14 days. The AUCs of renin and lactate concentrations were 0.71 (95% CI, 0.61–0.80) and 0.57 (95% CI, 0.46–0.67), respectively (P =0.030). The AUC of renin activity (0.70; 95% CI, 0.60–0.80) was also higher than that of lactate concentration (P =0.044). Conclusions: Renin concentration and renin activity show comparable performance to lactate concentration in predicting 28-day mortality in patients with septic shock but superior performance in predicting AKI. [ABSTRACT FROM AUTHOR]

Life‐threatening hypertension remains inadequately controlled in clinics due to its heterogeneous renin levels. Rapid stratification of hypertension through renin analysis is crucial for effective personalized treatment, yet an ultrasensitive detection approach is currently lacking. Here, we report activatable renin nanoprobes (ARNs) for non‐invasive and ultrasensitive profiling of renin activity and guiding antihypertensive treatment decision through near‐infrared fluorescence (NIRF) in vivo imaging and in vitro urinalysis. ARNs are intrinsically non‐fluorescent due to NIRF reporter connected to a gold nanocluster through a renin‐responsive peptide. In hyperreninemia mouse models, ARNs specifically react with renin to liberate the renal clearable NIRF reporter for accurate renin detection that outperforms the gold standard radioimmunoassay. Such specific and sensitive detection also enables imaging‐based high‐throughput screening of antihypertensive drugs. In hypertensive rat models, ARNs enable ultrasensitive detection of both plasma and urinary renin, facilitating renin‐guided precision treatment and significantly improving hypertension control rate (90 % versus 58 %). Our nanoprobe platform holds great potential for assisting clinicians in rapidly and accurately classifying hypertensive patients and improving outcomes through tailored treatment selection. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to analyze the distribution of plasma aldosterone, renin activity, deoxycorticosterone (DOC), cortisol, cortisone, and 24 h urinary aldosterone (24 h-uAld) levels based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Materials and methods: Plasma and 24 h urine were collected from 129 healthy volunteers in Northeast China. The effect of sodium intake, age, gender, blood sampling time on plasma aldosterone concentration (PAC), plasma renin activity (PRA), PAC to PRA ratio (ARR), DOC, cortisol, cortisone, cortisol to cortisone ratio, and 24 h-uAld were investigated by nonparametric test, multiple linear regression and Harris–Boyd's standard deviate test. Results: There was no significant difference observed in 24 h-uAld, PAC (AM), PRA(AM), ARR (AM), DOC (AM), cortisol (AM), cortisone (AM), and cortisol to cortisone (AM) between high and low sodium intake group. Significant differences were observed between morning and afternoon sampling groups in terms of PAC, ARR, DOC, cortisol, and cortisone. Reference intervals (RIs) of 24 h-uAld, PAC (AM) were recommended to be partitioned by gender. RI of PRA was recommended age stratification. Conclusion: We recommend that the same reference interval could be used regardless of sodium intake. Gender is the main influence factor for 24 h-uAld, PAC, and ARR. Age is key influence factor for PRA. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the commutability of external quality assessment (EQA) materials and candidate reference materials (RMs) for plasma renin activity (PRA) assay. Commutabilities of 16 candidate RMs were measured along with 40 clinical samples by the four different routine PRA assays, including three LC‒MS/MS assays and one chemiluminescence immunoassay. Sixteen candidate RMs included native/spiked human plasma pools (small-scale pools with <50 individuals) and current EQA materials (large-scale pools with >1,000 individuals). Difference in bias approach and linear regression with prediction interval approach were adopted to determine the commutability. Two-way variance analysis was used to estimate the effects of spiked and pool size on the commutability. Stability and homogeneity studies were performed. Precision and correlation performance of all assays was acceptable. In the difference in bias approach, the commutability results were not satisfactory (noncommutability: 14/16) and significant sample-specific effects were detected in assay pairs using different incubation buffers. For the prediction interval approach, no commutability was observed in the spiked small-scale pools; EQA materials (4/9) had more satisfactory commutability among all assays than the small-scale pools (2/7); RMs of large-scale pools tend to have better commutability no matter spiked or not. Commutable RMs were obtainable but challenging. Current EQA materials with relatively good commutability, stability, and homogeneity were appropriate RMs. Large-scale pools are tending to be commutable. Spiking in small-scale pools was not suggested to prepare RMs. MPs adopting a uniform incubation buffer would be preferable for further commutability research. [ABSTRACT FROM AUTHOR]

This study aims to investigate and update the consistency and comparability of plasma renin activity (PRA) assays in measuring clinical samples. The contributions of recalibration, blank subtraction, and incubation strategies to interchangeability were also explored. Five different laboratories were evaluated using forty-six individual plasma samples, including four liquid chromatography-tandem mass spectrometry (LC‒MS/MS) assays and one chemiluminescence immunoassay (CLIA). Spearman correlation coefficient (R), Passing–Bablok regression, and Bland‒Altman plot analyses were used to evaluate the consistency among assays. Consistency before and after recalibration, blank subtraction, and incubation strategy unification was compared. A good correlation was observed among all assays (R>0.93). None of the samples measured by all assays showed coefficient variation (CV) <10 %, and 37 % of samples showed overall CVs >20 %. The 95 % confidence intervals (CIs) for slopes did not contain 1 for most assay pairs. Large relative biases (−85.1–104.2 %) were found, and 76 % (52–93 %) of samples had unacceptable biases. Recalibration reduced the calibration bias. Ignoring blank subtraction improved the comparability across all assays while unifying incubation did not. The interchangeability of PRA measurement was unsatisfying. Harmonization on calibrator and ignoring blank were recommended. Unifying incubation strategy was unnecessary. [ABSTRACT FROM AUTHOR]

Background: Lactate is a commonly used biomarker for sepsis, although it has limitations in certain cases, suggesting the need for novel biomarkers. We evaluated the diagnostic accuracy of plasma renin concentration and renin activity for mortality and kidney outcomes in patients with sepsis with hypoperfusion or hypotension., Methods: This was a multicenter, prospective, observational study of 117 patients with septic shock treated at three tertiary emergency departments between September 2021 and October 2022. The accuracy of renin activity, renin, and lactate concentrations in predicting 28-day mortality, acute kidney injury (AKI), and renal replacement requirement was assessed using the area under the ROC curve (AUC) analysis., Results: The AUCs of initial renin activity, renin, and lactate concentrations for predicting 28-day mortality were 0.66 (95% confidence interval [CI], 0.55-0.77), 0.63 (95% CI, 0.52-0.75), and 0.65 (95% CI, 0.53-0.77), respectively, and those at 24 hrs were 0.74 (95% CI, 0.62-0.86), 0.70 (95% CI, 0.56-0.83), and 0.67 (95% CI, 0.54-0.79). Renin concentrations and renin activity outperformed initial lactate concentrations in predicting AKI within 14 days. The AUCs of renin and lactate concentrations were 0.71 (95% CI, 0.61-0.80) and 0.57 (95% CI, 0.46-0.67), respectively ( P =0.030). The AUC of renin activity (0.70; 95% CI, 0.60-0.80) was also higher than that of lactate concentration ( P =0.044)., Conclusions: Renin concentration and renin activity show comparable performance to lactate concentration in predicting 28-day mortality in patients with septic shock but superior performance in predicting AKI.

Purpose: Neurogenic orthostatic hypotension (nOH) is the hallmark of neurodegenerative forms of autonomic failure, including pure autonomic failure, multiple system atrophy, and Parkinson's disease. Studies have shown autonomic physiological differences in Africans Americans (AA) such as lower heart rate variability, enhanced blood pressure reactivity, and blunted sympathetic neural response compared to non-Hispanic whites. However, the clinical characteristics and neurohormonal profile of autonomic failure in AA is unknown. Methods: A total of 65 patients with nOH participated in this study (9 AA and 56 non-Hispanic whites). Both groups were of similar age and comorbidity status, and they underwent standardized autonomic testing and assessment of neurohormonal levels and renin activity and aldosterone in supine and upright positions. Results: There were no significant differences in baseline autonomic clinical characteristics between non-Hispanic whites and AA with nOH. Non-Hispanic whites demonstrated a significant increase in upright renin activity compared to AA (295 ± 88% vs. 13 ± 13%, respectively). AA showed a blunted increase in aldosterone compared to non-Hispanic whites (188 ± 27% vs. 59 ± 38%, respectively). These results indicated persistent suppression of the renin-angiotensin system in AA, particularly during upright posture. Conclusion: Our findings demonstrate that AA with nOH have similar clinical characteristics and hemodynamic autonomic profiles, but lower upright renin activity and aldosterone levels, compared to non-Hispanic whites. Renin suppression persists in AA with severe autonomic failure and can potentially contribute to postural changes and supine hypertension. [ABSTRACT FROM AUTHOR]

Artery fenestration is a congenital vascular malformation, often of the intracranial arteries, that causes an aneurysm. However, there have been no reports of artery fenestration causing renal aneurysm. We present the case of a 58-year-old man who developed renin-dependent hypertension. He was aware of heaviness of the head, and his blood pressure was 196/134 mm Hg on 5 mg of amlodipine. Laboratory tests showed hypokalemia, hyperreninemia, and hyperaldosteronemia. An enhanced 3-dimensional computed tomography scan showed a 19-mm renal aneurysm in a branch of the left renal artery, and renal arteriography showed a fenestration in the aneurysm-forming branch. Coil embolization was performed on the central side of the artery forming the aneurysm and fenestration, after which blood pressure, serum potassium, and plasma renin levels improved. The patient in the present case had renin-dependent hypertension as a result of decreased renal blood flow caused by the renal aneurysm and fenestration, which is considered an extremely rare etiology of hypertension. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationship between plasma renin activity (PRA), Clq/TNF-related protein 3 (CTRP3) and carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Methods Totally 137 patients with T2DM were selected and divided into the plaque group of 83 cases and non-plaque group of 54 cases according to carotid intima-media thickness. The general clinical data [age, gender, BMI, blood pressure (systolic blood pressure, diastolic blood pressure), basic diseases (hypertension, hyperlipidemia), smoking history, drinking history, family history of cardiovascular and cerebrovascular diseases, diet and exercise mode ] and laboratory examination data [ TC, TG, LDL-C, HDL-C, FPG, fasting insulin (FINS), insulin resistance index (HOMA-IR), glycosylated hemoglobin (HbAl c), PRA, CTRP3] were collected. The general clinical data and laboratory examination data of the two groups were compared. The above indexes with statistical difference were included in the multiple stepwise Logistic regression model, the risk factors affecting TIDM complicated with carotid atherosclerosis was analyzed. Receiver operating characteristic (ROC) curve was used to evaluate the efficacy of plasma PRA and CTRP3 levels in predicting TIDM complicated with carotid atherosclerosis. Results Twelve factors were included in the general clinical data of the two groups. Univariate analysis showed that there were significant differences in BM!, systolic blood pressure, smoking history, hypertension, hyperlipidemia, unreasonable diet and lack of exercise between the two groups (all P <0. 05); there were no significant differences in gender, age, diastolic blood pressure, drinking history, family history of cardiovascular or cerebrovascular disease (all P > 0. 05). Ten factors were included in the laboratory examination data of the two groups. Univariate analysis showed that there were significant differences in TC, FPG, FINS, HOMA-IR, HbAl c, PRA, and CTRP3 between the two groups (all P < 0. 05), but there was no significant difference in TG, HDL-C or LDL-C between the two groups (all P > 0. 05) Multiple stepwise Logistic regression analysis showed that systolic blood pressure, TC, HbAl c, PRA and CTRP3 were risk factors of carotid atherosclerosis in DM (all P < 0. 05). ROC curve analysis showed that the area under the curve (AUC) of plasma PRA level in predicting T2DM complicated with carotid atherosclerosis was 0. 731 (95% Cl: 0. 644- 0. 817), and its cut-off value was 4. 21 µ.g/(L · h). At this time, the sensitivity and specificity in predicting DM complicated with carotid atherosclerosis were 72. 29% and 79. 63%, respectively. The AUC of plasma CTRP3 level in predicting DM complicated with carotid atherosclerosis was 0. 801 (95% C/: 0. 720-0. 881), the cut-off value was 90. 31 ng/mL, and the sensitivity and specificity in predicting DM complicated with carotid atherosclerosis were 78. 31 % and 87. 04%, respectively; the AUC of the combination of PRA and CTRP3 was O. 903 (95 % CI: 0. 843-0. 964), and the sensitivity and specificity in predicting TIDM complicated with carotid atherosclerosis were 91. 57% and 92. 59%, respectively. Conclusion The level of plasma PRA in patients with DM complicated with carotid atherosclerosis increases and the level of plasma CTRP3 decreases; the levels of plasma PRA and CTRP3 are risk factors for TIDM complicated with carotid atherosclerosis and can be used as the predictive indexes. [ABSTRACT FROM AUTHOR]

Renin-Angiotensin-Aldosterone System (RAAS) measurements are influenced by several factors. We investigated the effect of sample delivery conditions on RAAS measurements including sample storage temperature and time. Blood samples were collected from thirty participants using enzyme inhibitor tubes and serum separation gel evacuated tubes. Plasma and serum from fresh blood samples without further storage (as baseline), and from blood samples that were stored at either 0 °C, 4 °C, or 25 °C for 3 h, 6 h and 24 h, respectively, were extracted and stored at -30 °C for batch measurements using radioimmunoassay. Concentrations of Aldosterone (Ald) decreased following delivery temperature and time, and were significantly different when samples were set aside at 0 °C for 24 h (p < .01), 4 °C for 6 h (p < .01), and 25 °C for 3 h (p < .05). However, levels of Angiotensin (Ang I) increased following delivery temperature and time, and were significantly different when samples were set aside at 0 °C and 4 °C for 6 h (p < .05) and at 25 °C for 3 h (p < .001). However, no changes were observed for the concentrations of plasma renin activity (PRA) and Ang II, except for Ang II which increased significantly when samples were set aside at 25 °C for 24 h (p < .001). Our results indicate that samples used for RAAS measurement should be placed at a low temperature and analyzed as soon as possible after collection. [ABSTRACT FROM AUTHOR]

Namyi Gu,1,2 Joo-Youn Cho,3 Kwang-Hee Shin,4 In-Jin Jang,3 Moo-Yong Rhee2,5 1Department of Clinical Pharmacology and Therapeutics, 2Clinical Trial Center, Dongguk University College of Medicine and Ilsan Hospital, Goyang, 3Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 4Pharmacotherapy & Translational Research Lab., College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 5Cardiovascular Center, Dongguk University College of Medicine and Ilsan Hospital, Goyang, Republic of Korea Abstract: A low sodium diet enhances the hemodynamic effect of renin–angiotensin system blockers. It was suggested that the substrates of P-glycoprotein or cytochrome P450 3A4 were reduced on a high sodium diet. This study aimed to investigate the influence of high sodium diet on the pharmacokinetics and pharmacodynamics of fimasartan, which is a substrate of cytochrome P450 3A4 but not P-glycoprotein. The study design was a two-diet, two-period, two-sequence, randomized, open-label, and crossover with 1-week washout for diet. Eligible subjects were fed with either low sodium (50 mEq/day) diet or high sodium diet (300 mEq/day) for 7 days in the first hospitalization period and the other diet in the second period. On the seventh morning of each period, subjects received a single dose of fimasartan 60 mg in a fasted state. The serial plasma concentrations of fimasartan, serum aldosterone concentration (SAC), and plasma renin activity (PRA) were measured for pharmacokinetic–pharmacodynamic analysis. Sixteen subjects completed the study satisfying the compliance test for diets. Although the mean systemic exposure of fimasartan is slightly (≈10%) decreased on a high sodium diet, the difference was not statistically or clinically significant (P>0.05). The SAC and PRA after fimasartan administration were highly dependent on their baseline levels. The dietary sodium content influenced the baseline of SAC and PRA, but did not influence the ratio change of SAC and PRA after fimasartan treatment. The ratio change of SAC after fimasartan treatment was correlated to the systemic exposure of fimasartan (P0.05). In conclusion, the pharmacokinetics of fimasartan and ratio changes of SAC and PRA after fimasartan treatment were not significantly influenced by dietary sodium content. Keywords: aldosterone, renin activity, angiotensin receptor blocker, aldosterone, renin, cytochrome P450 3A4, P-glycoprotein, healthy, sodium diet

Abstract: Pseudohypoaldosteronism (PHA) comprises a diverse group of rare diseases characterized by sodium and potassium imbalances incorrectly attributed to a defect in aldosterone production. Two different forms of PHA have been described, type I (PHAI) and type II (PHAII). PHAI has been subclassified into renal and systemic. Given the rarity and heterogeneity of this group of disorders we report three patients who carry PHA and a brief revision of current literature focused on the comparative analysis of PHAI and PHAII. Cases 1 and 2 presented with hyponatremia, hyperkalemia, metabolic acidosis and elevated plasma aldosterone and plasma renin activity in the neonatal period. Sequence analysis of the NRC2 gene demonstrated a novel heterozygous c.403C>T mutation in case 1 and a complete deletion in case 2, confirming the diagnosis of renal PHAI. Case 3 was a 4-year-old with hypertension, hyperkalemia, metabolic acidosis, normal plasma aldosterone and decreased plasma renin activity. Sequence analysis of the CUL3 gene demonstrated a previously unreported heterozygous c.1377+2T>3 mutation, confirming the diagnosis of PHAII-E. We highlight the importance of the determination of plasma aldosterone and plasma renin activity in the context of persistent sodium and potassium imbalances in children. [ABSTRACT FROM AUTHOR]

The (pro)renin receptor (PRR) is abundantly expressed in the collecting duct (CD) and the expression is further induced by angiotensin II (ANG II). The present study was conducted to investigate the role of CD PRR during ANG II-induced hypertension and to further explore the underlying mechanism. Radiotelemetry demonstrated that a 1-wk ANG II infusion gradually and significantly induced hypertensive response in floxed mice and this response was significantly attenuated in mice lacking PRR in the CD (termed CD PRR KO). ANG II infusion in floxed mice increased urinary renin activity and selectively induced renal medullary α-epithelial sodium channel (α-ENaC) mRNA and protein expression, all of which were blunted in the null mice. In cultured mpkCCD cells grown in Transwells, transepithelial Na+ transport as measured by using a volt-ohmmeter was transiently stimulated by acute ANG II treatment, which was abolished by a PRR antagonist, PRO20. In a chronic setting, ANG II treatment induced α-ENaC mRNA expression in mpkCCD cells, which was similarly blocked by PRO20. Chronic intramedullary infusion of an ENaC inhibitor amiloride in rats significantly attenuated ANG II-induced hypertension. Overall, the present study suggests that CD PRR contributes to ANG II-induced hypertension at least partially via activation of renal medullary ENaC. [ABSTRACT FROM AUTHOR]

Background: (Pro)renin receptor (PRR) is a new component of the renin-angiotensin system and regulates renin activity in vitro. Within the kidney, PRR is highly expressed in the renal medulla where its expression is induced by angiotensin II infusion. The objective of the present study was to test a potential role of renal medullary PRR during angiotensin II-induced hypertension.Methods: A rat AngII infusion model (100 ng/kg/min) combined with renal intramedullary infusion of PRO20, a specific inhibitor of PRR, was builded. And the intravenous PRO20 infusion serve as control. Mean arterial pressure was recorded by radiotelemetry for one week. Further analysis of kidney injury, inflammation, biochemical indices and protein localization were performed in vivo or in vitro.Results: Radiotelemetry demonstrated that AngII infusion elevated the mean arteria pressure from 108 ± 5.8 to 164.7 ± 6.2 mmHg. Mean arterial pressure decreased to 128.6 ± 5.8 mmHg (P < 0.05) after intramedullary infusion of PRO20, but was only modestly affected by intravenous PRO20 infusion. Indices of kidney injury, including proteinuria, glomerulosclerosis, and interstitial fibrosis, inflammation, and increased renal medullary and urinary renin activity following angiotensin II infusion were all remarkably attenuated by intramedullary PRO20 infusion. Following one week of angiotensin II infusion, increased PRR immunoreactivity was found in vascular smooth muscle cells. In cultured rat vascular smooth muscle cells, angiotensin II induced parallel increases in soluble PRR and renin activity, and the latter was significantly reduced by PRO20.Conclusion: Renal medullary PRR mediates angiotensin II-induced hypertension, likely by amplifying the local renin response. [ABSTRACT FROM AUTHOR]

(Pro)renin receptor (PRR) is predominantly expressed in the distal nephron where it is activated by angiotensin II (ANG II), resulting in increased renin activity in the renal medulla thereby amplifying the de novo generation and action of local ANG II. The goal of the present study was to test the role of cycloxygenase-2 (COX-2) in meditating ANG II-induced PRR expression in the renal medulla in vitro and in vivo. Exposure of primary rat inner medullary collecting duct cells to ANG II induced sequential increases in COX-2 and PRR protein expression. When the cells were pretreated with a COX-2 inhibitor NS-398, ANG II-induced upregulation of PRR protein expression was almost completely abolished, in parallel with the changes in medium active renin content. The inhibitory effect of NS-398 on the PRR expression was reversed by adding exogenous PGE2. A 14-day ANG II infusion elevated renal medullary PRR expression and active and total renin content in parallel with increased urinary renin, all of which were remarkably suppressed by the COX-2 inhibitor celecoxib. In contrast, plasma and renal cortical active and total renin content were suppressed by ANG II treatment, an effect that was unaffected by COX-2 inhibition. Systolic blood pressure was elevated with ANG II infusion, which was attenuated by the COX-2 inhibition. Overall, the results obtained from in vitro and in vivo studies established a crucial role of COX-2 in mediating upregulation of renal medullary PRR expression and renin content during ANG II hypertension. [ABSTRACT FROM AUTHOR]

Objective. To test the hypothesis that the blood antithrombin (AT) activity is correlated with the plasma aldosterone concentration (PAC), the plasma renin activity (PRA), and/or the PAC-to-PRA ratio during the late stage of pregnancy. Methods. The AT activity, PAC, and PRA were determined within 7 days prior to delivery in 47 women, consisting of 30 normotensive and 6 hypertensive women with singleton pregnancies and 11 normotensive women with twin pregnancies. Results. The median values of the 47 women were 86% of the normal activity level for the AT activity, 442 pg/mL for the PAC, 3.7 ng/mL/h for the PRA, and 108 pg/mL per ng/mL/h for the PAC-to-PRA ratio. Women with an AT activity ≤86% had a significantly lower PRA and a higher PAC-to-PRA ratio than women with an AT activity >86% (3.5 ± 3.0 vs. 6.6 ± 4.7 ng/mL/h for PRA, p = 0.008; 156 ± 109 vs. 97 ± 46 pg/mL per ng/h for PAC-to-PRA ratio, p = 0.021). The AT activity was significantly correlated positively with the PRA and negatively with the PAC-to-PRA ratio. Conclusions. The existence of a common pathophysiological background between a reduced AT activity and a reduced PRA during the late stage of pregnancy was suggested. [ABSTRACT FROM AUTHOR]

Objective: Changes in the plasma aldosterone concentration (PAC) and the plasma renin activity (PRA) have not been extensively studied in women with twin pregnancies. Methods: The PAC and PRA levels were determined during the second and third trime-sters and on postpartum day 3 in 14 normotensive women with twin pregnancies and 80 normotensive and 7 preeclamptic women with singleton pregnancies. Results: In women with twin pregnancies, elevated PAC and PRA levels (598 ± 248 pg/mL and 10.0 ±4.7 ng/ mL/h, respectively) in the second trimester decreased significantly during the third trimester (to 396 ± 210 pg/mL and 3.5 ± 2.9 ng/mL/h, respectively), whereas the corre-sponding PAC increased significantly (from 421 ± 207 to 667 ± 371 pg/mL) and the PRA did not change significantly (from 7.3 ± 3.4 to 6.9 ± 4.2 ng/mL/h) in women with normal singleton pregnancies. These changes in the PAC and PRA levels in women with twin pregnancies resembled those in hypertensive women with singleton pregnancies. Conclusions: In women with twin pregnancies, both the PAC and PRA levels were significantly enhanced during the second trimester, whereas those in the third trimester were significantly reduced compared with those in women with normal singleton pregnancies. [ABSTRACT FROM AUTHOR]

The present study aims to investigate the regulatory effect of hydrogen sulfide (H2S) on cAMP homeostasis and renin degranulation in As4.1 and rat reninrich kidney cells. It was found in the present study that NaHS at 0.1-10 μM significantly decreased cAMP production in As4.1 cells treated with isoproterenol (a β-adrenoceptor agonist), forskolin (an adenylyl cyclase activator), or 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor). NaHS at 10 μM suppressed adenylate cyclase activity but stimulated phosphodiesterase activity. We continued to study whether H2S may mediate cAMP-dependent renin degranulaion in As4.1 cells. It was found that NaHS at 0.1-10 μM significantly increased intracellular renin protein level. Moreover, NaHS reversed the declined renin content within As4.1 cells and normalized the upregulated renin activity in the culture medium of As4.1 cells treated with the above three stimuli. RT-PCR showed that cystathionine-γ-lyase is the main enzyme to produce endogenous H2S in As4.1 cells. Overexpression of cystathionine-γ-lyase increased endogenous H2S production and suppressed isoproterenol-induced renin release, suggesting that endogenous H2S may also inhibit renin release from As4.1 cells. We also tested whether H2S has a similar effect in renin-rich kidney cells. It was found that isoproterenol elevated intracellular cAMP level and extracellular renin activity but decreased renin protein level in the renin-rich kidney cells. Pretreatment with NaHS abolished these effects. In conclusion, H2S regulates cAMP homeostasis via inhibition of adenylate cyclase and stimulation of phosphodiesterase. Our findings suggest that H2S plays a critical role in regulation of renin degranulation in As4.1 and rat renin-rich kidney cells. [ABSTRACT FROM AUTHOR]

Objective(s) We investigated the effects of low-dose morphine on nitric oxide (NO) and angiogenesis in two-kidney one clip hypertensive (2K1C) rats. Materials and Methods Male rats were divided into two groups: sham-clip operated and 2K1C. Each group subdivided into saline and morphine (3 mg/kg i.p. 8 weeks) groups. Blood pressure, heart rate, plasma renin activity (PRA), NO concentration and murine matrigel angiogenesis were evaluated. Results Morphine had no effects on blood pressures and HR in sham normotensive rats but attenuated diastolic blood pressure (DBP) (P< 0.01) and mean arterial pressure (MAP) (P< 0.01) in 2K1C compared with saline. PRA level was significantly higher in 2K1C compared with sham groups (P< 0.01) but morphine decreased it in 2K1C compared with saline (P< 0.01). After clipping, NO in 2K1C hypertensive rats was decreased (P< 0.01) and morphine increased it compared with saline (P< 0.01). Morphine promoted angiogenesis in both sham (P< 0.01) and 2K1C (P< 0.0001) groups. Conclusion Low-dose morphine stimulated angiogenesis in two-kidney one clip hypertensive rats probably via NO pathways. [ABSTRACT FROM AUTHOR]

These experiments examined water-drinking and arterial blood pressure responses to β-adrenergic receptor activation in young (4 mo), "middle-aged" adult (12 mo), and old (29 mo) male rats of the Brown-Norway strain. We used isoproterenol to simultaneously activate β1- and β2-adrenergic receptors, salbutamol to selectively activate β2-adrenergic receptors, and the combination of isoproterenol and the β2-adrenergic receptor antagonist ICI 118,551 to stimulate only β1-adrenergic receptors. Animals received one of the drug treatments, and water drinking was measured for 90 min. About 1 wk later, animals received the same drug treatment for measurement of arterial blood pressure responses for 90 min. In some rats, levels of renin and aldosterone secretion in response to isoproterenol or salbutamol were measured in additional tests. Old and middle-aged rats drank significantly less after isoproterenol than did young rats and also had greater reductions in arterial blood pressure. Old and middle-aged rats drank significantly less after salbutamol than did young rats, although reductions in arterial blood pressure were equivalent across the ages. The β2-adrenergic antagonist ICI 118,551 abolished drinking after isoproterenol and prevented most of the observed hypotension. Renin secretion after isoproterenol and salbutamol was greater in young rats than in middle-aged rats, and wholly absent in old rats. Aldosterone secretion was reduced in old rats compared with young and middle-aged rats after treatment with isoproterenol, but not after treatment with salbutamol. In conclusion, there are age-related differences in β-adrenergic receptor-mediated drinking that can be explained only in part by age-related differences in renin secretion after β-adrenergic receptor stimulation. [ABSTRACT FROM AUTHOR]

Abstract: We have previously shown that centrally injected melittin, a phospholipase A2 (PLA2) activator, increases blood pressure and decreases heart rate in the normotensive conscious rats. In the current study we aimed to determine the cardiovascular effects of melittin in hemorrhaged hypotensive rats and to investigate the mediation of peripheral adrenergic, vasopressinergic and renin angiotensin system in the pressor effect of centrally administrated melittin in both normotensive and hypotensive conditions. Acute hypotensive hemorrhage was performed by withdrawing a total volume of 2.2ml of blood/100g body weight over a period of 10min. Melittin was injected intracerebroventricularly (i.c.v.) at the doses of 1.5μg, 3.0μg or 6.0μg after the stabilization period of hemorrhage procedure. We also repeated previous experiments by injecting melittin (1.5μg, 3.0μg or 6.0μg; i.c.v.) to the normotensive animals. Melittin caused dose- and time-dependent increases in mean arterial pressure (MAP) in normal and hypotensive conditions and decreases in heart rate (HR) in normotensive conscious animals. In hypotensive rats, melittin injected at the dose of 6.0μg completely restored the decrease in blood pressure. Plasma adrenaline, noradrenaline, vasopressin levels and renin activity increased after melittin (3.0μg; i.c.v) administration in normal conditions. Hemorrhage, itself, produced an increase in these plasma hormone levels and melittin (3.0μg; i.c.v.) caused additional increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity in hypotensive conditions. Intravenous pretreatments of rats with prazosin (0.5mg/kg), an α1 adrenoceptor antagonist, [β-mercapto-β,β-cyclopentamethylenepropionyl1, O-Me-Tyr2-Arg8]-vasopressin (10μg/kg), a vasopressin V1 receptor antagonist, or saralasin (250μg/kg), an angiotensin II receptor antagonist, partially blocked the pressor response to melittin (3.0μg; i.c.v.) in both normotensive and hypotensive conditions. Besides, the combined administration of these three antagonists before melittin completely abolished the pressor responses to drug in both conditions. Results show that centrally administered melittin, a PLA2 activator, increases blood pressure and reverses hypotension in hemorrhagic shock. The increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity mediate the pressor responses to melittin in normal and hypotensive conditions. [Copyright &y& Elsevier]

Background: The epithelial sodium channel (ENaC) is a candidate gene associated with the development of essential hypertension. A potentially polymorphic repetitive region (GT dinucleotide short tandem repeat [STR]) was identified in intron 8 of β-ENaC gene (SCNN1B). The aim of this study was to identify the prevalence and distribution of a polymorphic GT-STR in SCNN1B in Chilean essential hypertensive (EH) patients and to analyze the correlation between the different genotypes with plasma renin activity (PRA) and serum aldosterone (SA), and furthermore, to evaluate the β-ENaC gene expression in vitro. Methods: We studied 133 patients with EH and 69 normotensive (NT). In both EH and NT subjects we measured PRA, SA, urine sodium, and genotyped them according to the GT-STR length using sequencing analysis. We detected 11, 13 and 14 GT alleles in EH and NT subjects. Both groups were classified according to genotype: 14/14, 14/13, 13/13, 13/11, and 11/11. Influence of the GT-STR on β-ENaC minigene expression was evaluated by real-time polymerase chain reaction. Results: In EH, PRA decreased with the length of the STR region 11/13, 1.40 ± 0.69; 13/13, 1.16 ± 0.61; 13/14, 0.90 ± 0.56; 14/14, 0.32 ± 0.09 ng/mL/h; P < .01. Likewise, PRA in patients with EH with 14/14 or 14/13 genotypes were lower than EH with 13/13 or 13/11 genotypes (0.77 ± 0.5 v 1.24 ± 0.6 ng/mL/h; P < .01). Real-time polymerase chain reaction demonstrated an increased β-ENaC expression in minigenes containing 14 GT-STR. Conclusions: We have identified a polymorphic GT-STR in the β-ENaC gene, which is present in the EH and NT Chilean population. Biochemical analysis showed a possible linkage between this polymorphic region and low renin hypertension. The in vitro assay suggests that GT-STR could regulate the β-ENaC expression. [Copyright &y& Elsevier]

Abstract: Background: Female humans and rodents are relatively protected against the development of hypertension and renal disease. Whether this protection is modified during insulin resistance and obesity, however, is not known. Objective: Because renal sodium reabsorption has a central role in determining blood pressure, we hypothesized that lean female rats would bave reduced renal expression, activity, and urinary excretion of 8 major sodium transporters/channels. Methods: Lean and obese, male and female Zucker rats (n = 4–8 per group) were fed progressively higher levels of dietary NaCl over a period of 54 days. Urinary excretion of renal sodium transport proteins was determined for 3 different dietary levels (0.04%, 0.4%, and 4%) of NaCl. With the high-NaCl diet, natriuretic responses to benzamil, furosemide, and thiazide were used as in vivo markers for activity of the epithelial sodium channel (ENaC), the bumetanide-sensitive Na-K-2C1 cotransporter (NKCC2), and the thiazide-sensitive NaCl cotransporter (NCC), respectively. Results: Female rats (of both body types) had lower plasma renin activity and insulin levels than their male counterparts. Likewise, immunoblotting revealed female rats had increased whole kidney abundance of NCC and of the α, β, and γ subunits of ENaC, as well as decreased abundance of the type 3 sodium hydrogen exchanger (NHE3), type 2 sodium phosphate cotransporter (NaPi-2), and α-1 sodium-potassium-adenosine triphosphatase (Na-K-ATPase), compared with males. Obese rats had reduced levels of NKCC2, NHE3, and γ-ENaC, but higher levels of NaPi-2 and NCC. Urine excretion of sodium transporters in lean female rats was nearly undetectable, whereas obese rats of both sexes excreted markedly more NKCC2 and NCC, which agreed with greater natriuretic responses to thiazide and furosemide. Conclusions: Obese female rats are similar to lean female rats with regard to the sex-distinct pattern of renal sodium transporters. However, obese female rats are more like obese male rats with regard to increased natriuretic response tofurosemide and thiazide, and to urine excretion of several transporters including NCC. Our results suggest that, with obesity, there is some loss of the protective female advantage. [Copyright &y& Elsevier]

Aim: This study focused on static and dynamic changes in total renal blood flow (RBF) during volume expansion and tested whether a change in RBF characteristics is a necessary effector mechanism in saline-induced natriuresis. Methods: The aortic flow subtraction technique was used to measure RBF continuously. Identical amounts of NaCl (2.4 mmol kg−1) were given as slow isotonic (Iso, 120 min), slow hypertonic (Hyper, 120 min), and rapid isotonic loads (IsoRapid, 30 min). Results: During Iso and IsoRapid, arterial blood pressure increased slightly (6–7 mmHg), and during Hyper it remained unchanged. Iso and Hyper increased sodium excretion (4 ± 1 to 57 ± 27 and 10 ± 4 to 79 ± 28 μmol min−1, respectively) and decreased plasma renin activity (by 38% and 29%), angiotensin II (by 56% and 58%) and aldosterone (by 47% and 65%), while RBF remained unchanged. IsoRapid caused a similar increase in sodium excretion (to 72 ± 19 μmol min−1), a similar decrease in renin system activity, but a 15% elevation of RBF (282 ± 22 to 324 ± 35 mL min−1). Selected frequency domain parameters of RBF autoregulation did not change in response to any load. Conclusions: In response to slow saline loading simulating daily sodium intake, the rate of sodium excretion may increase 10–20-fold without any change in mean arterial blood pressure or in RBF. Regulatory responses to changes in total body NaCl levels appears, therefore, to be mediated primarily by neurohumoral mechanisms and may occur independent of changes in arterial pressure or RBF. [ABSTRACT FROM AUTHOR]

During exercise heat stress, ad libitum drinking frequently fails to match sweat output, resulting in deleterious changes in hormonal, circulatory, thermoregulatory, and psychological status. This condition, known as voluntary dehydration, is largely based on perceived thirst. To examine the role of preexercise dehydration on thirst and drinking during exercise-heat stress, 10 healthy men (21 ± 1 yr, 57 ± 1 ml · kg-1 · min-1 maximal aerobic power) performed four randomized walking trials (90 min, 5.6 kin/h, 5% grade) in the heat (33°C, 56% relative humidity). Trials differed in preexercise hydration status [euhydrated (Eu) or hypohydrated to -3.8 ± 0.2% baseline body weight (Hy)] and water intake during exercise [no water (NW) or water ad libitum (W)]. Blood samples taken preexercise and immediately postexercise were analyzed for hematocrit, hemoglobin, serum aldosterone, plasma osmolality (Posm), plasma vasopressin (PAVP), and plasma renin activity (PRA). Thirst was evaluated at similar times using a subjective nine-point scale. Subjects were thirstier before (6.65 ± 0.65) and drank more during Hy+W (1.65 ± 0.18 liters) than Eu+W (1.59 ± 0.41 and 0.31 ± 0.11 liters, respectively). Postexercise measures of Posm and PAVP were significantly greater during Hy+NW and plasma volume lower [Hy+NW = -5.5 ± 1.4% vs. Hy+W = +1.0 ± 2.5% (P = 0.059), Eu+NW = -0.7 ± 0.6% (P < 0.05), Eu+W = +0.5 ± 1.6% (P < 0.05)] than all other trials. Except for thirst and drinking, however, no Hy+W values differed from Eu+NW or Eu+W values. In conclusion, dehydration preceding low-intensity exercise in the heat magnifies thirst-driven drinking during exercise-heat stress. Such changes result in similar fluid regulatory hormonal responses and comparable modifications in plasma volume regardless of preexercise hydration state. [ABSTRACT FROM AUTHOR]

In the present study, we investigated the cardiovascular effects of centrally injected U-46619, a thromboxane A[sub 2] (TXA[sub 2] ) analog, and the central and peripheral mechanisms of these effects in hemorrhagic shock conditions. Hemorrhage was performed by withdrawing a total volume of 2.1 ml of blood/100 g body weight over a period of 10 min. Injections were made into the lateral cerebral ventricle (LCV), nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM) and paraventricular nucleus of hypothalamus (PVN). U-46619 (0.1, 1 and 2 μg) increased blood pressure and reversed hypotension in hemorrhagic shock. The pressor effect was dose- and time-dependent in all investigated brain areas. Heart rate changes were not significantly different in all groups. Pretreatment of rats with an injection of SQ-29548 (4 or 8 μg), a TXA[sub 2] receptor antagonist, into the LCV, NTS, RVLM and PVN completely blocked the pressor effect of U-46619 (1 μg) injected into respective brain areas. Hemorrhage itself increased plasma adrenaline, noradrenaline, vasopressIN levels and renin activity. U-46619 (1 μg) injected into the LCV, PVN, RVLM and NTS produced additional increases in these hormone levels and in renin activity. Intravenous pretreatments of rats with prazosin (0.5 mg/kg), an α[sub 1] -adrenoceptor antagonist, [β-mercapto-β,β-cyclopentamethylenepropionyl[sup 1] , O-Me-Tyr[sup 2] ,Arg[sup 8] ]- vasopressin (10 μg/kg), a vasopressin V[sub 1] -receptor antagonist, or saralasin (250 μg/kg), an angiotensin II receptor antagonist, in hemorrhaged rats partially blocked the pressor response to U-46619 (1 μg) injected into the LCV, PVN, RVLM and NTS. Results show that centrally administered U-46619, a TXA[sub 2] analog, increases blood pressure and reverses hypotension in hemorrhagic shock. Activation of central TXA[sub 2] receptors mediates the pressor effect of the drug. Furthermore, the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity are involved in these effects. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Characteristics of hydrochlorothiazide (HCZ)-induced sodium appetite were examined in rats fed with low sodium diet to which HCZ was added. Compared with controls, HCZ induced a robust appetite for 0.1 and 0.3 M NaHCO3. The intake of 0.3 M NaCl was only about one half that of NaHCO3, but was still greatly above control. In both cases, the intake of the sodium solution exceeded that of water, so the rats were taking a hypertonic mixture. The appetite was evident in both Sprague–Dawley and Long–Evans rats, but appeared to be more stable in the latter strain over at least 1 month. The diuretic and natriuretic effect of HCZ was sustained over this period. Plasma renin activity was elevated substantially in HCZ-treated rats, but aldosterone concentration was decreased. Administration of HCZ in food is a simple and reliable method for inducing a sustained, substantial, and need-based salt appetite in rats. [Copyright &y& Elsevier]

Hyperaldosteronism in a male terrier cross was diagnosed with history of transient period of recumbency, shallow respiration, flaccidity of muscles and ventroflexion of neck. The dog was subjected to physical, haemato-biochemical, radiographic, ultrasonographic and electrocardiographic examination. Supplementary examinations included low dose dexamethasone suppression test (LDDST), plasma renin activity, blood gas and aldosterone level analysis. Findings of plasma renin activity and aldosterone level analysis, confirmed diagnosis of hyperaldosteronism. [ABSTRACT FROM AUTHOR]

In this study the effect of acculturation on endocrine reactivity was studied in a population of Tswanas in South Africa. It was found that significant differences in endocrine reactivity exist not only between rural Tswanas and urban whites but in some instances also between rural and urban Tswanas. During the cold pressor test, the testosterone reactivity and to a lesser extent the prolactin reactivity of the urban Tswanas tended to approach that of the white group as a function of their level of acculturation. All the Tswana groups had a significantly higher plasma renin activity during acute stress than the whites, which could have the bearing on the tendency of urban blacks to develop hypertension. [ABSTRACT FROM AUTHOR]

In a placebo controlled, single blind, randomized cross over study catecholamines (CA) and renin activity (PRA) in plasma were measured in 2 female and 4 male healthy volunteers, at rest in the supine position, following a single intravenous injection of 0.15 mg/kg ketanserin (K) and placebo (P, 10 ml saline). K caused a significant increase in the area under the plasma norepinephrine (NE) time curve (AUC) from 13,200 to 18,100 ng × 1 × min for 1 hour after the injection. The area under the plasma epinephrine (E) time curve (AUC) was also increased but to a lesser extent; it was significantly elevated from 54 to 68 ng × 1 × min for 1 minute after the injection. Dopamine (DA) and PRA did not show any significant response to ketanserin. Following the P injection, none of the four parameters showed any significant change. [ABSTRACT FROM AUTHOR]

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The present experiments were performed to study the effect of chronic extracellular volume expansion on the magnitude of tubulo-glomerular feedback responses in the rat kidney. Extracellular volume expansion was achieved by giving isotonic saline as drinking water and by injecting DOCA in a dose of 2.5 mg/kg · day. When Ringer perfusion rate through the loop of Henle was elevated in control rats (receiving only saline as drinking water) stop flow pressure (SFP) fell by an average of 0.47±0.81 mm Hg (mean±S.D.) and 7.93±2.85 mm Hg at the flow rate steps of 0-15 nl/min and 15-40 nl/min respectively. SN-GFR was reduced by a mean of 1.3±0.97 nl/min (0-15 nl/min) and 10.3±2.45 nl/min (15-40 nl/min). In DOCA treated rats the mean reductions of SFP were 0.98±0.9 mm Hg and 2.1±1.4 mm Hg and of SN-GFR 0.06±1.8 nl/min and 1.94±2.3 nl/min. Thus, significantly smaller changes of both SFP and SN-GFR were found in DOCA treated animals when flow rate was elevated from 15-40 nl/min. Net loop NaCl absorption rates did not significantly differ between control andDOCA rats. Renin activity of 5 pooled microdissected glomeruli was 15.6±17.1 ng/hr·0.1 ml in control and 2.94±2.6 ng/hr·0.1 ml in DOCA treated rats ( P<0.01). It is possible therefore that the reduced feedback reactivity in DOCA treated rats is related to the diminished juxtaglomerular renin activity. [ABSTRACT FROM AUTHOR]

To evaluate the renin-angiotensin-aldosterone system in relation to circulatory catecholamines, we determined renin activity, angiotensin II, aldosterone, adrenaline, and noradrenaline in plasma before and during a submaximal bicycle exercise test in 23 Type 1 (insulin-dependent) diabetic patients (aged 19-57 years, mean 37; duration of diabetes 2-32 years, mean 16), 17 with signs of cardiac autonomic neuropathy, and in 18 healthy non-diabetic subjects (aged 24-41 years, mean 29). At rest, Type 1 diabetic patients showed significantly lower aldosterone values than control subjects (0.14±0.02 nmol/l and 0.22±0.02 nmol/l; p<0.01) while renin activity (1.0±0.1 nmol·l·h and 0.9±0.1 nmol·l·h) and angiotensin II (14±1 nmol/l and 18±2 nmol/l) did not differ significantly between patients and control subjects. During exercise, increments (increase from the resting value to the value at 80% of maximal working capacity) in renin (1.5±0.4 nmol·l·h and 3.7±0.5 nmol·l ·h; p<0.001), angiotensin II (28±8 nmol/l and 60±8 nmol/l; p<0.01), aldosterone (0.16±0.04 nmol/l and 0.25±0.05 nmol/l; p<0.05), adrenaline (1.96±0.49 nmol/l and 2.92±0.51 nmol/l; ps<0.05), and noradrenaline (12.01±1.25 nmol/l and 18.74±1.45 nmol/l; p<0.01) were significantly lower in the patients than in control subjects. There was no difference in the renin-angiotensin-aldosterone response to exercise between patients with and without cardiac autonomic neuropathy but the impaired catecholamine reaction was confined to patients with cardiac autonomic neuropathy. In conclusion, Type 1 diabetic patients demonstrated low resting plasma aldosterone and reduced increments in renin activity, angiotensin II, aldosterone, and catecholamines during exercise. The low aldosterone values might be related to dysfunction of adrenal zona glomerulosa cells while it is unlikely that the reduced response to exercise of the renin-angiotensin-aldosterone system simply reflects sympathetic nerve failure. [ABSTRACT FROM AUTHOR]

Responses of canine saphenous veins to bradykinin and angiotensin and the effect of cyclosporine-A were investigated both in conscious dogs in vivo and on ring preparations from canine saphenous veins in vitro. In vivo local infusion of bradykinin into the saphenous vein elicited dose-dependent reduction in compliance, i. e., venoconstriction, whereas local infusion of angiotensin elicited dose-dependent venodilation, which was markedly enhanced during blockade of endogenous thromboxane A synthesis by dazoxiben (2.5 mg/kg i. v.). The venoconstrictor response to bradykinin was attenuated after oral administration of both the thiazide-like diuretic clopamide (0.5 mg/kg) or cyclosporine-A (30 mg/kg), and by concomitant local infusion of cyclosporine-A (1-10 μg/min). Systemic i. v. infusion of the renin inhibitor H-77 (0.1 mg/kg/h) reversed the inhibition of bradykinin by both clopamide and cyclosporine-A. In vitro bradykinin elicited relaxation at low (0.1-10 nmol/l) but constriction at higher concentrations. The venoconstrictor response to bradykinin was resistant to blockade of thromboxane A synthesis and only partially attenuated after selective blockade of cyclooxygenase or lipoxygenase. Concomitant blockade of both lipoxygenase and cyclooxygenase activity by nordihydroguaiaretic acid (NDGA 10-30 μmol/l) nearly abolished the contractile response thereby enhancing the relaxant component of the bradykinin effect. Angiotensin 11 also elicited biphasic responses of partially contracted venous rings. Concomitant blockade of both lipoxygenase and cyclooxygenase by NDGA (10 μmol/l) again attenuated the contractile component of the angiotensin effect thereby unmasking the venodilator activity which could be inhibited by the angiotensin II receptor blocker saralasin (0.01-1 μmol/l). Blockade of converting enzyme by enalaprilic acid, the active metabolite of the converting enzyme inhibitor enalapril, attenuated responses to angiotensin I but shifted the concentration-response curve to bradykinin to the left. Compared to angiotensin I or angiotensin II, angiotensinogen was about ten times less potent in relaxing venous rings, but its potency was enhanced by a factor 10 in the presence of the serine protease kallikrein. Neither in the absence nor in the presence of kallikrein did the renin inhibitor H-77 modify the venodilator responses to angiotensinogen in vitro. Furthermore, venous responses to both bradykinin and angiotensinogen were unchanged in rings incubated for 1 h with 1 μmol/l cyclosporine-A. It is suggested, that the venoconstrictor response to bradykinin is mediated through enhanced formation and/or release of both prostaglandins and leukotrienes and that the bradykinin effect is modulated by endogenous angiotensin. Furthermore, the present data suggest (1) that the canine saphenous vein possesses a local renin-angiotensin system with activatable angiotensin forming enzyme(s) and (2) that activation of circulating prorenin rather than of tissue renin contributes to the vascular effect of cyclosporine-A. [ABSTRACT FROM AUTHOR]

The article presents a study which evaluates the clinical utility of plasma renin activity using liquid chromatography tandem mass spectroscopy (LC-MS/MS) offline solid phase extraction. The study performed solid phase extraction of samples prepared in duplicate and incubated. The study found similar results of offline method for plasma rennin activity to the on-line method across concentration range and comparable analytical performance.

• Plasma ALD, PRA and angiotensin II are able to be quantified within five minutes per sample based on our newly LC-MRM/MS assay. • The method solves the problems that the three hormones cannot be quantified in clinical testing at the same time. • The assay shows good performance in method validation and has excellent correlation with the respective one. Accurate quantification of plasma aldosterone (ALD) and renin activity (PRA) is critical for the diagnosis of primary aldosteronism (PA). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is considered the "gold standard" method for the determination of ALD and PRA. The aim of this study is to develop a new LC-MRM/MS assay for quantifying plasma ALD, PRA, and angiotensin II (Ang II) simultaneously and validate its effectiveness. To be more specific, plasma samples were prepared by solid-phase extraction and separated in an ultra-performance reversed-phase column. MS detection was performed via a triple quadrupole mass spectrometer containing both positive and negative ion monitoring modes. The developed assay was then validated according to the standard guidelines and the influence of sample incubation on ALD and Ang II concentration was evaluated. In addition, the variation of endogenous Ang I was explored. The proposed LC-MRM/MS method was compared another LC-MS/MS method, which detects ALD, Ang I, and Ang II separately. Analytes were separated and quantified within 5 min. The assay was validated to be linear up to 5000 pg/ml for ALD and Ang II and 33.3 ng/ml/h for PRA. The lower limit of quantification (LLOQ) was 15 pg/ml, 15 pg/ml, and 0.1 ng/ml/h for ALD, Ang II, and PRA respectively. Specificity, precision, accuracy, and stability were tested to meet the requirements of the guidelines. Significant changes were not found in ALD and Ang II concentrations over the 3 h-incubation. In addition, it was demonstrated that the result of PRA was not strongly influenced by the endogenous Ang I. Comparison with another LC-MS/MS method was performed using the same apparatus and the proposed method was proved to be in good coincidence with the correlation coefficients ranging from 0.955 to 0.996. A sensitive and reliable method for simultaneous quantification of ALD, PRA, and Ang II has been developed and this study will significantly promote laboratory workflow efficiency and throughput. [ABSTRACT FROM AUTHOR]