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Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone.
Brown, JM, Williams, JS, Luther, JM, Garg, R, Garza, AE, Pojoga, LH, Ruan, DT, Williams, GH, Adler, GK, Vaidya, A
Hypertension (Dallas, Tex. : 1979). 2014;(2):273-80
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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 mg×1); 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.
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Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.
Anavekar, NS, McMurray, JJ, Velazquez, EJ, Solomon, SD, Kober, L, Rouleau, JL, White, HD, Nordlander, R, Maggioni, A, Dickstein, K, et al
The New England journal of medicine. 2004;(13):1285-95
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Abstract
BACKGROUND The presence of coexisting conditions has a substantial effect on the outcome of acute myocardial infarction. Renal failure is associated with one of the highest risks, but the influence of milder degrees of renal impairment is less well defined. METHODS As part of the Valsartan in Acute Myocardial Infarction Trial (VALIANT), we identified 14,527 patients with acute myocardial infarction complicated by clinical or radiologic signs of heart failure, left ventricular dysfunction, or both, and a documented serum creatinine measurement. Patients were randomly assigned to receive captopril, valsartan, or both. The glomerular filtration rate (GFR) was estimated by means of the four-component Modification of Diet in Renal Disease equation, and the patients were grouped according to their estimated GFR. We used a 70-candidate variable model to adjust and compare overall mortality and composite cardiovascular events among four GFR groups. RESULTS The distribution of estimated GFR was wide and normally shaped, with a mean (+/-SD) value of 70+/-21 ml per minute per 1.73 m2 of body-surface area. The prevalence of coexisting risk factors, prior cardiovascular disease, and a Killip class of more than I was greatest among patients with a reduced estimated GFR (less than 45.0 ml per minute per 1.73 m2), and the use of aspirin, beta-blockers, statins, or coronary-revascularization procedures was lowest in this group. The risk of death or the composite end point of death from cardiovascular causes, reinfarction, congestive heart failure, stroke, or resuscitation after cardiac arrest increased with declining estimated GFRs. Although the rate of renal events increased with declining estimated GFRs, the adverse outcomes were predominantly cardiovascular. Below 81.0 ml per minute per 1.73 m2, each reduction of the estimated GFR by 10 units was associated with a hazard ratio for death and nonfatal cardiovascular outcomes of 1.10 (95 percent confidence interval, 1.08 to 1.12), which was independent of the treatment assignment. CONCLUSIONS Even mild renal disease, as assessed by the estimated GFR, should be considered a major risk factor for cardiovascular complications after a myocardial infarction.
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Development of diabetes is retarded by ACE inhibition in hypertensive patients--a subanalysis of the Captopril Prevention Project (CAPPP).
Niklason, A, Hedner, T, Niskanen, L, Lanke, J, ,
Journal of hypertension. 2004;(3):645-52
Abstract
OBJECTIVE The Captopril Prevention Project (CAPPP) was designed as a prospective intervention trial comparing the effect of a treatment based on the angiotensin-converting enzyme (ACE) inhibitor captopril with that of a conventional diuretic and/or beta-blocker-based therapy, in 10,985 hypertensive patients. There was no difference in the primary cardiovascular morbidity and mortality endpoint. A lower incidence of diabetes mellitus during captopril treatment was observed in the whole CAPPP cohort that was non-diabetic at baseline (n = 10,413) as well as in such CAPPP patients that were previously untreated (n = 5033). METHODS AND RESULTS A multivariate analysis of variables associated with the risk of developing diabetes in CAPPP demonstrated that glucose, body mass index (BMI), haemoglobin (Hb), age, 'SBP x Untreated' (the interaction between systolic blood pressure at baseline and newly diagnosed hypertension), cholesterol and prior antihypertensive treatment came out as risk factors. Based on these factors, a risk score for development of diabetes was calculated for all non-diabetic patients, who were divided into tertiles. For each tertile of risk, captopril therapy was associated with a reduced risk of diabetes development compared with conventional diuretic and/or beta-blocker therapy. When the non-diabetic cohort was divided into two subcohorts; previously treated and previously untreated patients, it turned out that the risk factors for developing diabetes differed between these two subcohorts. Only glucose, BMI and Hb came out as risk factors in all analysed cohorts. CONCLUSION A captopril-based antihypertensive treatment regimen is associated with a lower risk of diabetes development, compared with conventional therapy based on diuretics and/or beta-blockers.
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Chronic kidney disease, cardiovascular risk, and response to angiotensin-converting enzyme inhibition after myocardial infarction: the Survival And Ventricular Enlargement (SAVE) study.
Tokmakova, MP, Skali, H, Kenchaiah, S, Braunwald, E, Rouleau, JL, Packer, M, Chertow, GM, Moyé, LA, Pfeffer, MA, Solomon, SD
Circulation. 2004;(24):3667-73
Abstract
BACKGROUND Persons with end-stage renal disease and those with lesser degrees of chronic kidney disease (CKD) have an increased risk of death after myocardial infarction (MI) that is not fully explained by associated comorbidities. Future cardiovascular event rates and the relative response to therapy in persons with mild to moderate CKD are not well characterized. METHODS AND RESULTS We calculated the estimated glomerular filtration rate (eGFR) using the 4-variable Modification of Diet in Renal Disease method in 2183 Survival And Ventricular Enlargement (SAVE) trial subjects. SAVE randomized post-MI subjects (3 to 16 days after MI) with left ventricular ejection fraction < or =40% and serum creatinine <2.5 mg/dL to captopril or placebo. Cox proportional hazards models were used to evaluate the relative hazard rates for death and cardiovascular events associated with reduced eGFR. Subjects with reduced eGFR were older and had more extensive comorbidities. The multivariable adjusted risk ratio for total mortality associated with reduced eGFR from 60 to 74, 45 to 59, and <45 mL x min(-1) x 1.73 m(-2) (compared with eGFR > or =75 mL x min(-1) x 1.73 m(-2)) was 1.11 (0.86 to 1.42), 1.24 (0.96 to 1.60) and 1.81 (1.32 to 2.48), respectively (P for trend =0.001). Similar adjusted trends were present for CV mortality (P=0.001), recurrent MI (P=0.017), and the combined CV mortality and morbidity outcome (P=0.002). The absolute benefit of captopril tended to be greater in subjects with CKD: 12.4 versus 5.5 CV events prevented per 100 subjects with (n=719) and without (n=1464) CKD, respectively. CONCLUSIONS CKD was associated with a heightened risk for all major CV events after MI, particularly among subjects with an estimated glomerular filtration rate <45 mL x min(-1) x 1.73 m(-2). Randomization to captopril resulted in a reduction of CV events irrespective of baseline kidney function.
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Effect of angiotensin II receptor blocker on plasma levels of TGF-beta 1 and interstitial fibrosis in hypertensive kidney transplant patients.
el-Agroudy, AE, Hassan, NA, Foda, MA, Ismail, AM, el-Sawy, EA, Mousa, O, Ghoneim, MA
American journal of nephrology. 2003;(5):300-6
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BACKGROUND/AIM: Transforming growth factor-beta1 (TGF-beta 1) is involved in the pathogenesis of chronic allograft nephropathy after kidney transplantation. The aim of the study was to evaluate the effect of the angiotensin receptor blocker losartan on TGF-beta 1 plasma levels and proteinuria in hypertensive transplant recipients. METHODS A total of 162 transplant recipients were included in the study. The patients were randomized into 3 groups: group 1 received losartan; group II received an angiotensin-converting enzyme inhibitor (captopril), and group III received a calcium channel blocker (amlodipine). All the parameters were recorded at the time of therapy initiation and at 1, 4 and 12 weeks and 12 months thereafter. Graft biopsy before the start and at the end of the study was done to evaluate histopathological progression. RESULTS Blood pressure was controlled in the 3 groups; however, the need for other antihypertensive agents was significant in groups I and II. Treatment with losartan significantly decreased the plasma level of TGF-beta1, 24-hour urinary protein and serum uric acid (p < 0.05). No significant changes were seen in the hemoglobin or serum potassium levels. The rate of histopathological progression was significantly lower in the losartan group. No patient was discharged from the study due to side effects. CONCLUSIONS After transplantation all drugs were able to control blood pressure with good safety and tolerability. The study demonstrates that ARB significantly decreases the plasma levels of TGF-beta1, proteinuria and uric acid. These results could play an important and decisive role in the treatment and prevention of chronic allograft nephropathy.
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[Study on effect of jiangya tongmai recipe on vascular activating substances in patients of hypertension with left ventricular hypertrophy].
Wang, S, Wang, SR, Zhao, YR
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2002;(4):274-6
Abstract
OBJECTIVE To study the effect of Jiangya Tongmai Recipe (JYTMR), a Chinese herbal medicine preparation for activating blood circulation to remove stasis, on vascular activating substances in treating patients of hypertension with left ventricular hypertrophy. METHODS The 37 patients with hypertension were randomly divided into two groups, the treated group (n = 21) and the control group (n = 16). They were treated with JYTMR and captopril respectively for 8 weeks. Left ventricular mass weight (LVMI), peak flow velocity of early diastole (Emax), peak flow velocity of atrial contraction (Amax), Emax/Amax, ejection fraction (EF), as well as levels of plasma endothelin (ET), calcitonin gene-related peptide (CGRP) and angiotensin II (Ang II) were measured before and after treatment and compared. RESULTS JYTMR could enhance the left ventricular dilation and contractile functions, lower the levels of plasma ET and Ang II and increase the level of plasma CGRP. CONCLUSION JYTMR shows good effect in improving left ventricular function and regulating vascular activating substances, it could prevent and treat hypertension and its complications for prolonged treatment via multiple paths and links.
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Captopril enhances transforming growth factor (TGF)-beta1 expression in peripheral blood mononuclear cells: a mechanism independent from angiotensin converting enzyme inhibition? A study in cyclosporine-treated kidney-transplanted patients.
Di Paolo, S, Schena, A, Stallone, G, Grandaliano, G, Soccio, M, Cerullo, G, Gesualdo, L, Paolo Schena, F
Transplantation. 2002;(12):1710-5
Abstract
BACKGROUND Angiotensin (Ang) II blockade has been shown to prevent the development of renal injury in immunologically mediated diseases, but the mechanism whereby it exerts its protective effect has not been clearly defined. Transforming growth factor (TGF)-beta1 is a multifunctional cytokine with a potent immunomodulatory activity that has the potential to counteract many of the pro-inflammatory effects apparently evoked by the activation of renin-angiotensin system (RAS) in immune cells. METHODS We set up an ex vivo and in vitro model to evaluate the effect of the angiotensin converting enzyme inhibitor (ACEi) captopril on the gene and protein expression of TGF-beta1 in human peripheral blood mononuclear cells (PBMC). RESULTS In 20 kidney transplant recipients chronically treated with cyclosporine (CsA), 1-month treatment with captopril increased TGF-beta mRNA by 120% and TGF-beta1 protein release by 140% upon stimulation of PBMC with phytohemagglutinin (PHA) and phorbol myristate acetate (PMA) ( P<0.01). PBMC from healthy controls, when exposed in vitro to 5 microM captopril, showed a significant increase of TGF-beta1 release, whereas the ACEi enalapril failed to modify the expression of the cytokine. Ang II (100 pM) strongly inhibited TGF-beta1 synthesis by PBMC, and such effect was completely abolished by the addition of 200 ng/mL CsA, as well as by 1 micrpM losartan. Thus, captopril enhances TGF-beta1 gene and protein expression by PBMC by way of a mechanism independent, at least in part, from ACE inhibition, while CsA abrogates the inhibition of TGF-beta1 expression induced by Ang II. CONCLUSION Collectively, these findings support the utility of combined treatment with captopril and CsA in the multitherapeutic management of organ transplant and, possibly, a strategy to decrease the dose of the calcineurin inhibitor in kidney-transplant recipients.
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Additional beneficial effects of canrenoate in patients with anterior myocardial infarction on ACE-inhibitor treatment. A pilot study.
Di Pasquale, P, Cannizzaro, S, Giubilato, A, Vitrano, MG, Scandurra, A, Giambanco, F, Saccone, G, Sarullo, FM, Paterna, S
Italian heart journal : official journal of the Italian Federation of Cardiology. 2001;(2):121-9
Abstract
BACKGROUND Recent evidence suggests that, via the mineralocorticoid receptors present in cardiovascular tissues, aldosterone exerts profibrotic effects, and that partial aldosterone escape occurs during ACE-inhibitor treatment. METHODS A double-blind, randomized study was performed in order to evaluate the feasibility, tolerability, and the effects of the administration of 25 mg/day of canrenoate plus captopril versus captopril alone to patients with anterior acute myocardial infarction (AMI) unsuitable for or not receiving thrombolytic treatment and to patients in whom such treatment resulted or did not result in reperfusion. One hundred eighty-seven patients with anterior AMI were included in the present study. In all cases serum creatinine concentrations and serum K concentrations were < 2.0 mg/dl and < 5.5 mmol/l respectively. The patients were randomized in two groups: the canrenoate group included 94 patients who received captopril and 25 mg i.v. of canrenoate (1 mg/hour for the first 72 hours and then orally 25 mg/day) whereas the placebo group (93 patients) received captopril and placebo. On admission and on days 10, 90 and 180 all patients underwent echocardiography in order to determine the end-systolic volume (ESV), the ejection fraction (EF), the end-diastolic diameter, the E/A ratio, the E deceleration time as well as the isovolumetric relaxation time (IVRT) and the E and A peak velocities. RESULTS Unreperfused patients did not show patency of the infarct-related artery whereas in reperfused patients this vessel was patent (7-10 days after AMI). The two groups were similar in age, sex, incidence of diabetes, smoking habits, hypertension, creatine kinase enzymatic peak, adjuvant therapy, baseline EF, ESV, and incidence of coronary artery bypass grafting/coronary angioplasty. Following 10 days of treatment (canrenoate group), only 9 patients presented with serum K and creatinine concentrations respectively > 5.5 mmol/l and > 2.0 mg/dl. Among those patients receiving canrenoate, the mitral E/A ratio was higher compared to the placebo group (p = 0.001) whereas the ESV was significantly reduced (p < 0.05). The deceleration time for reperfused patients receiving canrenoate was higher than that observed for reperfused patients in the placebo group. The intragroup EF was significantly increased (p = 0.042). Compared to the placebo group, the IVRT was significantly higher for unreperfused patients receiving canrenoate than in the placebo group (p = 0.001). Serum creatinine, blood urea and K levels as well as the incidence and extent of vessel disease were similar for both groups. No side effects were observed during the study period. CONCLUSIONS Our data suggest that the combination of captopril plus canrenoate is feasible for the initial treatment of patients presenting with AMI. Besides, compared to captopril alone it is more efficacious in improving the E/A ratio, the ESV, the EF, and the IVRT.
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[Effect of songling xuemaikang capsule combined with captopril on quality of life in primary hypertension patients].
Chen, WQ, Chen, FR
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2001;(9):660-2
Abstract
OBJECTIVE To compare the hypotensive effects of captopril and combined medication of Songling Xue-maikang Capsule (SXC) with captopril on quality of life (QOL) in treating primary hypertension patients. METHODS For 166 hypertension patients, a perspective randomized double blind study was performed with both sexes, aged 42-78 years, blood pressure (BP) ranged > or = 140/90 mmHg and < or = 200/110 mmHg. Patients were randomly divided into two groups: captopril group and combined medication group. Each patient should answer the QOL questionnaire independently before and after experiment. 60 age-matched normotensive subjects without chronic diseases served as control. RESULTS Both hypertension groups showed an improvement of BP and QOL after treatment, but the combined medication group had a higher score in sense of well being, physical symptom-signs, work performance and life satisfaction than the captopril group had. CONCLUSION Combined medication of captopril and SXC had better effect than captopril alone either in lowering BP or in improving QOL of primary hypertension patients.
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[Clinical study on therapeutic effects of treatment according to syndrome differentiation of traditional Chinese medicine combined with captopril on severe viral myocarditis complicated heart failure].
Kong, QF, Song, SZ, Xie, XY
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2001;(7):513-5
Abstract
OBJECTIVE To observe the therapeutic effect and mechanism of the treatment according to Syndrome Differentiation of TCM combined with captopril (CAP) on severe viral myocarditis (SVM) complicated heart failure (CHF). METHODS One hundred and nine patients of SVM complicated CHF were randomly divided into the treated group (n = 72) and the control group (n = 37), the former was treated with TCM combined with CAP, while the latter was treated with dexamethasone and interferon. The TCM prescriptions were made depending on types of diseases by Syndrome Differentiation, i.e. Heart-Spleen deficiency type, Qi-Yin deficiency type and Spleen-Kidney Yang deficiency type. The efficacy of treatment was evaluated by the criteria including NYHA classification, myocardial enzymology, electrocardiogram, cardiac function and motorial toleration measured before and after treatment. RESULTS The therapeutic effect of the treated group according to NYHA classification was obviously better than that of the control group; the creatine phosphokinase isoenzyme (CPK-MB), aspartate transaminase (AST), lactate dehydrogenase (LDH) content lowered in both groups, but more significantly lowered in the treated group than in the control group (P < 0.05, P < 0.01); the improvement of S-T segment of ECG in the treated group was better than that in the control (P < 0.01); also some parameters of heart function and motorial toleration were bettered in the treated group more significantly (P < 0.01). CONCLUSION TCM treatment according to Syndrome Differentiation combined with CAP in treating SVM complicated CHF could elevate the clinical efficacy.