Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin (RAS) and the alpha1 sympathetic nervous system (SNS) interact at different levels in cardiovascular regulation. Concurrent use of angiotensin-converting enzyme (ACE) inhibitors and alpha1 receptor antagonists result in a synergistic antihypertensive action and is of wide utility in cardiovascular therapy. We examined the impact of concurrent inhibition of RAS (captopril or losartan) and the SNS (prazosin) before and after acute nitric oxide (NO) synthase inhibition with L-nitro-L-arginine methyl ester (L-NAME) on renal cortical perfusion (RCF) and blood pressure (MAP) in healthy and acute ischemic renal failure (ARF) rats (n = 6). Captopril or losartan reduced MAP and increased RCF more in healthy (p < 0.001) and ARF rats (p < 0.02). Prazosin alone reduced both MAP and RCF (p < 0.001). The combination of prazosin with captopril or losartan caused an additive fall in MAP, and mitigated the fall in RCF. Captopril + prazosin caused a profound fall in RCF following L-NAME, in healthy but not ARF rats (p < 0.001). Acetylcholine (Ach), a vasodilator which stimulates endogenous NO production caused a profound paradoxical fall in RCF in ARF, but not in healthy rats (p < 0.001 ANOVA). These results indicate a significant interaction between angiotensin II and phenylephrine in renal vasomotion. It establishes that endogenous NO homeostatically opposes angiotensin II-alpha1-mediated renal vasoconstriction, and that the vasodilator role of NO is diminished in ARF. The paradoxical fall in RCF induced by Ach in ARF is speculated to result, at least in part, from the formation of peroxynitrite (ONOO-), which acts as a renal vasoconstrictor, following the combination of ischemia-generated super oxide anion (O-2), with endothelial NO released by Ach.
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PMID:Interactions of the renin-angiotensin system and alpha-1 adrenoceptors on renal hemodynamics in healthy and acute renal failure rats: the role of nitric oxide. 1180 63

The physiological role of adrenomedullin (ADM) in volume and pressure homeostasis remains unclear. Accordingly, we assessed possible modulatory actions of ADM infusions on the neurohumoral response to acute volume loading with dextran in normal conscious sheep. Dextran (15 ml/kg), given with concurrent ADM (5.5 pmol/kg per min--raising plasma ADM from below detection to approximately 10 pmol/l) or vehicle control infusions, induced matched significant (P<0.001 by ANOVA) falls in hematocrit (27-30%) during both ADM and control and similar increases in right atrial pressure (approximately 10 mmHg). Compared with control, both systemic (P=0.033) and pulmonary (P=0.005) arterial pressure and peripheral resistance (P=0.004) were reduced during ADM but were raised post-infusion. The dextran-induced increase in cardiac output was augmented by ADM (P=0.048). Dextran-induced increases in plasma atrial natriuretic peptide (ANP; P=0.008), brain natriuretic peptide (BNP; P=NS) and cyclic guanosine monophosphate (cGMP; P=0.003) were augmented post-ADM infusions. The dextran-induced fall in plasma renin activity (PRA) was attenuated by ADM (P=0.039) whereas plasma aldosterone levels were unaltered. ADM augmented the increase in urinary volume during the second 2-h clearance period post-dextran. Our data indicate that ADM modifies the hemodynamic and hormonal response to an acute volume challenge, enhances natriuretic peptide secretion and reduces systemic vascular resistance. These results provide further evidence that ADM plays a physiological role in volume and pressure homeostasis.
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PMID:Adrenomedullin modulates the neurohumoral response to acute volume loading in normal conscious sheep. 1192 91

Type II diabetic patients with albuminuria are at high risk for cardiovascular complications; the intense antihypertensive treatment required often involves using drug combinations. The aim of the present study was to compare the effect of two different, renin-angiotensin blocking combinations, on blood pressure (BP), albuminuria and glycemic control. Its design was prospective, randomised, controlled, of parallel branches, and performed in one Endocrinology Department, in Spain. 77 type-II diabetic patients, with stable albuminuria (30-1,000 mg/day) were included. After a pre-inclusion time of 2 weeks, patients were randomised to verapamil SR/trandolapril 180/2 (VT) or losartan/hydrochlorothiazide (LH) 20/12.5 mg/day. Duration of treatment was 1 year. The evaluated parameters were changes in blood pressure, urinary albumin excretion for 24 hours, glycated hemoglobin and plasmatic urea. Overall BP significantly decreased from 161.6 +/- 18.7/83.6 +/- 10.2 mmHg to 137.2 +/- 15.7/70.9 +/- 8.3 mmHg (p < 0.0005). Values, by treatment, were: For VT, 164.3 +/- 18.5/87.2 +/- 10.7 mmHg at baseline and 135.0 +/- 15.1/71.3 +/- 8.4 mmHg at conclusion. For LH, 158.8 +/- 17.4/80.1 +/- 8.4 mmHg at baseline and 139.3 +/- 16.1/70.5 +/- 8.2 mmHg at conclusion. Albuminuria significantly decreased from 308.2 +/- 544.7 mg/day to 198.0 +/- 285.3 mg/day. Both parameters showed no significant difference between treatments. Glycated hemoglobin decreased from 7.59 +/- 1.3% to 7.14 +/- 1.2% in the VT group, and from 7.96 +/- 1.29% to 7.84 +/- 1.62% in the LH group (ANOVA, p = 0.022). Changes adjusted from baseline values showed a trend to the difference between both treatments (p = 0.092). Plasmatic urea increased from 39.8 +/- 12.7 to 40.5 +/- 11.1 mg/dL in the TV group and from 43.4 +/- 12.0 mg/dL to 52.4 +/- 19.4 mg/dL in the LH group (ANOVA, p = 0.028). In conclusion, both treatments reduce blood pressure and albuminuria in a similar way in type II diabetic patients. The verapamil/trandolapril combination contributes to a better carbohydrate metabolism than losartan/hydroclorothiazide.
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PMID:[Effect of antihypertensive combinations on arterial pressure, albuminuria, and glycemic control in patients with type II diabetic nephropathy: a randomized study]. 1208 18

The Dex/CRH test is one of the most reliable neuroendocrine function tests for hypothalamic-pituitary-adrenocortical (HPA) system dysregulation in depression. Persistent overdrive of HPA system activity after successful antidepressant treatment predicts an enhanced risk for relapse of a depressive episode. As the renin-angiotensin system has been shown to play a role in HPA system activity, we investigated the impact of the angiotensin converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism, which determines ACE plasma concentrations, on HPA system dysregulation. We performed repeated combined Dex/CRH tests in 115 patients suffering from major depression. Dex/CRH test results were related to the I/D polymorphism within the ACE gene, which was assessed by PCR. Genotype frequencies were comparable to those in the general population (I/I 16.8%, I/D 59.3%, D/D 23.9%). D/D genotypes showed a higher cortisol stimulation during the first Dex/CRH test after admission than homozygous I-allele carriers (repeated measurement ANOVA: P=0.034). Cortisol area under the curve values were highest in those with the D/D genotype (mean+/-SEM [nmol/l*75 min]: 12700+/-2220), intermediate in those with the I/D genotype (9570+/-1000), and lowest in those with the I/I genotype (5160+/-1000; ANOVA: P=0.04). After successful antidepressive treatment and attenuation of HPA system overdrive these differences were no more detectable. The HPA axis stimulating properties of higher ACE and consecutively higher AT-II and/or lower substance P concentrations may be crucial factors for the HPA system hyperactivity during major depressive episodes.
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PMID:Hypothalamic-pituitary-adrenocortical axis dysregulation in patients with major depression is influenced by the insertion/deletion polymorphism in the angiotensin I-converting enzyme gene. 1214 30

Renin-angiotensin system reactivity and the constitutive capacity of the renal tubule to reabsorb sodium play a role in the individual response to diuretic therapy; therefore we evaluated the blood pressure (BP) response to hydrochlorothiazide in 87 never-treated individuals with mild essential hypertension, according to ACE gene I/D and alpha-adducin Gly460Trp polymorphism. These genotypes where chosen because previous data showed their interaction in determining the BP response to salt probably was the result of their involvement in the activation of the renin-angiotensin system (ACE) and in the constitutive capacity of the kidney to reabsorb sodium (alpha-adducin) (treatment for 2 months). BP was measured after 3 run-in visits and after the first and second months of treatment by means of a standardized procedure. Data were analyzed by ANOVA, t test, and multivariate ANOVA for repeated measures (covarying for gender, age, and body mass index). Although basal mean BP (MBP) was similar in the different ACE and alpha-adducin genotypes, patients carrying at least one I allele of ACE and one 460Trp allele of alpha-adducin had the largest MBP decrease with treatment (12.7+/-1.9 mm Hg), the effect of the combination of genotypes being additive but not epistatic. These patients had an odds ratio of 15.75 of being a responder to hydrochlorothiazide compared with patients with Gly460Gly+DD, with the least MBP decrease (3.4+/-1.7 mm Hg). Alpha-adducin and ACE I/D polymorphism may be useful to predict the interindividual degree of response to hydrochlorothiazide; the analysis of the combination of the 2 genotypes increases the accuracy of the prediction of response to the drug.
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PMID:ACE and alpha-adducin polymorphism as markers of individual response to diuretic therapy. 1262 34

Limited information exists on the relations between heart rate variability, hypertension, lifestyle factors and renin-angiotensin-aldosterone system. A total of 191 newly diagnosed yet untreated hypertensive men and women, 35-54 years of age, were compared with an age- and gender-stratified random population sample of 105 normotensive men and women to find out independent determinants of heart rate variability. Heart rate variability was computed from 5-min ECG time series using the standard deviation of normal-to-normal RR intervals (SDNN), the square root of the mean of squared differences between adjacent normal RR intervals (RMSSD) and the fast Fourier transform spectral analysis. All absolute measures of heart rate variability were reduced in hypertension (P<0.001 for each, ANOVA). In multivariate regression analyses, reduced heart rate variability was independently associated with higher heart rate (P<0.001 for all absolute measures of heart rate variability), higher age (P=0.001 for SDNN, total and LF powers; P<0.001 for RMSSD and HF power) and higher mean arterial pressure (P<0.05 for total power, P<0.01 for the other absolute measures) but not with sodium and alcohol intakes, body mass index and smoking. Increased plasma renin activity (PRA) was an independent attributor of reduced HF power (P<0.05) and reduced RMSSD (P<0.01). Increased blood pressure and heart rate are associated with decreased heart rate variability without any direct effects on heart rate variability of lifestyle factors. High PRA is an independent determinant of diminished modulation of vagal activity.
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PMID:Reduced heart rate variability in hypertension: associations with lifestyle factors and plasma renin activity. 1262 7

To test the hypothesis that normal volume expansion during pregnancy is impaired during chronic renal failure, we evaluated the effects of 5/6 nephrectomy (Nx) in Sprague-Dawley rats. Partial Nx was produced by ligation of 2/3 renal arteries and contralateral Nx. Control rats had a sham operation. Four weeks later, rats were assigned to nonpregnant (n=6/each) or pregnant groups (n=11 to 12/each). At day 21, blood pressure, plasma volume, renal function, hormonal levels, and reproductive outcome were determined. Statistical analysis was performed by ANOVA, and values were expressed as mean+/-SEM. Rats with 5/6 Nx had proteinuria and lower creatinine clearance; pregnancy did not affect these parameters. Blood pressure increased in 5/6 Nx rats and was reduced by pregnancy. Both pregnant groups had lower hematocrit and higher plasma volume values (nonpregnant control, 13.4+/-0.2; nonpregnant 5/6 Nx, 14.4+/-0.2; pregnant control, 19.1+/-0.7, pregnant 5/6 Nx, 19+/-0.9 mL, P<0.001). Pregnancy increased plasma renin activity only in control rats (nonpregnant control, 2.0+/-0.7; nonpregnant 5/6 Nx, 1.6+/-1.1; pregnant control, 36.1+/-7.9, pregnant 5/6 Nx, 6.1+/-1.8 ng AI/mL per hour, P<0.001). Serum aldosterone levels were unaffected by 5/6 Nx and were higher in pregnant than in nonpregnant rats. Urinary kallikrein activity was reduced by 5/6 Nx and not changed by pregnancy (nonpregnant control, 1499+/-237; nonpregnant 5/6 Nx, 346+/-90; pregnant control, 1595+/-180, pregnant 5/6 Nx, 374+/-95 nmol/16 hours, P<0.001). No significant differences in fetal and placental weights were observed between control and 5/6 Nx rats. Present data indicate that 5/6 Nx pregnant rats were able to normally expand plasma volume despite lower renin and kallikrein levels.
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PMID:Pregnant rats with 5/6 nephrectomy have normal volume expansion despite lower renin and kallikrein. 1290 Apr 34

We sought to determine whether genes of the renin-angiotensin-aldosterone system can predict the nonmodulating intermediate phenotype in essential hypertension. Aldosterone responses to angiotensin II were assessed in 298 subjects with hypertension. Subjects were genotyped at the angiotensinogen M235T, angiotensin-converting enzyme I/D, aldosterone synthase C-344 T, renin, angiotensin II type 1 receptor, and adducin loci. The data were analyzed by Student t test, ANOVA, stepwise linear regression and general linear model or GENMOD regression techniques, and chi2 analysis odds ratios (ORs). Aldosterone response varied by genotype for angiotensin and aldosterone synthase but not for the other loci. The combination of angiotensinogen 235 TT and angiotensin-converting enzyme DD showed further reduction (P=0.0377) when compared with angiotensinogen 235 TT alone, an example of genetic epistasis. When the subject was required also to possess the CYP11B2 -344 TT genotype, there was a further substantial reduction. Of these 3 loci, only angiotensinogen 235 TT significantly increased the OR of predicting the nonmodulating hypertensive phenotype (OR, 2.00; 95% confidence interval, 1.152 to 3.51). However, when angiotensin-converting enzyme DD was combined with angiotensinogen 235 TT, the OR nearly doubled to 3.74, with a further increase to 5.36-fold when the subject possessed all 3 genotypes. Thus, the angiotensinogen, angiotensin-converting enzyme, and aldosterone synthase genotypes identified individuals with the nonmodulating phenotype with an increasing degree of fidelity. For this subclass of essential hypertension, it is likely that genotyping can be substituted for complex phenotyping for therapeutic and preventive decision making.
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PMID:Genetic determinants of nonmodulating hypertension. 1453 Feb 92

Mitochondrial dysfunction subsequent to increased oxidative stress and alterations in energy metabolism is considered to play a role in the development of cardiac hypertrophy and its progression to failure, although the sequence of events remains to be elucidated. This study aimed at characterizing the impact of hypertrophy development on the activity and expression of mitochondrial NADP+-isocitrate dehydrogenase (mNADP+-ICDH), a metabolic enzyme that controls redox and energy status. We expanded on our previous finding of its inactivation through posttranslational modification by the lipid peroxidation product 4-hydroxynonenal (HNE) in 7-wk-old spontaneously hypertensive rat (SHR) hearts before hypertrophy development (Benderdour et al. J Biol Chem 278: 45154-45159, 2003). In this study, we used 7-, 15-, and 30-wk-old SHR and Sprague-Dawley (SD) rats with abdominal aortic coarctation. Compared with age-matched control Wistar-Kyoto (WKY) rats, SHR hearts showed a significant 25% decrease of mNADP+-ICDH activity, which preceded in time 1) the decline in its protein and mRNA expression levels (between 10% and 35%) and 2) the increase in hypertrophy markers. The chronic and persistent loss of mNADP+-ICDH activity in SHR was associated with enhanced tissue accumulation of HNE-mNADP+-ICDH and total HNE-protein adducts at all ages and contrasted with the profile of changes in the activity of other mitochondrial enzymes involved in antioxidant or energy metabolism. Two-way ANOVA of the data also revealed a significant effect of age on most parameters measured in SHR and WKY hearts. The mNADP+-ICDH activity, protein, and mRNA expression were reduced between 25% and 35% in coarctated SD rats and were normalized by treatment of SHR or coarctated SD rats with renin-angiotensin system inhibitors, which prevented or attenuated hypertrophy. Altogether, our data show that cardiac mNADP+-ICDH activity and expression are differentially and sequentially affected in hypertrophy development and, to a lesser extent, with aging. Decreased cardiac mNADP+-ICDH activity, which is attributed at least in part to HNE adduct formation, appears to be a relevant early and persistent marker of mitochondrial oxidative stress-related alterations in hypertrophy development. Potentially, this could also contribute to the aetiology of cardiomyopathy.
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PMID:Decreased cardiac mitochondrial NADP+-isocitrate dehydrogenase activity and expression: a marker of oxidative stress in hypertrophy development. 1527 67

Angiotensin II stimulates the expression of tissue factor (TF) and plasminogen activator inhibitor type-1 (PAI-1), and AT1 receptor blockade (ARB) reduces PAI-1 and TF activities in experimental studies. We investigated the effects of ARBs on TF activity, tissue plasminogen activator (tPA), PAI-1 antigen levels, plasma renin activity (PRA) and aldosterone levels in hypertensive patients. Placebo, losartan 100mg, irbesartan 300 mg, and candesartan 16 mg daily were administered to 122 patients for 2 months. Compared with placebo, ARBs significantly reduced TF activity (P <0.001 by ANOVA), and candesartan was the most potent. Compared with placebo or losartan, irbesartan and candesartan significantly lowered plasma levels of PAI-1 antigen (P <0.001 by ANOVA) with no differences between the two. Compared with placebo, all ARBs lowered plasma levels of aldosterone (P=0.012 by ANOVA) and increased PRA (P=0.005 by ANOVA). There were significant correlations between the degree of change in TF activity and PAI-1 antigen levels (r=0.458, P <0.0001) and between the change in TF activity and PRA (r=-0.296, P=0.006), but not with the magnitude of reduction in blood pressure following ARB therapy. ARBs significantly reduced TF activity, PAI-1 antigen levels, and aldosterone levels in hypertensive patients. The clinical significance of the varying potency of some ARBs needs to be further investigated.
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PMID:Angiotensin II type 1 receptor blockers reduce tissue factor activity and plasminogen activator inhibitor type-1 antigen in hypertensive patients: a randomized, double-blind, placebo-controlled study. 1548 78


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