Use of spironolactone and indapamide in the treatment of low-renin arterial hypertension

AIM: To compare efficacy of use of the blocker of aldosteron receptors spironolactone and diuretic indapamide in low-renin arterial hypertension (AH), their action on blood pressure, serum concentrations of sodium, potassium, creatinine, plasmic renin activity (PRA), plasmic aldosteron concentration (PAC). MATERIAL AND METHODS: The study included 31 females aged 40-60 years with hardly correctable AH and high PAC to (PRA) ratio. Biochemical parameters were measured before 2-week treatment with indapamide (1.5 mg/day) and spironolactone (25 mg/day) and after the treatment. Between the courses there was a 2-week interval. RESULTS: In AH patients with high PAC/PRA spironolacton reduced AP more significantly (-15.5 / -8.2 mmHg) than indapamide (-10.9 / -5.9 mmHg). Indapamide lowered potassium serum levels by 0.28 mmol/l (p < 0.05), spironolacton raised it by 0.26 mmol/l (p = 0.05). Sodium concentration in the serum reduced only after treatment with spironolactone. Both drugs increased blood concentrations of creatinine, aldosteron, PRA, but spironolactone was more active. CONCLUSION: In treatment-resistant AH it is necessary to perform screening for detection of patients with low-renin hypertension. Such patients are effectively treated with spironolacton in low doses.     

Converting enzyme inhibition with captopril in patients with primary hyperaldosteronism

The humoral and hemodynamic effects of converting enzyme inhibition captopril are presented in two patients with primary hyperaldosteronism (PHA). In all, 20 patients with resistant hypertension were treated with the angiotensin converting enzyme inhibitor captopril. In 18 patients with essential or renovascular hypertension mean (+/- SEM) plasma renin activity (PRA) rose from 5.0 +/- 1.4 to 35.3 +/- 5.3 ng/ml/hr (P less than 0.01) and mean (+/- SEM) plasma aldosterone (PA) declined from 25.8 +/- 2.9 to 15.1 +/- 1.9 ng/ml (P less than 0.01) after captopril. In two patients with PHA the PRA was not stimulated by converting enzyme inhibition, although there was modest decline in PA and a temporary reduction in blood pressure. After surgical removal of aldosterone-producing adenomas, PRA responsed appropriately to captopril. These cases illustrate that a disease process can modify the response to a drug and demonstrate that, in patients with PHA, captopril does not stimulate PRA, induces only minor decrements in PA, and is relatively ineffective as an antihypertensive.     

The renin-angiotensin-aldosterone system and arterial hypertension in patients with rheumatoid arthritis

Renin-angiotensin-aldosterone++ system was investigated in 60 patients suffering from rheumatoid arthritis. Forty-four of them (group 1) had arterial hypertension (144 +/- 4/94 +/- 2 mm Hg), sixteen were free of hypertension (120 +/- 3/80 +/- 1 mm Hg). Twenty-nine control subjects comparable by AH standing and demographic parameters had essential hypertension stage IB-IIA by A. L. Myasnikov classification (141 +/- 3/89 +/- 1 mm Hg). A tendency to renin suppression was dominating in 72% of group 1 patients (plasma renin activity less than 1.0 ng/ml/h). In this group there appeared high concentrations of A II (14.2 +/- 3.1 pg/ml) and plasma aldosterone++ (238 +/- 94 ng/ml). Rheumatoid vasculitis manifested in 86% of patients. Control subjects exhibited plasma renin activity greater than 3.0 ng/ml/hin 48%, average A II concentration was similar to that of group 1 (12.4 +/- 2.7 ng/ml/h, p greater than 0.05), plasma aldosterone++ level was significantly lower (176 +/- 29 ng/ml, p less than 0.05). Correlations were established between A II concentration and ESR (r = 0.39, p less than 0.05), A II and rheumatoid factor titers (r = 0.40, p less than 0.05). These indicate that immunopathological reactions are responsible for shifts in renin-angiotensin-aldosteron system in hypertensive rheumatoid arthritis subjects.     

慢性肾功能衰竭患者血液透析前后血管活性因子的变化及临床意义

目的了解血液透析患者血浆一氧化氮（NO）、内皮素（ET）、心房利钠多肽（ANP）、肾素（PRA）及血管紧张素Ⅱ（ATⅡ）在透析前后的水平变化及临床意义。方法设正常对照、慢性肾功能不全失代偿期患者及慢性肾功能衰竭（CRF）患者各30例。用比色法测定NO,放射免疫法测定ANP、ET、PRA及ATⅡ水平。结果CRF组NO、ANP、ET、PRA、ATⅡ浓度明显高于对照组（P<0.05或P<0.01）;透析后NO和ANP显著下降（P<0.05和P<0.01）,PRA和ATⅡ浓度明显升高（P均<0.01）,ET透析前后无明显变化（P>0.05）。结论血液透析可使CRF患者血浆NO、ANP降低,PRA、ATⅡ升高,提示ET升高可增加ANP和PRA水平,ANP浓度可抑制ATⅡ的分泌。     

Metabolic effects of berlipril-5 in patients with non-insulin dependent diabetes mellitus and arterial hypertension

AIM: To study metabolic effects of berlipril-5 (enalapril) in patients with non-insulin-dependent diabetes mellitus (NIDDM) and arterial hypertension (AH). MATERIALS AND METHODS: 24 patients with NIDDM and AH were divided into three groups by the level of basal C-peptide: > 2 ng/ml (group 1), 2-4 ng/ml (group 2) and < 4 ng/ml (group 3). RESULTS: A correlation was found between the level of basal C-peptide and duration of AH (r = 0.7) and NIDDM (r = -0.47), between the level of triglycerides (TG) and glycolized hemoglobin Hb A1c (r = 0.48). Berlipril treatment reduced basal C-peptide level in groups 2 and 3 by 20.65 +/- 1.95% and elevated it in group 1 by 16.4 +/- 1.5%. Fasting glucose levels lowered by 9.2 +/- 1.95% indicating better sensitivity of the liver to insulin. Blood glucose levels 2 hours after meal fell by 8.3 +/- 0.95% (p < 0.05) and Hb A1c by 8.14 +/- 1.25% showing indirectly diminishing insulin-resistance at the level of peripheral tissues. TG and VLDLP significantly declined. CONCLUSION: Inhibitors of angiotensin converting enzyme (enalapril, in particular) produce a positive effect on carbohydrate and lipid metabolism in patients with NIDDM and AH.     

Cardiac troponins and left ventricular hypertrophy in hemodialysis patients

BACKGROUND: Cardiovascular diseases are the leading cause of death in hemodialysis patients. Left ventricular (LV) hypertrophy is an important predictor of cardiovascular morbidity and mortality in these patients. Cardiac troponins (cTnT and cTnI) are indicators of myocardial cell damage. AIM: The aim of this study was to determine prevalence of LV hypertrophy, prevalence of elevated serum cTnT and cTnI in hemodialysis patients, and identify the correlation between cardiac troponins and LV hypertrophy. METHODS: The study included 115 hemodialysis patients (71 men and 44 women), mean age 53.30 +/- 12.17 years, mean time on dialysis 4.51 +/- 4.01 years and average Kt/Vsp 1.17 +/- 0.23. Mean serum cTnT was 0.14 +/- 0.23 ng/ml, mean serum troponin I 0.20 +/- 0.48 ng/ml. Mean LV posterior wall thickness in diastole (LVPWd) was 11.44 +/- 2.09 mm, mean LV interventricular septal wall thickness in diastole (IVSd) 11.21 +/- 2.12 mm, mean LV end diastolic volume index (iLVEDV) 100.80 +/- 34.62 mL/m2 and mean LV mass index (LVMi) 143.85 +/- 41.21 g/m2. RESULTS: We found statistically significant positive correlations (p <0.05) between serum troponin T concentration, IVSd, LVPWd and iLVEDV. A highly significant positive correlation (p < 0.01) was found between serum troponin T and LVMi. One-year follow-up showed that patients with cardiac troponin T > 0.10 ng/ml and cardiac troponin I > 0.15 ng/ml had significantly lower (p < 0.01) survival rate than patients with troponin T < or = 0.10 ng/ml and troponin I < or = 0.15 ng/ml. CONCLUSION: A significant positive correlation exists between serum troponin T concentration and echocardiographic indicators of LV hypertrophy in hemodialysis patients. Patients with higher serum levels of cardiac troponins have lower survival rates during one year follow up.     

Abnormal Adrenal Responsiveness and Angiotensin II Dependency in High Renin Essential Hypertension

Adrenal responsiveness to angiotensin II (AII) and the diastolic blood pressure responses to saralasin were studied in 19 patients with high renin essential hypertension (HREH) on a 10-meq Na(+)/100 meq K(+) diet. The increment in plasma renin activity (PRA) between supine and upright positions was used as an estimate of the acute stimulation of the adrenal gland by endogenous AII; the normal increment in plasma aldosterone divided by the increment in PRA was >3.8. 7 of 19 had abnormal upright posture responses with significantly greater mean PRA increments (24+/-6 ng/ml per h) and significantly smaller plasma aldosterone increments 47 +/- 16 ng/dl) (P < 0.036) compared to the increments observed in HREH patients with normal adrenal responsiveness (PRA = 15 +/- 1 ng/ml per h; plasma aldosterone = 87 +/- 17 ng/dl). When AII was infused at doses of 0.1-3 ng/kg per min, only patients with normal posture responses had normal plasma aldosterone increments; plasma aldosterone levels failed to significantly increase even at the highest infusion rate in the patients with the abnormal upright posture responses. The AII competitive inhibitor, saralasin (0.3-30 mug/kg per min) was then infused to study the occurrence of angiotensinogenic hypertension in both HREH subgroups. The mean decline in diastolic blood pressure to saralasin in the subnormal adrenal responsive patients (-15 +/- 3 mm Hg) was significantly greater than in the normal adrenal responsive group (-3 +/- 2 mm Hg) (P < 0.02).It is concluded that patients with HREH are not a homogeneous population; approximately one-third have AII-dependent hypertension. In these patients, the mechanism responsible for the elevated renin and blood pressure could be a compensatory increase secondary to decreased adrenal responsiveness to AII. In the remainder, the high PRA levels have little, if any, causal role in the pathogenesis of the hypertension but could reflect a marker of other pathophysiologic processes.     

The role of major vessels remodeling in development of left ventricular hypertrophy in patients with a predialysis stage of chronic renal failure

AIM: To study correlation between development of left ventricular hypertrophy (LVH) and remodeling of major arteries at a predialysis stage of chronic renal failure (CRF). MATERIAL AND METHODS: A total of 95 non-diabetic patients (48 males-51% and 47 females-49%) with stage I-III CRF entered the trial. A mean age of the patients was 46.7 years (95% CI 43.7-49.8 years). Glomerular filtration rate calculated by Cockrott-Gault formula was 37.7 ml/min (33.9-41.4 ml/min), blood creatinine level--2.9 mg/dl (2.6-3.2 mg/dl). Arterial hypertension (AH) was registered in 96% patients, smoking--in 40%, cardiovascular hereditary burden--in 54%, hyperlipidemia--in 66%, overweight--in 60%, anemia--in 34%, hyperphosphatemia--in 45%. Echocardiography, ultrasonic dopplerography of the common carotid arteries (CCA) and common femoral artery (CFA) were performed in 83 and 37 patients, respectively. RESULTS: LVH (LV myocardium mass index > 134 g/m2 for males and > 110 g/m2 for females) was detected in 37.3% patients. Concentric remodeling was recorded in 31.3%, concentric myocardial hypertrophy--in 19.1% patients, excentric hypertrophy--in 18.1%. Development of LVH was linked with age, high systolic and pulse blood pressure, marked renal dysfunction, anemia, elevated ESR and hyperphosphatemia. The presence of L VH correlated with increased thickness of intima-media complex (IMC) of CCA and CFA (r = 0.65, p < 0.01 and r = 0.51, p < 0.05, respectively). There was correlation between thickness of LV posterior wall and impairment of CCA elasticity (r = -0.42, p < 0.05). CONCLUSION: Patients with initial and moderate disorders of renal function frequently have LVH related to conventional and "renal" risk factors. A LV mass increase and structural-functional changes of major vessels strongly correlate.     

Risk of chronic renal failure in patients with non-insulin dependent diabetes mellitus with diabetic nephropathy and the stage of permanent proteinuria and arterial hypertension: role of clinical factors

AIM: To reveal prognostic factors which determine the risk of development of chronic renal failure (CRF) in patients with diabetes mellitus (DM) type II associated with diabetic nephropathy (DN) at the stage of continuous proteinuria in combination with arterial hypertension (AH). MATERIAL AND METHODS: A total of 60 AH patients suffering from type II DM with permanent proteinuria were examined. Chronic renal failure was registered in 21 patients. RESULTS: Among CRF patients, more frequent were males, high proteinuria and nephrotic syndrome, IHD, macroangiopathy of the lower limbs, VLDLP. CONCLUSION: Independent predictors of CRF in diabetes mellitus type II with AH and proteinuria were male gender, overweight, faster development of stable proteinuria from the time of diabetes diagnosis.     

Pathophysiologic and pharmacokinetic determinants of the antihypertensive response to propranolol.

The tendency for patients with essential hypertension to differ markedly in antihypertensive response to propranolol could arise from pathophysiologic or pharmacokinetic differences between them. This possibility was investigated in 23 men with mild to moderately severe essential hypertension. At each of three propranolol doses, 40 mg, 80 mg, and 320 mg daily, approximately a 20-fold range in steady-state plasma propranolol concentrations was observed. Clinical response however was unrelated to plasma propranolol: oral dose ratio, since patients with higher plasma levels were less sensitive to the existing plasma drug concentration. When falls in blood pressure and plasma propranolol concentration were compared overall, a biphasic dose-response relationship was noted, with a first component at plasma propranolol concentrations of 3 to 30 ng/ml and a second at concentrations above 30 ng/ml. Only patients with increased sympathetic nervous system activity and high plasma renin activity (PRA) had substantial falls in pressure at propranolol levels of 3 to 30 ng/ml. Cardiac beta adrenergic receptor blockade, not suppression of PRA, seemed to be the antihypertensive mechanism. This relation of pretreatment sympathetic nervous activity and PRA to antihypertensive response existed only at lower plasma propranolol concentrations. With a propranolol dose of 320 mg daily, both plasma norepinephrine concentration and PRA were unrelated to the clinical response.     

Decreased Adrenal Responsiveness to Angiotensin II: A Defect Present in Spontaneously Hypertensive Rats: A POSSIBLE MODEL OF HUMAN ESSENTIAL HYPERTENSION

30% of patients with essential hypertension have a decreased adrenal response to angiotensin II (A II) on a low but not a high sodium intake. They also have a compensatory increase in the activity of the renin-angiotensin system best documented in a sodium-restricted state.To assess whether such a mechanism could account for the hypertension in genetically hypertensive rats, adrenal responsiveness to A II was determined in three groups of rats; spontaneously hypertensive rats (SHR), normotensive Wistar rats (WKY), and normotensive Sprague-Dawley rats (SDR). Animals in each group were placed on either a low or high sodium diet for 14 d with balance assessed by sodium excretion. The animals were then decapitated, blood was obtained for plasma renin activity (PRA), A II and aldosterone and adrenals isolated for the preparation of purified glomerulosa cells. The cells were incubated in Krebs-Ringer bicarbonate solution, containing bovine serum albumin, for 60 min in the absence and presence of increasing concentrations of A II.The PRA, basal aldosterone output, and adrenal sensitivity to A II were similar in the three groups of rats on the high sodium diet. On the low sodium diet the SHR had a significantly (P < 0.01) higher PRA (25+/-7 ng/ml per h) than either the WKY (12+/-2 ng/ml per h) or the SDR (7+/-1 ng/ml per h) and lower basal aldosterone output (68+/-17 vs. 154+/-43 and 197+/-21 ng/10(6) cells per h, respectively). In addition, the slope of the A II dose response curve was more shallow (P < 0.01) in the cells from the SHR than those obtained from the WKY and SDR.Thus, the SHR PRA and aldosterone responses to sodium restriction and aldosterone response to A II were similar to that previously described in a subgroup of patients with essential hypertension suggesting that the SHR will serve as a model for exploring the mechanism(s) responsible for the hypertension in these patients.     

A functional role for endogenous atrial natriuretic peptide in a canine model of early left ventricular dysfunction.

Asymptomatic or early left ventricular dysfunction in humans is characterized by increases in circulating atrial natriuretic peptide (ANP) without activation of the renin-angiotensin-aldosterone system (RAAS). We previously reported a canine model of early left ventricular dysfunction (ELVD) produced by rapid ventricular pacing and characterized by an identical neurohumoral profile and maintenance of the natriuretic response to volume expansion (VE). To test the hypothesis that elevated endogenous ANP suppresses the RAAS and maintains sodium excretion in ELVD, we assessed the effects of antagonism of ANP on cardiorenal and neurohumoral function in ELVD. Chronic ANP suppression was produced by bilateral atrial appendectomies before the production of ELVD by rapid ventricular pacing (ELVD-APPX, n = 5). This group was compared with a separate group with ELVD and intact atrial appendages (ELVD-INTACT, n = 8). ELVD-APPX was characterized by lower circulating ANP (50 +/- 11 vs. 158 +/- 37 pg/ml, P < 0.05), activation of plasma renin activity (PRA) (9.4 +/- 2.4 vs. 0.6 +/- 0.4 ng/ml per h, P < 0.05) and aldosterone (36.4 +/- 12.5 vs. 2.5 +/- 0.0 ng/dl, P < 0.05) when compared to ELVD-INTACT. In comparison to the ELVD-INTACT group, sodium excretion was decreased before and during VE in the ELVD-APPX group. Acute ANP antagonism was produced by administration of the particulate guanylate cyclase coupled natriuretic peptide receptor antagonist, HS-142-1, to seven conscious dogs with ELVD and intact atrial appendages (ELVD-INTACT). HS-142-1 decreased plasma concentrations and renal generation of the ANP second messenger, cGMP, and was associated with activation of PRA and sodium retention with enhanced tubular sodium reabsorption. These data support a significant role for elevated endogenous ANP in the maintenance of sodium excretion and regulation of the RAAS in experimental ELVD.     

Ednit effects on activity of renin-angiotensin-aldosterone system and renal function in hypertensive subjects with diabetes mellitus

AIM: To evaluate effects of enalapril (ednit) therapy on activity and reactivity of renin-angiotensin-aldosteron system (RAAS) and renal function. MATERIALS AND METHODS: Ednit was given in a dose 5-10 mg/day to 30 patients with mild or moderate arterial hypertension (AH) in combination with moderate or severe non-insulin-dependent diabetes mellitus (NIDDM) in compensation or subcompensation of carbohydrate metabolism. RESULTS: Ednit lowered blood pressure after 6-7 days of treatment. Normal blood pressure was achieved on the treatment week 4-6. Antihypertensive effect of ednit resulted from a significant reduction in a total peripheral vascular resistance under unchanged cardiac output. Adequate hypoglycemic and antihypertensive therapy normalized carbohydrate metabolism. Renal elimination of nitrogen did not change much. Glomerular filtration rate in patients with hyper- and hypofiltration returned to normal. Proteinuria reduced, microalbuminuria was not registered. RAAS activity normalized. CONCLUSION: Ednit has both high antihypertensive activity and marked renoprotective effect with minor influence on carbohydrate metabolism in AH patients with NIDDM.     

Inadequate RAAS suppression is associated with excessive left ventricular mass and systo-diastolic dysfunction

Background

Inadequate suppression of renin–angiotensin–aldosterone system (RAAS) following postural maneuvers may have detrimental effects on cardiac structure and function. In this study, we aimed to appraise the clinical significance of this phenomenon by assessing its relation with inappropriate ventricular mass (ILVM), an adverse phenotype of LV remodeling and dysfunction.

Methods

Both supine and upright plasma renin activity (PRA) and aldosterone concentrations (PAC) were measured in 115 young newly diagnosed hypertensive subjects. 24-h ambulatory blood pressure monitoring and echocardiographic evaluation including tissue Doppler imaging (TDI) were also performed. Patients were divided as follows: (1) normal PRA and PAC (N) (n = 63); (2) suppressible RAAS (SR) in supine position (n = 27); (3) not suppressible RAAS (NSR) (n = 25). ILVM was expressed as the observed/predicted LV mass ratio ×100 (%PLVM), while LV dysfunction (LVD) was identified by TDI-derived myocardial performance index (MPI).

Results

NSR showed a higher prevalence of ILVM than SR and N. As compared with N and SR, NSR patients had reduced indices of systolic and diastolic function. MPI of the LV as well as prevalence of LVD was also significantly higher in the NSR group. Regression models showed that lack of RAAS suppression was independently associated with ILVM and LVD.

Conclusions

Prevalence of ILVM and LVD is higher in patients without clinostatic RAAS suppression. Our findings encourage the assessment of RAAS deregulation to better estimate individual cardiovascular risk in patients with arterial hypertension.     

合并OSAS的难治性高血压患者醛固酮水平的研究

目的观察难治性高血压（RH）患者中阻塞性睡眠呼吸暂停综合征（OSAS）的患病率,及RH患者的血压和血浆醛固酮（ALD）、血浆肾素活性（PRA）的水平,OSAS对RH患者的影响及可能的机制。方法选择100例RH患者,均行多导睡眠监测,根据结果分为合并OSAS的RH组,和单纯RH组作为对照,分别测睡前（10：00PM）、夜间（02：00AM）和清晨（6：00AM）的血压及晨起（6：00AM）卧位血浆ALD、血浆PRA水平,ALD、PRA检测采用放射免疫分析法。结果抵抗型高血压患者中85％存在OSAS。与RH患者相比合并OSAS的RH患者血浆醛固酮增高（11．0ng／dl对5．5．g／dl,P〈0．05）,血浆肾素活性水平无差异[（0．20±0．12）μg/（L·h）对（0．27±0．14）μg/（L·h）,P〉0．05]。还观察到男性患者OSAS的患病率更高（89．O％对61．1％,P〈0．05）,OSAS的病情更重[中位呼吸暂停-低通气指数（AHI）分别为20．8次／h对10．8次／h,P〈0．01]且中位的ALD明显较高（12．0ng／dl对8．8ng／dl,P〈0．01）。结论RH患者中有较高的OSAS患病率,且合并OSAS的RH患者有较高的血浆醛固酮水平,可能是OSAS患者引起血压增高的机制。     

Angiotensin-converting enzyme labeled with [3H]captopril. Tissue localizations and changes in different models of hypertension in the rat.

In vitro autoradiography with [3H]captopril was used to localize and quantitate angiotensin-converting enzyme (ACE) in various tissues in two-kidney, one-clip (2K-1C) hypertension, one-kidney, one-clip (1K-1C) hypertension, desoxycorticosterone acetate (DOCA)-salt hypertension, and a normotensive control group. There were no significant differences in mean systolic blood pressure among the hypertensive groups. Plasma renin activity (PRA) was highest in the 2K-1C group (6.20 +/- 2.17 ng/ml per h), intermediate in the 1K-1C group (2.19 +/- 0.62 ng/ml per h) and control group (3.20 +/- 0.53 ng/ml per h), and lowest in the DOCA-salt group (0.07 +/- 0.06 ng/ml per h). In the lungs, aorta, mesenteric arteries, and adrenal medulla, ACE labeling was highest in the 2K-1C group, intermediate in the 1K-1C and control groups, and lowest in the DOCA-salt group. ACE levels in these tissues correlated positively with PRA. In the kidney, anterior pituitary, testis, and choroid plexus of the brain, ACE levels correlated negatively with PRA, with lowest ACE levels in the 2K-1C group and highest levels in the DOCA-salt group. In the epididymis, posterior pituitary, and other regions of the brain, ACE levels did not differ significantly among the groups.     

Soluble interleukin-2 receptors in the serum of patients with chronic renal failure

The levels of soluble form of the interleukin-2 receptor (sIL-2R) were evaluated in the peripheral blood of 29 patients with chronic renal failure (CRF) using enzyme-linked immunosorbent assay. All patients had undergone hemodialysis and the mean (+/- S.D.) BUN was before hemodialysis was 80.9 +/- 22.4 mg/100 ml. The mean level of sIL-2R was 1146 +/- 258 U/ml, which was significantly higher than the level (288 +/- 118 U/ml) in 12 individuals with a normal BUN level (p = 0.01). In patients with CRF, the elevated sIL-2R level was not influenced by hemodialysis, and not correlated with creatinine or beta 2-microglobulin levels. The kidneys may play an important role in the catabolism of serum sIL-2R. The elevated sIL-2R level may be related to compromised immunoregulation in CRF.     

Effect of the partial beta-agonist prenalterol on plasma renin activity in patients with left ventricular failure

Beta agonist therapy for heart failure has been disappointing, perhaps because of renin induced aldosteronism. To investigate this possibility we measured plasma renin activity (PRA) in 23 patients (17 male, 6 female, age 41-70) with New York Heart Association stage III heart failure due to ischaemic heart disease in a placebo controlled trial over one month. All patients received constant doses of digoxin and diuretics throughout the trial. Compliance was confirmed in all patients by digoxin and prenalterol assay. In a preliminary (dose titration) study of 9 patients there was a progressive, but non-significant rise of mean PRA from 14.8 to 17.6 and 27.7 ng/ml per h with doses of 20, 50 and 100 mg of prenalterol, respectively. After one month of treatment with prenalterol (n = 11), PRA was 12.8 +/- 2.4 (SEM) ng/ml per h which was not significantly different from the initial level of 14.4 +/- 2.3 ng/ml per h (n.s.). The placebo group (n = 12) results were 13.8 +/- 4.2 ng/ml per h at entry and 14.4 +/- 5.2 ng/ml per h at one month (n.s.). These results indicate that PRA is elevated by acute treatment with the partial beta agonist prenalterol but stimulation of renin secretion does not appear to occur with chronic therapy.     

Effects of iloprost, a prostacyclin analog derivative, on renal plasma flow, renal function, and renin-aldosterone system in humans

The effects of iloprost, a stable analog derivative of prostacyclin, on heart rate, blood pressure, renal plasma flow (RPF), glomerular filtration rate, filtration fraction, urine flow, fractional excretion of sodium (FENa), proximal fractional sodium reabsorption (PFRNa), fractional sodium resorption at the ascending limb of Henle's loop (HFRNa), plasma renin activity (PRA), and plasma aldosterone concentration (PA) were evaluated in patients with peripheral vascular disease and normal renal function. In 10 patients the drug was administered intravenously for 6 hours daily for 6 days at a rate of 1 ng/kg/min. In 7 patients iloprost was also administered at a dose of 2 ng/kg/min for the same time. There was no significant change in heart rate and blood pressure at both iloprost doses. At the dose of 1 ng/kg/min the drug had no effect on renal hemodynamics and function, PRA, and PA. At the dose of 2 ng/kg/min iloprost significantly increased RPF (p less than 0.025) and FENa (p less than 0.025) and significantly decreased HFRNa (p less than 0.025) without affecting glomerular filtration rate, filtration fraction, urine flow, PFRNa, PRA, and PA. No correlation was found between the increase in RPF and FENa (r = 0.01). We conclude that at a dose of 2 ng/kg/min, but not 1 ng/kg/min, iloprost has a natriuretic effect secondary to inhibition of sodium reabsorption at the ascending limb of the Henle's loop and not related to the renal hemodynamic effect.     

Mechanisms of Renin Secretion during Hemorrhage in the Dog

The importance of renal perfusion pressure (RPP), the sympathetic beta adrenergic nervous system and renal prostaglandins (PG) on renin release during a uniform 15-17% reduction in blood pressure by hemorrhage (HH) was studied systematically in anesthetized dogs. All groups of animals had similar decrements in systemic and renal hemodynamics with HH. In control dogs (n = 7), both plasma renin activity (PRA, 4.1-9.0 ng angiotensin I/ml per h, P < 0.05) and renin secretory rate (RSR, 26-228 ng/ml per h.min, P < 0.005) increased significantly with HH. This increase in renin release during HH was not abolished by any single maneuver alone including beta adrenergic blockade with d,l-propranolol (n = 6), renal PG inhibition with indomethacin (n = 7), or control of RPP (n = 6). However, when beta adrenergic blockade was combined with control of RPP (n = 7) during HH, neither PRA (1.9-2.7 ng/ml per h, NS) nor RSR (16-53 ng/ml per h.min, NS) increased significantly. Similarly, a combination of beta adrenergic blockade and PG inhibition (n = 6) also abolished the increase in PRA (1.5-1.4 ng/ml per h, NS) and RSR (14-55 ng/ml per h.min, NS) during HH despite significant decreases in sodium excretion. Finally, a combination of PG inhibition and RPP control was associated with significant increases in PRA and RSR during HH. These results support a multifactorial mechanism in renin release during HH and implicate both the beta adrenergic receptors, renal baroreceptors, and possibly the macula densa as constituting the primary pathways of renin release during HH of this magnitude. Because either constant RPP or PG inhibition blunted renin release during HH in the setting of beta adrenergic blockade, the present results strongly suggest that the renal baroreceptor, and probably the macula densa mechanism are PG mediated.