Acute changes in the renin-angiotensin-aldosterone system, catecholamines and prostaglandins during captopril in man

The acute hypotensive effect of 25 mg captopril was investigated in 26 hypertensive patients (11 essential and 15 with renal arterial disease). Intra-arterial blood pressure was recorded continuously and arterial blood was sampled for renin, angiotensin I and II, aldosterone, kininase II, catecholamines and prostaglandins. Captopril provoked increases in plasma renin activity, active and total plasma renin concentration and angiotensin I; decreases in plasma kininase II activity, angiotensin II, aldosterone, prostaglandins E2 and F2 alpha and no changes in plasma (nor)adrenaline, dopamine and inactive renin concentration.     

Raised aldosterone to renin ratio predicts antihypertensive efficacy of spironolactone: a prospective cohort follow-up study

AIMS: Aldosterone/renin ratio is an index for inappropriate aldosterone activity, and it is increasingly being used to screen for primary aldosteronism within the hypertensive population. It may also be a good index to help predict the response to spironolactone. To assess the blood pressure response to oral spironolactone in hypertensive patients with primary aldosteronism identified with raised aldosterone to renin ratio. METHODS: We conducted a prospective cohort study of hypertensive patients with raised aldosterone/renin ratio, who failed to suppress plasma aldosterone with salt loading and fludrocortisone suppression test. These patients were treated with spironolactone and were followed-up for a period of up to 3 years. RESULTS: We studied 28 (12 male) subjects with a mean age of 55 (s.d. 10) years who were followed up for a mean period of 12.9 (7) months. At baseline, the patients were taking a mean of 2.1 (1.2) antihypertensive drugs, but despite this 16/28 (57%) had diastolic BP >90 mmHg, 39% with systolic BP >160 mmHg. After commencing spironolactone, three patients complained of breast tenderness but continued treatment and one patient was intolerant of spironolactone and had to stop treatment. Of the remaining 27 patients, the mean number of antihypertensive drugs used dropped to spironolactone plus 0.7 (s.d. 0.9). All but one patient (96%) achieved a diastolic BP相似文献   

Long-term captopril in young and old patients with mild hypertension

The decrease in renal blood flow (RBF) observed in patients with hypertension can be increased with converting enzyme inhibition (CEI). It is unknown whether the decrease in RBF observed with age can also be increased with CEI. This study compared the short- and long-term effects of captopril monotherapy in young (less than 50 years) and old (greater than 65 years) hypertensive patients. Captopril effectively decreased blood pressure in both groups (diastolic blood pressure less than 90 mm Hg), with the young patients requiring a lower dose (.7 mg/kg) than the elderly patients (1.2 mg/kg). Creatinine and para-aminohippurate clearances were maintained in both groups, with a decrease in renal vascular resistance being observed in the younger patients. Serum aldosterone levels fell significantly after each dose of captopril at all phases of the study, with no change observed in plasma renin levels. Atrial natriuretic peptide (ANP) level was increased in the elderly patients receiving placebo (48.8 +/- 8 pg/mL) when compared with the young subjects (24 +/- 3.8 pg/mL). Captopril did not alter ANP levels in either group.     

Acute effects of combined vasodilation and beta-adrenoceptor blockade with prizidilol on renal function.

1 The effects of a single oral dose of 600 mg of prizidilol on renal function were studied 5 to 6 h after dosing in six normal subjects and eight patients with essential hypertension. 2 Mean arterial blood pressure was reduced to 92% of the control value in normal subjects and to 75% in hypertensive patients. Heart rate increased slightly. 3 In normal subjects, effective renal plasma flow was increased to 107% of control values while glomerular filtration rate (83%), filtration fraction (79%), sodium (84%) and potassium (50%) clearances were significantly decreased. 4 In hypertensive subjects, effective renal plasma flow was increased to 120% of control values, while glomerular filtration rate (67%), filtration fraction (57%), sodium (27%) and potassium (72%) clearances were significantly decreased. 5 Plasma noradrenaline increased significantly in normal subjects (150%) and in patients (173%). Plasma renin activity, aldosterone and epinephrine levels did not change consistently. 6 The results indicate that the acute effects of prizidilol on blood pressure and renal function are more marked in hypertensive than in normotensive subjects. Prizidilol increases renal plasma flow like hydralazine and depresses glomerular filtration rate and fractional sodium excretion like endralazine. In addition to the fall in arterial pressure, efferent vasodilation and/or a specific effect on the glomerular ultrafiltration coefficient Kf may account for the striking decrease in filtration fraction.     

Studies on catecholamines, renin and aldosterone following catapresan® (2-(2,6-dichlor-phenylamine)-2-imidazoline hydrochloride) in hypertensive patients

The effect of the antihypertensive compound 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (St 155, Catapresan®) on urinary catecholamines, plasma renin activity and urinary aldosterone was studied in patients with hypertensive diseases of different types. Catapresan induced marked lowering of blood pressure and bradycardia in all cases except phaeochromocytoma. The fall in blood pressure was closely related to a reduction in catecholamines, renin activity and aldosterone. These findings are of interest in relation to the antihypertensive effect of catapresan and also with respect to the possible role of the sympathetic nervous system for the regulation of the production of renin and aldosterone. Our studies indicate that reduced sympathetic activity with decreased production of catecholamines is at least one mode of action of catapresan. It seems possible that the reduced sympathetic activity is of importance for the diminished production of renin and aldosterone which occurs following catapresan.     

Effects of amlodipine on renal haemodynamics in mild to moderate hypertensive patients

Summary In this study the efficacy and safety of short-term amlodipine administration on renal haemodynamics were evaluated in mild to moderate hypertensive subjects. Our final goal was to evaluate whether the reduced blood pressure induced by treatment was associated with maintenance of renal function.After a run-in period with placebo, 30 hypertensive patients without cardiac or renal diseases were randomly allocated to a double-blind 4 weeks controlled study with amlodipine 10 mg once a day (15 patients) or placebo (15 patients).Renal haemodynamic measurements included effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) by radionuclide study using ¹³¹I-hippuran and ^99mTc, with methods described by Schlegel and Gates, respectively. In addition, effective renal blood flow [ERBF=ERPF/(1-Ht)], filtration fraction (FF=GFR/ERPF) ERPF) and renal vascular resistance (RVR=MBP×80/ERBF) were calculated. Plasma renin activity (PRA), serum aldosterone (ALD) and urinary excretion of sodium (NaU) were evaluated.At the end of amlodipine administration a significant decrease (P<0.001) in SBP, DBP and MBP from baseline values was observed. A significant decrease (P<0.01) in RVR and significant increases (P<0.05) in ERPF, ERBF and in NaU were also found, without relevant changes in GFR, FF, PRA and ALD.No significant variation in clinical and renal measurements was observed in the placebo group.No relevant side effects were observed in either group. In conclusion, amlodipine was effective in lowering blood pressure in mild to moderate hypertension and exerted favourable effects on renal haemodynamics and function.     

RESPONSE OF PLASMA RENIN-ANGIOTENSIN SYSTEM TO A SINGLE CAPTOPRIL ADMINISTRATION IN PATIENTS RECEIVING LONG-TERM TREATMENT WITH CAPTOPRIL

1. The responses of angiotensin II (AII), AIII, aldosterone and plasma renin activity (PRA) to a single dose of captopril were investigated in hypertensive patients receiving long-term (more than 1 year) captopril therapy (CT patients) and compared with those of non-treated hypertensive patients (NT patients). 2. Baseline levels of AII and aldosterone were significantly lower in CT patients than in NT patients. AIII tended to be lower and PRA was slightly higher in CT than in NT patients, but these differences were not significant. 3. A single administration of captopril (50 mg orally) significantly decreased plasma levels of AII, AIII and aldosterone as well as blood pressure in both CT and NT patients. 4. These results demonstrate that chronically repeated administration of captopril to hypertensive patients effectively reduces the daily blood pressure and concomitantly the plasma AII level to acceptable levels in patients with no experience of ACE inhibition.     

Combination therapy in hypertension

Summary The acute hypotensive effect of captopril 25 mg was investigated in 26 hypertensive patients (11 with essential and 15 with renal arterial disease). Intra-arterial blood pressure was recorded continuously and arterial blood was sampled for renin, angiotensin I and II, aldosterone, kininase II, catecholamines and prostaglandins. Captopril led to an increase in plasma renin activity, active and total plasma renin concentration and angiotensin I, a decrease in plasma kininase II activity, angiotensin II, aldosterone, prostaglandins E₂ and F_2* and no change in plasma (nor)adrenaline, dopamine and inactive renin concentration. The hypotensive effect of captopril was related to the changes in plasma angiotensin II level and inversely to the change in prostaglandin E₂; the correlation coefficients were low, respectively 0.61 and −0.44. It is likely that the acute hypotensive effect of captopril to some extent is related to changes in plasma angiotensin II and in prostaglandins E₂ and F_2*. There is no evidence for a role of the adrenergic systems in the hypotensive response.     

Renal and adrenal function following acute administration of urapidil in hypertensive patients with normal and impaired renal function

The effects of i.v. injection of urapidil (Ebrantil) (25 mg) on arterial blood pressure, renal function and renin-aldosterone system were studied in a group of patients with hypertension and normal renal function, in patients with hypertension and chronic renal failure and in normotensive controls. The pharmacokinetics of urapidil were evaluated simultaneously by measuring blood levels of the compound and its main metabolite. In the controls and in patients with hypertension, systolic and diastolic blood pressure were lowered few minutes after injection. Minimal blood pressure values were reached after 15-20 min. Hypotensive action was more pronounced in hypertensive patients as compared to controls. In contrast, increment in heart rate was greater in the controls. Despite the fall in blood pressure, renal plasma flow and glomerular filtration rate remained unchanged. Following the injection of urapidil, plasma renin activity increased with no change in plasma aldosterone levels. Plasma half-life of urapidil averaged 1.96 +/- 0.17 h in controls, 3.31 +/- 0.75 h in patients with hypertension and normal renal function and 2.52 +/- 0.46 h in patients with hypertension and chronic renal failure. Urapidil effectively lowers arterial blood pressure in patients with normal and impaired renal function with no deterioration in renal function.     

Effect of alacepril on renin-angiotensin-aldosterone system and kallikrein-kinin-prostaglandin system in experimental animals

The effects of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219), an orally active angiotensin converting enzyme (ACE) inhibitor, on humoral factors which participated in the blood pressure control were examined with various experimental animals. In conscious renal hypertensive dogs, alacepril (3 mg/kg p.o.) showed decreases in plasma ACE activity and plasma aldosterone concentration, and increases in plasma renin activity and plasma angiotensin I concentration accompanied by a significant reduction in blood pressure. In conscious normotensive dogs, alacepril (1 and 3 mg/kg p.o.) showed an increase in urinary excretion of bradykinin accompanied by increases in urinary water and sodium excretion. In spontaneously hypertensive rats, alacepril (30 and 100 mg/kg p.o.) showed increases in urinary excretion of bradykinin and 6-keto-prostaglandin Fl alpha, and a decrease in that of aldosterone accompanied by increased in excretion of water and sodium. These results indicate that the antihypertensive activity of alacepril is due to the suppression of renin-angiotensin-aldosterone system and the enhancement of kallikrein-kinin-prostaglandin system through the inhibition of ACE (kininase II) activity in vivo.     

HAEMODYNAMIC, RENAL AND HORMONAL RESPONSES TO ENALKIREN IN FOUR PATIENTS WITH POST-SURGICAL OLIGURIA

1. The haemodynamic and hormonal responses of four patients with acute post-surgical oliguria (urine output <0.5 mL/kg perh) were measured in response to the renin inhibitor enalkiren. Enalkiren was infused at 0.01 up to 0.1 mg/kg perh for up to 4h. 2. Enalkiren infusion was associated with a progressive fall in blood pressure, clinically significant in three of the four patients. Systemic vascular resistance fell in proportion to blood pressure fall. Cardiac output and pulse rate remained unchanged. Effective renal plasma flow rose in all four cases (236 ± 19 to 327± 38). There was no change in urine flow rate, or urinary sodium excretion. 3. Plasma renin activity (ng angiotensin I/mL perh) fell from 1.9 ± 0.5 to 0.02 ± 0.01 (P<0.04), plasma angiotensin II (pg/mL) fell from 104 ± 93 to 7.7 ± 1.5, and plasma aldosterone (ng/dL) fell from 32 ± 8 to 21 ± 9 (P= 0.03) at the highest infusion dose. 4. Enalkiren inhibited plasma renin activity with reduced plasma angiotensin II and aldosterone concentrations. This was associated with vasodilation, reduced blood pressure and maintained cardiac output. There was no beneficial effect on renal function in these patients with post-surgical oliguria.     

Studies with fenoldopam, a dopamine receptor DA1 agonist, in essential hypertension.

A series of studies were undertaken to assess the effect of oral fenoldopam, a specific DA1 dopamine receptor agonist on blood pressure and renal function in patients with mild essential hypertension. Six patients with essential hypertension were entered into a dose-ranging study and received either placebo, 25, 50 or 100 mg fenoldopam. A significant, dose-related reduction in diastolic blood pressure, and increase in heart rate was demonstrated (both P less than 0.05), maximal at 45 min to 1 h. Fenoldopam increased plasma renin activity. In a double-blind study, seven patients received a single dose of fenoldopam 100 mg or placebo. Fenoldopam produced a significant fall in systolic (P less than 0.05) and diastolic (P less than 0.01) blood pressure and renal vascular resistance (P less than 0.01). Urine flow rate (P less than 0.05), sodium excretion (P less than 0.01), plasma renin activity (P less than 0.05) and plasma aldosterone (P less than 0.05) increased. Five patients underwent measurement of the above parameters following a single dose of fenoldopam 100 mg with a repeat of these measurements after they had taken fenoldopam 100 mg four times daily for 1 month. The acute response of blood pressure to the single dose appeared unchanged but tachyphylaxis was evident in the responses of heart rate, plasma renin activity and plasma aldosterone.     

Effects of chlorthalidone, oxprenolol, and their combination in hypertensive blacks: a randomized double-blind crossover study

One hundred twenty black patients with mild to moderate essential hypertension participated in a double-blind placebo-controlled crossover study of the efficacy and tolerability of slow release oxprenolol versus chlorthalidone singly and in combination. Oxprenolol as monotherapy produced no effect on blood pressure as compared with placebo even after doubling the dose. Chlorthalidone as monotherapy produced a significant decrease in blood pressure (p less than 0.01). Combining oxprenolol with chlorthalidone yielded hypotensive effects in excess of those of either of the components given singly. Oxprenolol produced a significant decrease in plasma renin activity (PRA) whereas chlorthalidone produced a significant increase in PRA. These results indicate that a beta-blocking agent alone is ineffective in lowering blood pressure in hypertensive blacks, even when the dose is high. Oxprenolol may increase the hypotensive effect of chlorthalidone by counteracting the hypokalemic effect of the diuretic and by attenuating the diuretic-induced increase in plasma renin activity.     

Renin-angiotensin-aldosterone system

Summary There is increased activity of the renin, angiotensin, aldosterone (RAA) system in infancy and childhood. An inverse relationship between plasma renin, aldosterone and age has been demonstrated. In childhood hypertension due to renovascular disease or pyelonephritic scarring peripheral plasma renin is increased. Renal vein renin measurements in children with renal hypertension have proved valuable in predicting surgical curability of the underlying lesion. The upper limit of normal for the renal venous renin ratio in normotensive children without renal disease is 1.5. Pharmacological blockade of the RAA system has a place in diagnosis and treatment of hypertensive children. The plasma renin aldosterone profile is diagnostically useful in the investigation of salt-wasting disease and can easily distinguish between aldosterone biosynthetic defects and pseudohypoaldosteronism.Presented at the International Workshop on Perinatal and Pediatric Aspects of Clinical Pharmacology, Heidelberg, Federal Republic of Germany, 27–29 February 1980     

The effect of nifedipine GITS on renal function in hypertensive patients with renal insufficiency

Twelve hypertensive patients with moderately severe renal dysfunction were entered into a protocol to assess the blood pressure and renal effects of the sustained release calcium antagonist, nifedipine GITS (30-180 mg/d given once a day) administered for 5 weeks. Nifedipine GITS monotherapy effectively lowered blood pressure in 50% of the patients. Glomerular filtration rate and effective renal plasma flow were increased 18% and 20%, respectively. The filtration fraction and urinary protein excretion remained unchanged. Changes that were observed in renal function were independent of the blood pressure responses of the patients; there was no correlation between the systemic and renal effect of nifedipine GITS monotherapy. Patients who had a poor systemic blood pressure response exhibited an increase in glomerular filtration rate (+11%) but had a decrease in effective renal plasma flow (-6%); patients who achieved a goal blood pressure response showed increases in both glomerular filtration rate (+35%) and effective renal plasma flow (+40%). These results show that nifedipine GITS monotherapy has the potential to improve renal function abnormalities that are encountered in hypertensive patients with renal disease; the improvement in renal function may be independent of their effect on systemic blood pressure.     

Influence of chronic renal failure on captopril pharmacokinetics and clinical and biological effects in hypertensive patients.

The pharmacokinetic parameters of unchanged plasma captopril and the kinetics of the drug effects on plasma converting enzyme activity (PCEA), plasma renin activity (PRA), plasma aldosterone (PA) and mean blood pressure (MBP) were studied over 24 h after oral administration in three groups of hypertensive patients: with normal renal function (group 1, plasma creatinine less than 110 mumol/l, n = 10), with moderate chronic renal failure (group 2, 135 less than plasma creatinine less than 450 mumol/l, n = 10) and with severe chronic renal failure (group 3, plasma creatinine greater than 500 mumol/l, n = 10). Renal impairment had no effect on plasma captopril Cmax, CLtot and relative bioavailability (AUC). In contrast, captopril kel decreased while T1/2 increased progressively from group 1 to group 3. PCEA blockade (T1/2 and AUC) was increased significantly and proportionally to the degree of renal impairment. However, there were no differences between the three groups regarding captopril-induced modifications of PRA and PA. Although the maximal reduction in MBP was identical in the three groups, the overall antihypertensive effect (AUC) of captopril increased significantly and progressively from group 1 to group 3, especially in duration. There was no correlation between basal plasma creatinine values and unchanged captopril relative bioavailability (AUC) and between unchanged captopril relative bioavailability (AUC) and the drug effects (AUC) on PCEA, PRA, PA and MBP. However there was a correlation between basal plasma creatinine values and plasma captopril T1/2, PCEA blockade (AUC) and overall antihypertensive effect (AUC). The apparent discrepancy between the lack of effects of chronic renal failure on plasma unchanged captopril bioavailability and its potentiating effects on PCEA blockade and MBP reduction may be accounted for by the renal impairment-induced accumulation of captopril metabolites.     

Need for beta-blockade in hypertension reduced with long-term minoxidil.

Sequential changes in plasma renin activity and urinary aldosterone and noradrenaline were assessed in eight patients with severe hypertension after minoxidil had been added to their treatment. Doses of 2.5--27.5 (mean 12.5) mg/day reduced the mean blood pressure from 166/113 +/-6/2 mm Hg to 124/88+/-4/2 mm Hg in one week. Plasma renin activity and urinary aldosterone and noradrenaline increased twofold to threefold initially but returned to baseline values within two to three weeks and remained unchanged during a mean follow-up of 5.1 months. Beta-blocking drugs were then withdrawn slowly in six patients without adverse effects, though blood pressure and heart rate increased in three patients, who required minimal doses of beta-blockers. Plasma renin activity and urinary aldosterone and noradrenaline did not change significantly after beta-blockade had been stopped. We conclude that the need for beta-blockade is greatly reduced with long-term minoxidil treatment and that it may be unnecessary in some patients.     

Renal and hormonal effects of alpha1-adrenoceptor blockade by bunazosin in essential hypertension

Summary The renal and hormonal effects of the ₁-adrenoceptor blocker bunazosin were examined in 6 patients with essential hypertension. Oral bunazosin for 4 to 12 weeks significantly decreased mean blood pressure by 10%, increased effective renal blood flow and creatinine clearance by 34% and 37%, respectively, the plasma norepinephrine concentration was elevated by 60%, and the plasma atrial natriuretic peptide level was lowered by 22%. The plasma renin activity and aldosterone concentration were unchanged. Thus, a moderate reduction in blood pressure was produced by bunazosin treatment while maintaining renal perfusion.     

Hypotensive effect of SA446, an angiotensin converting enzyme inhibitor, in 2-kidney, 1-clip renal hypertensive and normotensive dogs

Hypotensive effects of SA446, an angiotensin converting enzyme (ACE) inhibitor, and effects on the renin-angiotensin system were evaluated in conscious normotensive and 2-kidney, 1-clip renal hypertensive dogs. SA446 (1 mg/kg, p.o.) remarkably inhibited the pressor response to angiotensin (Ang) I between 1 and 6 hr after the administration in normotensive dogs. SA446 significantly decreased blood pressure at 10 mg/kg, p.o., in normotensive dogs. During repeated administration of SA446 (100 mg/kg/day, p.o.) for 13 weeks, the blood pressure was lowered, and the pressor response to Ang I and plasma ACE activity were strongly inhibited. ACE activities in the aorta and kidney were also inhibited. Plasma renin activity and plasma Ang I concentration increased by repeated SA446 application, while plasma aldosterone concentration decreased. The hypotensive effect of SA446 (5 mg/kg, p.o.) was more potent in 2-kidney, 1-clip renal hypertensive dogs than in normotensive dogs. SA446 had longer inhibitory effects on the pressor response to Ang I and more potent hypotensive effects than captopril. The hypotension caused by SA446 appears to be associated mainly with an inhibition of ACE in plasma and also in the vascular wall.     

Blood pressure, plasma renin activity and calcium metabolism in hypertensive pregnancy: the effect of nifedipine

The effects of nifedipine on blood pressure, plasma renin activity and calcium metabolism were studied in nine hypertensive pregnant patients. Nifedipine (10 mg thrice daily per os) reduced blood pressure from 158/103 +/- 4/1 to 150/96 +/- 4/2 mmHg (mean +/- s.e.m.) during 4 to 5 days' treatment (p less than 0.05). The percentage change in diastolic blood pressure correlated negatively with the initial ambulatory (p less than 0.001) and rest (p less than 0.01) plasma renin activity and the initial daily urine calcium excretion (p less than 0.01). Calcium excretion in urine correlated positively with the initial ambulatory and rest plasma renin activity (p less than 0.01). The blood pressure reduction did not correlate with serum ionized, or total calcium, or the initial blood pressure. In six non-pregnant women, the rest plasma renin activity increased (p less than 0.05) after four days' administration of nifedipine. In the patients with hypertensive pregnancy, no changes in plasma renin activity were found during the treatment. The results indicated that the initial plasma renin activity, but neither the serum ionized calcium, nor the initial blood pressure, predicted the blood pressure-lowering effect of nifedipine in hypertensive pregnancy.