Effect of aspirin on renal function and the prostaglandin-kallikrein systems early after myocardial infarction.

Using a double-blind procedure, 29 patients with a recent myocardial infarction were randomly allocated to a placebo group (n = 14) and to a group receiving aspirin, 300 mg three times a day (n = 15) over 7 days. No change in renal function was observed in either treatment group. Compared with the placebo group, the 24-h urinary excretion of prostaglandin E2 (PGE2) was significantly suppressed in the aspirin group, but the urinary kallikrein activity was unchanged. These results contrast with our previous study of similar patients, in which sulfinpyrazone decreased renal function, as well as the urinary PGE2 and kallikrein excretions. These divergent effects of aspirin and sulfinpyrazone on urinary kallikrein activity could explain the different trends in renal function observed early after myocardial infarction.

Urinary excretion of immunoreactive prostaglandin F2 alpha in healthy children and adults.

The 24-hours urinary excretion of immunoreactive prostaglandin F2 alpha (U-iPGF2 alpha) in normal children on a free diet was not significantly different in 30 boys (aged 3-15 years; geometric mean 589 ng/24 h) compared to 27 girls (aged 4-14 years; mean 473 ng/24 h). In both sexes this excretion rose with age until adolescence where it reached a plateau. In normal adults the men had significantly higher (p less than 0.001) excretions of U-iPGF2 alpha than the women; also body weight and urinary creatinine excretion were higher in men (p less than 0.001). In the children, as well as in the total population, U-iPGF2 alpha correlated best with body weight (r = 0.44 and r = 0.48 respectively; p less than 0.001) and the urinary creatinine excretion (r = 0.53 and 0.57 respectively; p less than 0.001); both body weight and urinary creatinine excretion are reflections of total body development. After the correction for urinary creatinine excretion or for body weight, the sex difference in the adult U-iPGF2 alpha totally disappeared.

Double-blind comparison between propranolol and bendroflumethiazide in captopril-treated resistant hypertensive patients.

In a double-blind crossover trial, 15 captopril (daily dose 600 mg) treated patients received in addition to the converting enzyme inhibitor, placebo, propranolol (240 mg), or bendroflumethiazide (7.5 mg). Propranolol produced an additional hypotensive effect, while pulse rate slowed, indicating effective beta-adrenoceptor blockade. Plasma renin activity decreased, but the hypotensive effect of propranolol was not accompanied by changes in the plasma angiotensin II and aldosterone levels or in the urinary aldosterone excretion. Also bendroflumethiazide lowered blood pressure, while body weight decreased slightly. During captopril-bendroflumethiazide treatment, serum sodium and potassium decreased while the plasma renin-angiotensin-aldosterone system was stimulated. In these captopril-treated patients, the hypotensive response to bendroflumethiazide tended to be somewhat larger than the response to propranolol, but the difference was small and statistically not significant.

Effects of tibalosine, a new alpha-adrenoceptor antagonist, in essential hypertension.

Tibalosine is a phenylethylamine derivative known to lower arterial pressure in hypertensive animal models. In a double-blind cross-over study, 12 patients with essential hypertension, on a constant sodium intake, received placebo and tibalosine, 150 mg daily. Standing (-5.5/-6.0 mm Hg) and supine (-8.5/-7.5 mm Hg) blood pressure and standing (-7.0 bmp) and supine (-7.5 bpm) pulse rate were reduced by tibalosine. Plasma renin activity (-0.41 ng/ml/hr) and plasma angiotensin 1 (-47 pg/ml) and angiotensin II (-3.0 pg/ml) levels decreased. There were no significant changes observed in plasma aldosterone or in the urinary excretion of aldosterone, kallikrein, or prostaglandin E2, F2 alpha, and F alpha metabolites. During tibalosine treatment, creatinine clearance decreased by 20 ml/min and serum creatinine rose by 0.04 mg/100 ml. The increase in serum sodium by 0.05 mmol/l was not accompanied by significant changes in body weight. There were small, but significant reductions in hemoglobin (-0.4 gm/100 ml), hematocrit (-1.5%), and erythrocyte count (-0.15 X 10(6) cells/mm3) during tibalosine intake, while blood glucose rose by 4.0 mg/100 ml. Apart from a slight tranquilizing effect in two anxious patients, no obvious sedation was observed. Subjective complaints were as frequent during placebo as during active treatment periods.

Decrease in renal function due to sulphinpyrazone treatment early after myocardial infarction.

Twenty-nine patients with recent myocardial infarction were randomly allocated to a placebo group (n = 14) and to a group (n = 15) who received sulphinpyrazone, 4 x 200 mg daily for 7 days. Renal function significantly and transiently deteriorated in the sulphinpyrazone group compared to the placebo group. In the sulphinpyrazone group the 24 hour-urinary prostaglandin E2 and kallikrein excretion were suppressed. These data suggest that the decrease in renal function caused by sulphinpyrazone early after myocardial infarction could be mediated by an inhibition of renal prostaglandin and/or kallikrein-kinin synthesis.

Prostaglandin-kallikrein-renin system during acute sulphinpyrazone administration in healthy volunteers.

Sulphinpyrazone administered acutely to 8 healthy male volunteers decreased the urinary (U) excretion of prostaglandin (PG)E2 (p less than 0.01)( but not of PGF2 alpha. Also, the ratio U-PGE2/U-PGF2 alpha and the urinary excretion of kallikrein declined (p less than 0.001 and p less than 0.05 respectively). Sulphinpyrazone therapy caused a significant inhibition of PRA (p less than 0.05). Renal function, as assessed by serum creatinine and creatinine clearance, remained constant in these normal men, possibly related to the fact that both the vasodilatory PG-kallikrein-kinin system and the vasoconstrictive renin-angiotensin system were inhibited by sulphinpyrazone. However, it is conceivable that in clinical situations where vasoconstrictive stimuli are enhanced, sulphinpyrazone can disturb the balance between those systems and can lead to an impaired renal function.

Antihypertensive therapy in patients above age 60 with systolic hypertension. A progress report of the European Working Party on High Blood Pressure in the Elderly (EWPHE).

1. Although systolic blood pressure elevation is responsible for increased incidence of cardiovascular accidents in old people, the preventive benefit of lowering systolic hypertension in elderly has not been confirmed. 2. A double blind study comparing the effects of a placebo and of an active regimen (hydrochlorothiazide-triamterene with or without methyldopa) in people over 60 years with isolated systolic hypertension has been undertaken by the European Working Party on High blood pressure in the Elderly (EWPHE). 3. The actively treated group shows a lowered sitting blood pressure (-15/6 mm Hg), a mild increase of serum creatine, serum uric acid and blood glucose and a mild decrease of serum potassium after two years of treatment when compared to the spontaneous changes observed in the placebo treated group. 4. The study is continuing to evaluate if the blood pressure reduction prevents or reduces the incidence of cardiovascular accidents, although some biochemical changes were provoked by the treatment.

Fluctuations in the plasma angiotensin I converting enzyme activity during long-term treatment with captopril.

Eight hypertensive patients on chronic captopril treatment were studied: blood pressure, plasma converting enzyme activity (pCEA) and various components of plasma renin-angiotensin-aldosterone system were measured repeatedly, immediately before and up to 7 hours after the usual morning dose of captopril in 5 patients, or a matching placebo in 3 patients. In the patients, receiving a placebo no significant changes were observed over a 7 hour period in pCEA, plasma rénin activity (PRA), plasma angiotensin II (ANG II) plasma aldosterone (PAC) and blood pressure. In patients receive captopril (200 mg) pCEA rapidly decreased, reaching after 2 hours a minimum, corresponding to nearly 20 per cent of its reference value. Thereafter pCEA increased and after 7 hours remained only slightly depressed. Within the first hour after captopril intake a small but significant decrease of ANG II and PAC was observed, while PRA and blood pressure remained unchanged throughout the study period. A continuous low pCEA level is therefore not necessary to achieve a sustained blood pressure lowering effect during chronic captopril treatment.

The hypotensive effect of propranolol in captopril-treated patients does not involve the plasma renin--angiotensin--aldosterone system.

1. With a double-blind cross-over protocol, 20 hypertensive captopril-treated patients were studied by adding in a variable sequence a placebo and propranolol (80 mg three times a day) to their captopril regimen (200 mg three times a day), during periods each lasting 1 month. During captopril--placebo treatment their diastolic blood pressure remained elevated between 90 and 114 mmHg. 2. The additional administration of propranolol produced a significant hypotensive effect, but no alterations of the plasma angiotensin II and aldosterone concentrations and of the urinary aldosterone excretion occurred. The present data indicate that in captopril-treated patients the hypotensive effect of propranolol is achieved independently of changes in the plasma angiotensin II and aldosterone concentration. 3. The additional administration of propranolol also produced an increase in the serum potassium levels in the absence of any change in plasma aldosterone concentration or in the urinary aldosterone excretion.

Rise in plasma concentration of aldosterone during long-term angiotensin II suppression.

The plasma concentration of aldosterone was followed in seven hypertensive patients before and during long-term angiotensin II suppression with the orally active angiotensin-I-converting-enzyme inhibitor, captopril. The plasma concentration of aldosterone decreased initially from 74 to 21 pg/ml (P less than 0.05) after 1 month of administration of captopril. Thereafter the plasma concentration of aldosterone began to rise and after 1 year reached a level of 165 pg/ml. During long-term captopril therapy the plasma renin activity remained increased and the plasma angiotensin II concentration suppressed. The mechanism responsible for the late rise of the plasma concentration of aldosterone during long-term angiotensin II suppression with captopril remains to be elucidated. A sizeable and lasting hypotensive effect was observed in all patients.

Role of various vasodepressor systems in the acute hypotensive effect of captopril in man.

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 F2 alpha 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 changes 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 F2 alpha. There is no evidence for a role of the adrenergic systems in the hypotensive response.

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.

Dose response in captopril therapy of hypertension.

Dose-response curves of blood pressure and of the biochemical components of the renin-angiotensin-aldosterone system were determined during long-term treatment with captopril in 21 hypertensive patients. Captopril was given in biweekly, doubling doses starting with 25 mg 3 times a day until control of blood pressure was achieved or a total daily dosage of 600 mg was reached. Recumbent and standing systolic and diastolic blood pressure fell on 75 mg captopril daily. Increasing the captopril dose did not induce further significant hypotensive effects. The pretreatment level of plasma renin activity (PRA) was a poor predictor of the hypotensive effect of captopril. The rises in PRA and plasma angiotensin I level (PA I) and the decrease in plasma angiotensin II level (PA II) and plasma aldosterone level (PAC) provide biochemical evidence for angiotensin-converting enzyme (ACE) inhibition in vivo. These effects were present on daily doses of 75 to 150 mg captopril.