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The present study was designed to evaluate the renal haemodynamic pattern of never-treated microalbuminuric and normoalbuminuric patients with essential hypertension. A total of 19 never-treated essential hypertensive patients with microalbuminuria were selected and, as control subjects, 24 never-treated essential hypertensive patients without microalbuminuria (determined on three 24-h urine collections) were recruited. In the two groups, we compared blood pressure values, standing plasma noradrenaline, plasma renin activity, plasma aldosterone, urinary aldosterone, lipid profile, serum glucose and uric acid, glomerular filtration rate and renal plasma flow. In comparison with normoalbuminuric patients, microalbuminuric patients showed significantly higher systolic blood pressure values (P < 0.05), higher renal vascular resistances (P < 0.05) and lower plasma renin activity values (P < 0.01). Urinary albumin excretion showed a significant positive correlation with systolic (r = 0.46, P < 0.005) and mean blood pressure (r = 0.38, P < 0.05), serum uric acid (r = 0.43, P < 0.005) and triglyceride values (r = 0.36, P < 0.005), and a significant negative correlation with plasma renin activity (r = -0.34, P < 0.05). The present data are consistent with the occurrence of renal vasoconstriction in microalbuminuric never-treated essential hypertensive patients.

SHORT- VERSUS LONG-ACTING ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS: Although ACE inhibitors are widely used in the treatment of hypertension, there are few data on trough:peak ratios and the data are contradictory. Part of the explanation for this lies in differences in pharmacological properties. Depending on the kinetics of elimination, the trough:peak ratio of short- and long-acting ACE inhibitors has to be evaluated according to a dose regimen of twice or once a day, respectively, and must take account of the dose used, since long-acting ACE inhibitors appear to have a dose-dependent trough:peak effect. Further explanations for the contradictory trough:peak ratios reported for ACE inhibitors include measurement methods (clinic blood pressure versus ambulatory monitoring) and study design. TROUGH:PEAK RATIO: Data from randomly allocated, placebo-controlled studies indicate that both the short-acting ACE inhibitors captopril and quinapril given twice a day and the long-acting ACE inhibitors enalapril, lisinopril, benazepril and cilazapril given once a day have an acceptable trough:peak ratio (> 50%). The evidence suggests that when chemically different ACE inhibitors with similar kinetics of elimination are administered at equipotent doses, similar trough:peak ratios are obtained.

Since hypertension is associated with nephrosclerosis and an increased progression toward end-stage renal failure, the therapeutic approach to the treatment of hypertension should aim to protect the kidney against damage or to halt the progression toward end-stage renal failure. It appears that compared with systolic and mean blood pressure, the level of diastolic blood pressure is particularly associated with renal damage. In the presence of kidney failure the choice of antihypertensive drug should be made according to pharmacokinetic and pharmacodynamic properties. From the pharmacokinetic point of view, drugs that are eliminated via the biliary route are preferable since no dosage adjustment is required, and those with a favorable trough to peak effect can achieve better blood pressure control by reducing blood pressure variability. Pharmacodynamic properties should include efficacy in lowering blood pressure, beneficial renal effects, and good tolerability. Hence, the dihydropyridine calcium antagonists, which are effective during volume repletion and which counteract vasoconstrictor mechanisms, seem to be particularly effective. There is some suggestion, but no definitive proof, that blood pressure should be lowered well below 140/90 mm Hg; to achieve this, combination therapy frequently must be used. The rationale for combining two or more antihypertensive drugs is based on the knowledge that this combination can exert an additive antihypertensive action while reducing side effects. The combination of an angiotensin converting enzyme inhibitor with a dihydropyridine calcium antagonist may well fulfill these criteria since this combination could enhance both antihypertensive and renal hemodynamic effects in comparison to single-drug treatment and could reduce the side effects of both drugs.

To evaluate the magnitude and duration of the antihypertensive effect of sustained release (SRO) isradipine, 37 uncomplicated essential hypertensive patients (diastolic blood pressure 100-115 mm Hg after a one month run-in on placebo) were randomised to receive, according to a double-blind cross-over design, isradipine SRO 5 mg once daily and the corresponding placebo for 1 month. At the end of each treatment period, sitting blood pressure and heart rate were measured immediately before and every hour for 6 h after the last dose. Thirty-four patients [16 m, age 54 (7) y] completed the study. As compared to randomised placebo, isradipine SRO significantly reduced the systolic (SBP) and diastolic (DBP) blood pressure. Absolute DBP decrements versus placebo peaked 6 h after dosing (-8.8 mm Hg) and were not significantly lower (-8.2 mm Hg) at the end of the dose interval. At the same times, the absolute decrements in SBP were -9.8 mm Hg and -9.7 mm Hg, respectively. DBP was normalised in 19 patients (56%) at peak and in 17 (50%) at trough time. The trough to peak efficacy ratio in patients with peak DBP < or = 90 mm Hg was 70%. Heart rate was slightly increased by isradipine SRO. Adverse effects monitored with a check-list occurred in 8/36 patients (22%) on isradipine SRO and in 4/35 (11%) on randomized placebo. The data suggest that isradipine SRO is an effective antihypertensive drug, with a trough to peak efficacy ratio supporting once daily administration in most mild to moderate essential hypertensives.

To study the effect of adenosine on renin release, n = 6 hypertensive patients, while on a constant 80 to 100 mEq/24 h Na+ diet, received oral 150 mg dipyridamole (an adenosine uptake inhibitor) three times daily for 3 days while upright plasma renin activity (PRA) and plasma aldosterone, urinary aldosterone, plasma and urinary Na+,K+, and creatinine clearance were monitored the day before (basal) the first and third day of the treatment and the day after the withdrawal (recovery). As compared to basal and to recovery, dipyridamole significantly decreased PRA, and plasma and urinary aldosterone without affecting plasma and urinary Na+ and K+, creatinine clearance, blood pressure, and heart rate. These data, showing that dipyridamole decreases PRA and aldosterone, confirm also in hypertensives that endogenous adenosine inhibits the circulating renin-angiotensin-aldosterone system.

Endothelium-dependent vasodilation is reduced in essential hypertensive subjects. To evaluate whether this abnormality is a primary defect or is a consequence of blood pressure increment, in offspring of essential hypertensive and normotensive subjects (n = 13 subjects for each group) matched for age, sex, body weight, and blood pressure, we studied the response of forearm vasculature to acetylcholine (ACh) (an endothelium-dependent vasodilator), sodium nitroprusside (a direct vasodilator of vascular smooth muscle), and forearm ischemia (13 min plus 1 min of exercise) to induce maximal vasodilation. Drugs were infused into the brachial artery at cumulative doses (ACh: 0.15, 0.45, 1.5, 4.5, and 15 micrograms/100 ml of forearm tissue/min; sodium nitroprusside: 1, 3, and 10 micrograms/100 ml of forearm tissue/min) while forearm blood flow was measured by strain-gauge venous plethysmography. The intra-arterial blood pressure and heart rate were continuously monitored. Despite a comparable forearm vascular response to sodium nitroprusside and to forearm ischemia, the effect of ACh was significantly (p < 0.001) reduced in offspring of hypertensive subjects compared to the offspring of normotensive subjects. These data indicate that ACh-mediated forearm vasodilation is reduced in normotensive subjects with a familial history of essential hypertension, a finding that suggests that endothelium dysfunction can precede the appearance of hypertension and that this abnormality might play a role in the pathogenesis of essential hypertension.

The effect of indomethacin on plasma renin activity (PRA), urinary aldosterone, 17 OH ketogenic steroids and plasma cortisol was studied in twenty-three patients with essential hypertension and compared in eleven patients to oxprenolol effect by 2 x 2 factorial trial. Indomethacin decreased PRA and urinary aldosterone: its effect was maintained when the drug was given for three days and it was related to basal PRA and aldosterone values. Therefore in patients with low PRA (renin-sodium index) PRA and aldosterone were unchanged, while they decreased in the normal high PRA group. Aldosterone changes were related to those of PRA, while 17 OH ketogenic steroids and plasma cortisol were unchanged. Both indomethacin and oxprenolol decreased PRA, but no interaction or additive effect was found between the two drugs. The present data indicate that indomethacin can decrease both PRA and aldosterone to an extent which is related to basal values and that aldosterone changes are mainly explained by those of PRA. The PRA unresponsiveness to indomethacin found in low renin patients may suggest renal prostaglandin deficiency. Finally the lack of interaction or of additive effect between indomethacin and oxprenolol may be explained by postulating either that the two drugs act on a common pathway or that an additive effect on PRA cannot be detected renin being maximally suppressed by full renal beta-receptors blockade.

Angiotensin-converting enzyme (ACE) inhibitors are a new class of drugs, whose main indications are the treatment of hypertension and of heart failure. Data obtained with captopril, the first orally active ACE inhibitor, affords an understanding of the rationale of their therapeutic use based on the knowledge of their mechanisms of action, efficacy, contraindications and precautions, dosage and frequency of administration, side-effects, interactions and advantages. ACE inhibitors appear to exert their haemodynamic effect mainly by inhibiting the renin-angiotensin-aldosterone system, but also by modulating sympathetic nervous system activity and by increasing prostaglandin synthesis. Therefore they act both on vasoconstrictor and volume factors, since they cause vasodilation (the main effect) and mild natriuresis without affecting the heart rate and contractility and, probably, favourably influencing renal, coronary and cerebral circulation. So far it appears that ACE inhibitors can be usefully employed in the treatment of heart failure, in which they reduce both pre- and after-load, and mainly of hypertension. In the past captopril has been used to treat only severe and or resistant hypertension and some secondary forms, like renal parenchymal and renovascular hypertension, but now it seems that captopril is useful also to treat mild to moderate essential hypertension. Their efficacy in reducing blood pressure is similar to that of thiazide diuretics and of beta-blockers, the two drugs now considered of first choice and they exert their hypotensive action without the development of pseudotolerance or tolerance. ACE inhibitors seem, at the moment, contraindicated in pregnancy and in hyperkalaemic syndromes and must be used with caution in patients with collagen disease (mainly associated with renal failure), with severe bilateral renal artery stenosis (and with severe artery stenosis of a solitary kidney) and with severe sodium depletion. It is now established that captopril has a flat dose response curve and that it must be given (twice daily) at a dose not exceeding 150 mg/day. The same pharmacological approach must be used with future ACE inhibitors in order to establish the right posology and the frequency of administration. In this respect enalapril seems to be a promising ACE inhibitor with a prolonged action (at least 24 hours). The exact posology of ACE inhibitors might be crucial, since it has been shown that the side-effects of captopril (skin rashes, fever, taste disturbances, proteinuria and neutropenia) are dose dependent.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of beta-adrenergic blockade, using oxprenolol, were studied in plasma renin activity, urinary sodium excretion and blood pressure in ten normal subjects and in 120 patients with essential and renovascular hypertension. Blood pressure was reduced by oxprenolol administration. The hypotensive action of the drug was independent of either the basal plasma renin activity or of the plasma renin activity response. Oxprenolol decreased plasma renin activity in normal subjects and in patients with essential hypertension with normal or high basal plasma renin activity. Patients with low plasma renin activity may show a lack of response to the beta-blockade. In patients with renovascular disease the response of plasma renin activity to oxprenolol was not a discriminant factor between patients cured or not cured by surgery. Some renovascular patients were unresponsive to beta-blockade with oxprenolol.

To evaluate the acute hemodynamic, both systemic and renal, and humoral effect of three increasing doses of Iloprost, a prostacyclin analogue, eight uncomplicated untreated hospitalized patients with mild to moderate essential hypertension, while on a constant sodium and potassium intake, received, after oral hydration, three doses of Iloprost (1,2 or 4 ng/kg/body weight for 45 min) in a single-blind randomized sequence. Each dose was preceded by placebo (saline infusion for 45 min) with a 48 h interval between each study. Iloprost significantly (P less than .05) reduced blood pressure, and increased heart rate, filtered sodium, urinary sodium excretion, fractional sodium excretion, noradrenaline, adrenaline, and plasma renin activity (PRA). The blood pressure lowering effect as well as the heart rate, renal plasma flow and noradrenaline increases were significantly greater on the 4 ng dose. Glomerular filtration rate and adrenaline showed a dose-dependent increase; urinary sodium excretion and fractional sodium excretion were similarly increased by the three doses. No correlation was found between urinary sodium excretion and either glomerular filtration rate or renal plasma flow. The data obtained indicate that Iloprost causes reduction of blood pressure with a reflex activation in the sympathetic nervous system and stimulation of renin secretion, renal vasodilation mainly at the level of the afferent arteriole, and natriuresis. This latter effect is probably due to a direct inhibition of tubular reabsorption, which, at variance with the other effects, is dose-independent.

We studied the role of alpha-adrenoceptors in controlling renin release by infusing increasing doses of phentolamine into six patients with essential hypertension. Furthermore, in order to evaluate the relative importance of alpha 1- and alpha 2-adrenoceptors, phentolamine infusion was repeated in the same patients after pretreatment with prazosin, a selective alpha 1-blocking agent, and oxprenolol, a nonselective beta-blocker. After placebo, phentolamine infusion did not change mean blood pressure or heart rate and increased plasma renin activity (PRA) in a dose-dependent fashion. This finding suggests that the drug acts directly on the intrarenal renin producing apparatus and seems to confirm the inhibitory role of alpha-adrenoceptors in the control of renin release. After prazosin and oxprenolol pretreatment, PRA was respectively increased and decreased but it was unmodified by phentolamine infusion. This latter finding may indicate that both alpha 1- and alpha 2-adrenoceptors are involved in renin release or that alpha-adrenoceptors cannot be clearly differentiated into alpha 1- and alpha 2-subtypes.

A double-blind, cross-over study in 16 patients with essential hypertension was carried out, to evaluate any possible interference by indomethacin, a known prostaglandin-synthetase inhibitor, with the antihypertensive effect of oxprenolol, a non-selective beta-adrenoceptor blocking agent. Both indomethacin and oxprenolol, as well as the two drugs combined, inhibited plasma renin activity; no change was found in urinary sodium excretion or body weight. Oxprenolol alone caused a highly significant decrease in the systolic ( - 10.4 mmHg, p less than 0.001), diastolic ( - 7.4 mmHg, p less than 0.001) and mean ( - 7.7 mmHg, p less than 0.01) blood pressures, whereas indomethacin did not influence blood pressure. When the two drugs were given in combination, blood pressure decreased (systolic: - 5.9 mmHg; diastolic: - 4.0 mmHg; mean: - 4.6 mmHg), but the changes induced in blood pressure were reduced by about 50% when compared with those in the oxprenolol alone period. The data show that indomethacin seems to interfere with the antihypertensive effect of oxprenolol, by an action which may be due to the inhibition of prostaglandin synthesis.

The effect of bumetanide on absolute and fractional sodium excretion, creatinine clearance, and plasma renin activity (PRA) was studied in eight patients with essential hypertension before and after indomethacin. After bumetanide, urinary sodium excretion increased only in the first 4 hr, creatinine clearance only in the first 2 hr, and PRA rose progressively. After indomethacin, bumetanide caused a smaller increase in urinary sodium excretion, decreased creatinine clearance, and caused a small early and late PRA rise. Prostaglandin inhibition and indomethacin did not, per se, affect the tubular natriuretic mechanism but they abolished both early vascular and sustained PRA-stimulating effects of bumetanide.

The behaviour of active (AR) and inactive (IR) renin was studied in 48 hypertensive patients (37 with uncomplicated essential hypertension and 11 with reno-vascular hypertension) treated with indomethacin alone or with AR stimulating (bumetanide, tienilic acid, captopril) and inhibiting (atenolol) drugs before and after indomethacin addition. In 10 pts indomethacin (50mg q.i.d./3 days) reduced (p less than 0.05) AR and to a lesser extent IR. In 6 pts bumetanide (1 mg) increased (p less than 0.05) only AR and this effect was abolished by indomethacin. In 6 pts tienilic acid (250 mg) increased (p less than 0.05) only AR and this action was unchanged by indomethacin. In 11 renovascular pts captopril (100mg) increased AR (p less than 0.01) and lesser IR and both these effects were uninfluenced by indomethacin. In 11 essential hypertensive pts captopril (25mg b.i.d./3 days) increased only AR (p less than 0.02), but after 1 year both AR and IR were increased (p less than 0.05) and these effects were abolished by indomethacin. In all the above reported protocols we did never find any inverse correlation between either AR and IR values or their induced changes. These data suggest that prostaglandins stimulate, even if not to a similar extent, both AR and IR and that drugs, which stimulate renin either through or independently of PGs, did not cause any apparent interconversion of plasma IR into AR. In 6 pts atenolol (100 mg daily/6 days) reduced AR (p less than 0.05) and tended to increase IR. Indomethacin addition further decreased AR and reduced IR (both p less than 0.05 vs atenolol alone): however the proportion (% of total) of IR was still reduced. These findings suggest that beta 1-adrenoreceptors blockade exerts a divergent effect on active and inactive renin and that this action is not influenced by PGs synthesis inhibition.

1. Four different doses of labetalol (150, 300, 600 and 900 mg/day) were given for 1 week to each of four groups of patients with essential hypertension (six patients for each group). 2. Labetalol decreased mean blood pressure and heart rate to the same extent on the first and the seventh days of treatment. Only standing blood pressure showed a dose-dependent inhibition both in the supine and upright position. 3. Labetalol exerted a net inhibitory effect on plasma renin activity, which was related to basal renin values and was already maximal at the lowest doses. This effect was well maintained in the supine position. This effect was well maintained in the supine position, although during standing it tended to be less evident with increasing doses. 4. Urinary aldosterone was decreased in a dose-dependent fashion and its changes were largely independent fashion and its changes were largely independent of plasma renin activity. 5. Neither basal values nor changes of renin and aldosterone were related to the hypotensive effect of labetalol. 6. During labetalol treatment urinary sodium excretion fell for 2-3 days and then returned to basal values. The retentive effect of labetalol on sodium was directly related to the decrease of blood pressure, and the successive sodium escape might be explained either by the observed increase of plasma volume (indirectly measured by packed cell volume) or by aldosterone inhibition.

We have previously shown that enalapril, when given acutely to renovascular patients, exerted a dose-dependent hypotensive effect. To address the same problem in chronically treated essential hypertensives, we studied 116 uncomplicated essential hypertensives, whose diastolic blood pressure was greater than or equal to 95 mm Hg at the end of a two-week placebo run-in period (time 0). According to a randomized crossover design, these patients received three doses (10, 20, or 40 mg) of enalapril qd and a placebo, each treatment being given for one month. At the end of each treatment period as well as at time 0, blood pressure and heart rate were measured 24 hours after the last dosing. In spite of a two-week run-in placebo period, placebo treatment further and significantly reduced blood pressure; however enalapril further and significantly reduced blood pressure when compared to placebo. Although absolute blood pressure values after 40 mg of enalapril were significantly lower than those after 10 mg of enalapril the relevance of this difference, mainly when compared to placebo, seems to be inconsistent. Taken together these data suggest that the hypotensive effect of enalapril chronically given to essential hypertensives and measured 24 hours after last dosing, is dose independent.

To investigate whether a K-rich/Na-poor salt is able to reduce blood pressure, 10 mildly hypertensive inpatients (six males) aged 28-53 years, with supine diastolic blood pressure (DBP) greater than 95 mmHg after 5 days of hospitalization, on a standard diet containing about 20 mmol Na plus 4 g common salt (CS) were randomly given, in double-blind conditions, 2 g twice daily of either CS (five patients) or K-rich/Na-poor salt (five patients) to add to food for a further 8 days. Mean blood pressure was significantly (P less than 0.01) reduced to a similar extent in both groups in the first 4 days, and declined significantly (P less than 0.01) only in the K/Na group in the following 8 days, reaching values significantly (P less than 0.01) lower than those of the CS group. The heart rate did not change significantly while body weight decreased to a similar extent in both groups. Urinary sodium excretion was similarly and significantly (P less than 0.01) reduced in both groups in the first 4 days (CS 100.8 +/- 7.9 and K/Na 100.2 +/- 11.0 mmol/24 h, and remained unchanged in the CS group (109.9 +/- 4.3 mmol/24 h) but declined significantly (P less than 0.05) by about 50% in the K/Na group (62.9 +/- 3.6 mmol/24 h) in the following 8 days. Plasma renin activity (PRA) and plasma noradrenaline did not differ significantly between the two groups, nor among the days of treatment, but the mean blood pressure response to mental stress was reduced significantly (P less than 0.4) in the Na/K group compared with the CS group.(ABSTRACT TRUNCATED AT 250 WORDS)