Vascular renin-angiotensin system and neurotransmission in hypertensive persons.

The existence of a vascular renin-angiotensin system and its role in modulating sympathetic activity were evaluated in forearm arterioles of hypertensive individuals. Isoproterenol (0.03, 0.01, 0.3 microgram/100 ml/min for 5 minutes each; n = 5) was infused into the brachial artery, and active and inactive renin, angiotensin II, and norepinephrine forearm balance (venous-arterial differences corrected for forearm blood flow by strain-gauge plethysmography) were measured. Isoproterenol caused vasodilation and a dose-dependent active and inactive renin, angiotensin II, and norepinephrine outflow, an effect blunted by propranolol (10 micrograms/100 ml/min). To evaluate the role of local angiotensin II on beta-mediated norepinephrine overflow, the experiment was repeated with captopril (2.5 micrograms/100 ml/min for 10 minutes; n = 5), which abolished angiotensin II release and significantly reduced norepinephrine overflow. To test whether angiotensin II facilitates both prejunctional norepinephrine release and its postjunctional action, we evaluated the effect of exogenous angiotensin II, infused into the brachial artery at low concentrations (0.001 microgram/100 ml/min), on forearm vasoconstriction and norepinephrine release induced by endogenous sympathetic activation (application of a lower body negative pressure: -10 and -20 mm Hg for 5 minutes, n = 10) and on the vasoconstrictor effect of local norepinephrine (0.0015, 0.005, 0.015, 0.05, 0.15 micrograms/100 ml/min for 3 minutes each; n = 6). Although angiotensin II increased the vasoconstricting effect and the norepinephrine release induced by lower body negative pressure, it failed to affect norepinephrine-mediated vasoconstriction. Our data indicate the existence in hypertensive individuals of a vascular renin-angiotensin system that seems to modulate sympathetic activity through the presynaptic facilitation of norepinephrine release.

An atrial natriuretic factor analogue at low doses attenuates forearm reflex vasoconstriction to cardiopulmonary receptor deactivation in patients with hypertension.

Contrasting data exist about a possible modulation of the autonomic function by atrial natriuretic factor (ANF) in human beings, particularly at low, biologically, significant concentrations. We have evaluated that possibility by increasing plasma ANF levels through the infusion of a synthetic analogue (WY-47,663, anaritide) in five male patients with mild to moderate uncomplicated hypertension. Nonhypotensive lower body negative pressure (-10 mm Hg x 5 min) was used to selectively deactivate cardiopulmonary receptors and to stimulate sympathetic efferent tone reflexogenically. ANF was given at either a low rate (0.005 micrograms/kg/min x 60 min, which was previously shown to increase plasma ANF in a range compatible with physiologic stimuli) or at a high rate (0.05 micrograms/kg/min x 60 min, each). Administration of ANF was preceded and followed by vehicle infusion (Haemacell x 30 min). Forearm blood flow (venous plethysmography), intraarterial blood pressure, and heart rate were monitored continuously, and venous immunoreactive ANF, plasma renin activity, aldosterone level, and venous hematocrit were measured at the end of both control and infusion periods. Arterial norepinephrine values, an indirect index of sympathetic discharge, were measured at rest and during lower body negative pressure conditions. Graded systemic ANF infusion increased immunoreactive ANF and venous hematocrit, decreased aldosterone level and plasma renin activity, whereas resting norepinephrine levels, blood pressure, and heart rate did not change. Lower body negative pressure decreased forearm blood flow during vehicle infusion, but it lost its vasoconstrictor effect during infusion of ANF. To identify the site of that inhibitory action, ANF was also infused into the brachial artery at rates that raised local but not systemic levels of immunoreactive ANF.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of dopamine-1 receptor blockade on the humoral and renal effects of low-dose atrial natriuretic factor in human hypertensives.

To test whether dopaminergic mechanisms can modulate the humoral and renal effects of atrial natriuretic factor (ANF), seven untreated, mildly hypertensive patients without complications were given a placebo (saline for 60 min) followed by a low dose of ANF (0.005 microgram/kg per min), or D-sulpiride (0.05 mg/kg per min), a specific dopamine-1 antagonist, or ANF + D-sulpiride at the same doses, for 60 min. The sequence of the three treatments was random, with a 72-h interval between treatments. The ANF infusion, which increased plasma ANF within the physiological range, significantly increased urinary sodium excretion, fractional sodium excretion and haematocrit; it reduced plasma aldosterone and tended to reduce plasma renin activity without changing blood pressure, the heart rate, renal plasma flow or the glomerular filtration rate. D-Sulpiride, when given alone, significantly increased mean blood pressure and reduced absolute and fractional sodium excretion without changing the heart rate, glomerular filtration rate, renal plasma flow, haematocrit, plasma renin activity or plasma aldosterone. When infused with D-sulpiride, ANF did not change absolute or fractional sodium excretion or haematocrit. This study provides evidence that dopaminergic mechanisms play a role in the natriuretic and plasma volume effects of a synthetic human ANF analogue infused at a low dose in patients with essential hypertension.

Long-term humoral and hemodynamic effects of celiprolol.

To evaluate the humoral and hemodynamic (both systemic and renal) effects of chronic treatment with celiprolol, six out-patients with mild to moderate uncomplicated essential hypertension received placebo for 1 month and celiprolol (400 mg qid) for 6 months. At the end of placebo and of the first and sixth month of treatment, blood pressure (BP), heart rate (HR), renal plasma flow (RPF), glomerular filtration rate (GFR), plasma renin activity (PRA), aldosterone (ALD) and noradrenaline (NA), urinary enzymes (NAG: N-acetyl-beta glucosaminidase, AAP: alanine aminopeptidase) were measured. Compared to placebo, celiprolol significantly and steadily reduced BP and HR. However, although the systemic hemodynamic effect was constant during the whole period of the study, the reduction of renovascular resistance and of plasma noradrenaline, detectable at the first month of therapy, disappeared at the sixth month. However, PRA, plasma aldosterone, GFR, and urinary enzymes did not change. These findings suggest that the antihypertensive effect of celiprolol is well maintained over the 6-month period; the drug did not exert any adverse effect on the kidney, and chronic celiprolol treatment does not influence renal hemodynamics.

Acute response to captopril as a predictive test for surgery in renovascular hypertension.

To test the hypothesis that acute angiotensin-converting enzyme (ACE) inhibition might predict the postoperative blood pressure outcome, a single oral dose of captopril ranging from 12.5 to 100 mg, was given to 26 patients with renovascular disease and its hypotensive effect was compared with that of surgery (21 patients) or of percutaneous transluminal angioplasty (PTA) (5 patients). Both systolic and diastolic blood pressure fell significantly (p less than 0.001) from 179.9 +/- 5.4/114.1 +/- 2.1 to 148.4 +/- 3.8/94.1 +/- 1.9 after captopril and to 141.1 +/- 3.7/88.9 +/- 2.0 at least 3 months after operation. Postoperative pressure values were directly related to those after captopril (SBP: r = 0.65, p less than 0.001; DBP: r = 0.45, p less than 0.05) as were their absolute decrements (SBP: r = 0.70, p less than 0.001; DBP: r = 0.64, p less than 0.001). However, after captopril, individual pressure tended to be higher (and their decrements to be lower) than after operation. 12 out of 19 patients cured by surgery were considered cured by captopril, while 5 out of the remaining 7 were improved and 2 not cured. The 6 patients improved by surgery or PTA were also improved by captopril and the only patient not cured by surgery was not cured by captopril. Therefore, if we consider both cure and improvement as a positive result, the captopril test gave 23 true-positive, 1 true-negative and 2 false-negative responses. Taken together, these data suggest that acute ACE inhibition may be an useful tool in predicting postoperative blood pressure of patients with renovascular disease.

Dose-response relationship of prizidilol hydrochloride (SK&F 92657): a comparison between acute and chronic effects in patients with essential hypertension.

Three different doses (50, 100 and 200 mg) of prizidilol hydrochloride (SK&F 92657), a novel antihypertensive agent with vasodilating and beta-adrenoreceptor blocking properties, were given to three (n = 5) groups of essential hypertensive patients in order to evaluate hypotensive dose-response relationship of the drug and its beta-adrenoreceptor blocking properties. Irrespective of the dose given, acute administration of prizidilol did not effectively decrease blood pressure; however after one-week of treatment prizidilol was effective in reducing blood pressure at both the 100 and the 200 mg b.i.d. schedules. At these doses the drug decreased resting heart rate and plasma renin activity for the first 4-6 h after both acute and steady-state dosing. Similarly postdynamic exercise tachycardia was reduced to a significant extent by the drug; after acute administration this effect lasted 2 h with the lowest dose and 4 h with the highest one. After chronic administration this effect lasted up to 10 h for both the 100 and 200 mg doses. These data indicate that: chronic prizidilol treatment can achieve a satisfactory control of blood pressure in patients with mild-moderate essential hypertension; when prizidilol is administered chronically in hypertensive patients, an equally effective control of blood pressure can be obtained with either a 200 mg b.i.d. or a 100 mg b.i.d. schedule; prizidilol possesses beta-adrenoceptor blocking properties in man which can contribute to its pharmacodynamic activity.

The renin-angiotensin-aldosterone system and blood pressure during oxprenolol treatment in hypertensive patients pretreated with diuretics.

The interrelationship between PRA, urinary aldosterone excretion, and blood pressure was studied in 11 patients with essential hypertension while receiving a diuretic (1st week) and subsequently a diuretic + oxprenolol (2nd week). The diuretic reduced blood pressure and body weight but increased PRA and aldosterone. Oxprenolol reduced PRA on the 1st day but to a lesser extent on the 7th day. Blood pressure was decreased 1 day after oxprenolol administration, but to a greater extent on the 7th day. Blood pressure decrements were independent of renin suppression, but directly correlated to aldosterone changes. These data suggest that the hypotensive effect of oxprenolol in patients receiving diuretic treatment is independent of its suppression of renin. Aldosterone suppression may instead contribute to the hypotensive effect of the drug.

The effect of clonidine on renin and aldosterone of hypertensive patients.

UNLABELLED: The behaviour of blood pressure, sodium balance, plasma potassium, urinary and plasma aldosterone, plasma cortisol, growth hormone, 17 OH ketogenic steroids were studied in 20 mild hypertensive in-patients (10 with low and 10 with normal PRA) before, 1 day and 5 days after clonidine. Blood pressure was significantly decreased by clonidine while PRA was as a mean unchanged. No correlation was found between blood pressure changes and either basal PRA or aldosterone values or PRA and aldosterone changes after clonidine. Urinary aldosterone was significantly decreased by clonidine and aldosterone changes were unrelated to those parameters (PRA, plasma potassium, sodium balance, ACTH) which are known to influence aldosterone secretion, while GH showed a small increment the first day but was unchanged the fifth day. Plasma aldosterone was not significantly changed by clonidine but its changes showed an inverse correlation to urinary aldosterone changes. CONCLUSIONS: In our normal and low renin patients the antihypertensive action of clonidine is neither predicted by basal PRA and urinary aldosterone values nor explained by their changes. The opposite effect of clonidine on urinary aldosterone and plasma aldosterone may point to a decrease of metabolic clearance rate of the hormone exerted by the drug.

Unusual prolactin response to luteinizing hormone-releasing hormone in some anovulatory women.

We studied PRL, FSH, and LH response to LRH in 82 anovulatory and 4 normally ovulating women. Ten anovulatory patients who were basally hyperprolactinemic showed no significant change in PRL concentration after LRH. Of the remaining 72 anovulatory patients with basal PRL levels in the normal range, 59 showed no PRL modification after LRH (as in normals) whereas in 13 patients, a prompt and significant rise of PRL concentration above basal levels in response to LRH was observed. In these 13 patients, the basal PRL levels were significantly higher than those of the other 59 normoprolactinemic women. No significant differences in gonadotropin concentrations were detected among the three groups. The unusual rise in PRL levels after LRH in these 13 patients can be interpreted as a paradoxical response of the pituitary to a specific stimulus, as seen in other clinical conditions. It is suggested that this phasic hyperprolactinemia might represent an intermediate phase between true normoprolactinemia and chronic hyperprolactinemia.

Direct radioimmunoassay of estradiol in serum extracts.

The feasibility of direct radioimmunoassay of unconjugated estradiol in dried serum extracts in the assessment of ovarian function in the regulation of the menstrual cycle has been investigated. Using an antiserum to an estradiol-6-conjugate, assay reliability was evaluated and the procedure standardized through a series of tests aimed at assessing accuracy, sensitivity, and precision. These included multiple titration with competing steroids, the definition of blank effects from solvent and sample, the assay both of samples to which known amounts of estradiol had been added and of serially diluted samples, and clinical validation using as a reference samples related to well-defined physiological situations. The variability of replicate estimates and the repeatability of the calibration curve were evaluated to obtain information on assay precision and sensitivity. The analytical performances proved to be perfectly adequate for the clinical purposes for which the assay was intended, in terms both of reliability of results and of methodologic practicability.

Methodological simplifications in radioimmunoassay of urinary aldosterone.

Simplification of radioimmunoassay procedures of urinary aldosterone-18-glucuronide was attempted, taking into consideration the aspects implied by the hydrolysis of urine and the assay itself. The procedure standardized for the hydrolysis step (samples diluted with a two-fold volume of 0.2 N HCl and incubated at 30 degrees C for 16-24 h) proved suitable in terms of practicability and accuracy. Aldosterone antisera, raised in the rabbit against an aldosterone-3-bovine albumin conjugate, were selected according to their specificity towards competing steroids. Depending on the characteristics of the antisera used, an assay of extracts, or even direct measurements of hydrolyzed urines excluding any extraction, were found to yield reliable results. In the case of a high-quality antiserum, evidence for the adequacy of assay on non-hydrolyzed urine extracts for the measurement of the excretion of unconjugated aldosterone was provided by some preliminary data. The results of the experiments, directed at the methodological and clinical validation of the simplified procedures, are reported and discussed in this paper.