Effect of pinacidil on blood pressure,plasma catecholamines and plasma renin activity in essential hypertension

Summary Pinacidil, a new cyanoguanidine derivative, is an antihypertensive agent with arteriolar vasodilating properties, which acts on precapillary resistance vessels. A trial was carried out in 30 patients with essential hypertension WHO I-II. The treatment period was divided into three phases. Hydrochlorothiazide (HCTZ) and amiloride were administered for 4 weeks in Phase 1 and supine and standing blood pressure decreased significantly. During Phase 2 pinacidil was added to HCTZ/amiloride for the following 3 months. A further significant reduction in blood pressure was obtained. In the next period of treatment (Phase 3) patients were divided into two groups. For 1 month Group A (15 patients) received pinacidil alone and Group B (15 patients) received HCTZ/amiloride. Conventional laboratory blood tests in all patients remained unchanged during treatment. Reported side effects during Phase 2 were headache (2 patients), dizziness (3 patients), palpitations (2 patients) and ankle oedema (2 patients). Plasma renin activity was slightly increased at the end both of Phases 1 and 2. Plasma catecholamines were increased but not significantly at the end of Phase 2 as compared to Phase 1. The results indicate that pinacidil is effective in lowering blood pressure in mild to moderate essential hypertension.     

Effects of low-dose atenolol on postural and postprandial changes in heart rate,blood pressure,venous plasma catecholamines,and plasma renin activity

Summary The administration of a single dose of atenolol 50 mg 1 h before a standard 3100 kJ cold meal in fasting healthy subjects reduced the supine preprandial heart rate and systolic blood pressure, and blunted the postural and postprandial rises in mean heart rate and systolic blood pressure relative to placebo. It did not affect the preprandial supine diastolic blood pressure, nor the postural rise and postprandial drop in diastolic blood pressure.Preprandial administration of atenolol blunted the postural and postprandial rises in mean plasma renin activity, and it enhanced the rise in plasma noradrenaline during eating in the sitting position, and the postprandial concentrations of noradrenaline.The findings do not permit the conclusion that beta₁-adrenergic stimulation was the predminant cause of these atenolol-responsive changes.     

Short-term effects of atenolol and nifedipine on atrial natriuretic peptide, plasma renin activity, and plasma aldosterone in patients with essential hypertension.

The short-term effects of atenolol and nifedipine on plasma levels of atrial natriuretic peptide (ANP), plasma renin activity (PRA), and plasma aldosterone (PA) were studied in two groups of patients with uncomplicated essential hypertension. Urinary catecholamines, and sodium and potassium excretion were also studied. A group of 20 patients with hypertension, after a wash-out period of at least 10 days, was randomly subdivided into two protocol therapy subgroups. One group (six men and four women) received atenolol (100 mg/d), and the other group (six men and four women) received nifedipine (30 mg/d). Circulating plasma levels of ANP, PRA, and PA were determined by radioimmunoassay, and other variables were determined by routine laboratory techniques before therapy and at day 3 and day 7 after the treatment began. Arterial blood pressure and heart rate were monitored during the study. Both drugs reduced arterial blood pressure (P less than .001) significantly. The atenolol therapy decreased heart rate (P less than .001), increased plasma ANP levels and urinary catecholamine excretion, and decreased PRA and circulating PA levels. Nifedipine treatment did not modify plasma ANP values, whereas it increased PRA and PA circulating levels and urinary catecholamine excretion. No differences were shown for urinary volume, urinary sodium, and potassium excretions during the two different treatments. These findings suggest that the increased plasma ANP levels could contribute to the antihypertensive effects of the beta-adrenoreceptor blockers, by a reduction in PRA and PA levels and a vasodilatative effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in blood pressure, plasma catecholamines and plasma renin activity during and after treatment with tiamenidine and clonidine.

1 Tiamenidine (Hoe 440) is an imidazoline with blood pressure lowering properties. Its pharmacology resembles that of clonidine. 2 The effect of both drugs on blood pressure, plasma noradrenaline (NA), plasma adrenaline (Ad), urinary catecholamines and plasma renin activity (PRA) was assessed in four previously untreated male hypertensive patients in a cross over study. 3 The maximum daily dose of tiamenidine was 3 mg. The maximum daily dose of clonidine was 450 micrograms. 4 During treatment, blood pressure, systolic and diastolic, supine and erect, fell on average between 12 and 15%. Levels of NA, Ad, PRA were reduced during treatment. 5 During withdrawal of either drug there was rebound of blood pressure and NA, Ad, PRA, overshooting baseline levels. 6 The withdrawal effects caused by clonidine were similar for tiamenidine.     

The effect of pindolol on plasma renin activity and blood pressure in hypertensive patients.

1 The effect of pindolol administered to twenty-six patients with hypertension of unknown origin was compared with respect to blood pressure and plasma renin activity change after increase of the dose over a period of 6 weeks. 2 There was no clear correlation between the fall of plasma renin activity, which in some patients was very marked, and the fall in blood pressure. Some patients with a fall in plasma renin activity did not drop their pressure. Conversely, some with a fall of pressure did not drop their plasma renin activity. 3 The addition of hydrochlorothiazide to the pindolol finally caused further lowering of the blood pressure in all but one patient and the plasma renin activity rose in all but two patinets. There was no clear correlation between change in plasma renin activity and the effect on blood pressure.     

Effect of isoproterenol on blood pressure, plasma renin activity, and water intake in rats

The effects of s.c. administered isoproterenol on blood pressure, plasma renin activity and water intake were studied in unanaesthetized rats as a function of both concentration and time. Isoproterenol (1, 10, 100 and 500 μg/kg) induced a rapid, dose-related decrease in blood pressure and increase in plasma renin activity. Both parameters were found to be nearly normal after 60 min, except after the highest dose. Isoproterenol (? 10 μg/kg) caused a dose-dependent increase in water intake; after the highest dose 5–6 mlH₂O/100 g b.w. was ingested within 60 min. In rats on a sodium-deficient diet, the effect of isoproterenol on renin release and water intake was potentiated whereas in DOCA-pretreated rats, the effect was inhibited. The different actions of isoproterenol, 100 μg/kg were blocked by propranolol, partly (0.5 mg/kg) or completely (2.5 and 10 mg/kg). The results indicate that the action of isoproterenol on water intake is correlated with its ability to induce renin release.     

A dose finding study of the combination of atenolol and nifedipine in hypertension

A randomized, double-blind, crossover study was carried out to compare the antihypertensive efficacy and tolerability of two doses of a fixed combination of 50 mg atenolol and 20 mg nifedipine slow release (1 capsule or 2 capsules once daily) in 16 hypertensive patients, treated for 4 weeks with each dose. The results suggest that the combination exerted a greater antihypertensive effect at 3 hours compared with 24 to 28-hours post-dose. Demonstrable differences in resting blood pressure between the low and high dose of the combination occurred at the 3-hour but not at the 24 to 28-hour post-dose time point. This apparent difference was also evident under exercise conditions, although no significance between dose differences were demonstrable at either time point. Thus, it appears that any additional benefit in efficacy obtained with the higher dose is not sustained over a 24-hours period. Side-effects were relatively uncommon with the combination, occurring least commonly with the lower dose.     

Beta-adrenergic blockade and plasma renin activity in borderline hypertension

Summary The influence of beta-adrenergic blockade on plasma renin activity (PRA) was studied in normotensive young men with a hyperkinetic circulation (Group A) and in young men with labile borderline hypertension (Group B). PRA in both groups, when supine and after standing upright for twenty minutes, was significantly lower after intravenous propranolol. The postural increase in PRA was significantly smaller during beta-adrenergic blockade, but the difference between supine and upright levels remained significant. Urinary excretion of adrenaline and noradrenaline was elevated in both groups. In borderline hypertensives, the excretion of noradrenaline did not decrease at night as in Group A subjects. The similarity of the response of PRA to beta-adrenergic blockade in both groups suggests that the quantitative contribution of the sympathetic nervous system to the control of renin secretion does not differ in normotensive and hypertensive subjects with a hyperkinetic circulation.     

Twenty-four-hour beta-blockade in stable angina pectoris: a study of atenolol and betaxolol.

We examined the importance of a long plasma half-life (t1/2) on the antianginal effects of beta-blockade by comparing equivalent doses of once-daily atenolol 100 mg (t1/2 6-8 h) and betaxolol 20 mg (t1/2 20-22 h) in a double-blind placebo-controlled cross-over study of 20 patients with stable angina pectoris. At 20 h postdose, heart rate (HR) was lower with betaxolol than with atenolol whereas blood pressure (BP) was equally reduced by both drugs. Twenty-four-hour ambulatory HR recording demonstrated that this difference existed for the last 6 h of the dosage cycle. During treadmill exercise, HR remained lower with betaxolol than with atenolol and exercise time was significantly prolonged only by betaxolol. With placebo, radionuclide ventriculography demonstrated that left ventricular ejection fraction (LVEF) decreased during exercise. Betaxolol, but not atenolol, significantly attenuated the exercise-induced decrease in EF. Thus, the long plasma t1/2 of betaxolol is associated with a reduction in exercise-induced ischemia when tested toward the end of the 24-h dosage cycle. Plasma t1/2 therefore is of clinical relevance to the antianginal, but not antihypertensive, actions of beta-blockers.     

The effects of intravenous L-dopa on plasma renin activity, renal function, and blood pressure in man

Summary L-dopa 7 µg·kg^–1·min^–1 was given intravenously over 2 h to six healthy subjects, controlled by an infusion of saline on a separate occasion, with measurement of plasma renin activity (PRA), urinary sodium and potassium excretion, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), blood pressure, and pulse rate.Mean PRA fell by 50% following L-dopa, which was significantly different from the slight rise which occurred after saline infusion. There was a significant increase in urinary sodium excretion and effective renal plasma flow on infusion of L-dopa. Mean diastolic blood pressure fell during L-dopa infusion, in contrast to the slight increase which occurred during the control study.These observations confirm the anticipated renal dopaminergic effects of L-dopa and also suggest a dopaminergic influence on renin release in man.     

Effects of cadralazine on systemic blood pressure, renal function and plasma renin activity in anesthetized dogs

Renal effects of ethyl 6-[ethyl(2-hydroxypropyl)amino]-3-pyridazinecarbazate (cadralazine), a newly synthesized vasodilator with a pyridazine ring, were studied in anesthetized dogs. 30 min after intravenous (i.v.) injection of cadralazine in a dose of 1 mg/kg diastolic blood pressure (DBP) decreased from the control value of 115 +/- 4 mmHg to 108 +/- 3 mmHg. The decrease continued, being accompanied by an increase in heart rate, throughout the experimental period of 5 h. Renal vascular resistance was decreased significantly, while glomerular filtration rate and urine volume remained unchanged. Urinary excretions of sodium and potassium were increased about 1.5 to 2 times as compared to pre-injection control values. Hypotension and natriuresis were followed by increased plasma renin activity in the artery or renal vein. On the other hand, i.v. injection of hydralazine (0.3 mg/kg) promptly decreased DBP and urinary sodium excretion, 15 min after administration, with blood pressure tending to revert to the control value. These results indicate that cadralazine has hypotensive and renal vasodilating actions, characterized by a slow onset and long duration, when compared with hydralazine.     

Plasma catecholamines,plasma renin activity and haemodynamics during sodium nitroprusside-induced hypotension and additional beta-blockade with bunitrolol

Summary The effects of -blockade on certain physiological and haemodynamic responses to sodium nitroprusside-induced hypotension have been studied in 5 patients, aged 18–54 years, undergoing inner ear surgery. Samples of blood were collected unter premedication, following induction of anaesthesia, during neuroleptanalgesia, during a sodium nitroprusside infusion adjusted to produce a 40% fall in blood pressure, during superimposed -blockade with bunitrolol and under stable haemodynamic conditions after discontinuation of sodium nitroprusside. The sodium nitroprusside-induced reduction in blood pressure led to a massive increase in plasma noradrenaline and adrenaline and in plasma renin activity. -blockade with bunitrolol did not affect the increased catecholamine concentrations, the increase in plasma renin activity was significantly reduced, the increase in heart rate was reversed, and total peripheral resistance and diastolic blood pressure were further reduced. These changes can be attributed to the intrinsic -sympathomimetic activity of bunitrolol in addition to its -blocking effect. Since no adverse effect was observed in this study, combined therapy with sodium notroprusside and -receptor blockade should be employed if the effects of increased sympathetic tone are considered to be undesirable.     

Effects of azepexole on blood pressure, pulse rate, plasma renin activity and urinary catecholamines in normotensive subjects

Single 5 mg oral doses of azepexole were administered to 6 normotensive male volunteers. Effects on blood pressure and pulse rate were recorded with the subjects supine, erect and during exercise for 8 hours after drug ingestion. Plasma renin activity and urinary catecholamine excretion were measured before and after treatment. Blood pressure was reduced when supine, erect and during exercise. The maximum reduction in systolic and diastolic blood pressure was 20.7 mmHg and 7.9 mmHg, respectively. There was a small reduction in the pulse rate when supine, significant from 2 to 3 hours after drug ingestion. Plasma renin activity increased significantly with drug treatment. There was an insignificant trend towards a reduced urinary catecholamine excretion. Only 1 subject developed significant side-effects. The similarity of azepexole to clonidine is discussed. It is considered that azepexole warrants further study as a hypotensive drug.     

Effects of azepexole on blood pressure,pulse rate,plasma renin activity and urinary catecholamines in normotensive subjects

Summary

Single 5?mg oral doses of azepexole were administered to 6 normotensive male volunteers. Effects on blood pressure and pulse rate were recorded with the subjects supine, erect and during exercise for 8 hours after drug ingestion. Plasma renin activity and urinary catecholamine excretion were measured before and after treatment. Blood pressure was reduced when supine, erect and during exercise. The maximum reduction in systolic and diastolic blood pressure was 20.7 mmHg and 7.9 mmHg, respectively. There was a small reduction in the pulse rate when supine, significant from 2 to 3 hours after drug ingestion. Plasma renin activity increased significantly with drug treatment. There was an insignificant trend towards a reduced urinary catecholamine excretion. Only 1 subject developed significant side-effects. The similarity of azepexole to clonidine is discussed. It is considered that azepexole warrants further study as a hypotensive drug.     

Labetalol in the treatment of essential hypertension: a single-blind dose ranging study

The hypotensive efficacy of labetalol was evaluated in 29 patients with essential hypertension in a single-blind dose ranging study. After a two-week period of placebo treatment, labetalol was given in oral doses of 0.6 g/d, 0.8 g/d, and 0.8 g/d combined with 25-50 mg/d of hydrochlorothiazide. Each regimen lasted four weeks. The decrease in blood pressure was dose dependent: 90% of patients showed a significant reduction in diastolic blood pressure and 75% showed a significant reduction in systolic blood pressure. In 69% of the patients, side effects of the drug were noted, and in five patients (17%), treatment was discontinued because of the side effects. Seven patients received labetalol intravenously before the oral treatment. Their heart rate and blood pressure reductions were similar to those found in patients only taking the medication orally. We conclude that labetalol is an efficient and safe antihypertensive agent in both oral and intravenous administration. However, the high incidence of side effects makes labetalol a drug of second choice in uncomplicated hypertensive patients.     

Beta-adrenergic receptor blocking drugs, hypertension and plasma renin.

1 Propranolol and pindolol reduced both the blood pressure and plasma renin activity when given chronically to hypertensive patients. 2 There was no correlation between the fall in blood pressure and the fall in plasma renin activity. 3 Neither the basal nor the random plasma renin activity predicted the patients who would respond to beta-adrenergic receptor blocking drugs. 4 Oral propranolol reduced plasma renin activity but did not reduce blood pressure within 4 h of administration; oral pindolol reduced blood pressure but did not reduce plasma renin activity within 4 h of administration. 5 The reduction of blood pressure by propranolol and pindolol does not seem to be mediated by changes in plasma renin in most patients.