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.     

Effect of oral labetalol on plasma catecholamines,renin and aldosterone in patients with severe arterial hypertension

Summary Arterial blood pressure and plasma catecholamines, renin activity and aldosterone concentration in 12 patients with severe essential hypertension were studied before and after combined -and -adrenergic receptor blockade induced by oral labetalol treatment for 2 months. Furosemide in a fixed dose was employed as a basic antihypertensive agent throughout the study. Blood pressure was adequately controlled in only 6 patients. Mean body weight increased by 1.8 kg and there was a rise in body weight which was inversely correlated with the fall in standing mean blood pressure. The mean plasma noradrenaline concentration decreased from 0.30 to 0.20 ng/ml, whereas plasma adrenaline did not change significantly. Plasma renin activity and aldosterone concentration varied greatly, but the mean values did not change significantly. Change in body weight was correlated inversely with changes in plasma noradrenaline and renin. The results suggest that labetalol, through its combined - and -adrenergic receptor blocking action, induces a rise in body weight, probably due to sodium and fluid retention, which partly counterbalances the antihypertensive effect of labetalol, and partly modifies both renin and sympathetic nervous activity.     

The relationship of plasma levels of pindolol in hypertensive patients to effects on blood pressure, plasma renin and plasma noradrenaline levels

1. Fifteen, previously untreated, hypertensive patients were given 20 mg of pindolol, orally. The systolic and diastolic blood pressures fell significantly in 1 h; the effect was maximal 4 h after pindolol, and persisted for at least 8 h. 2. After oral administration of 20 mg of pindolol, its concentration in the plasma reached a peak in 2-3 h. At the end of 8 h, pindolol was not detectable in the plasma. 3. There was a significant relationship between the peak concentration of pindolol in plasma and the maximal change in blood pressure in fifteen previously untreated hypertensive patients. In a separate study of nine-nine hypertensive outpatients taking 15-80 mg of pindolol daily, the blood pressure responses corresponded generally to the concentration of pindolol in plasma 2-3 h after the morning dose. 4. There were no significant changes in plasma renin activity, plasma renin concentration or plasma noradrenaline concentration in the previously untreated patients taking 20 mg of pindolol. There was no relationship between initial plasma renin or noradrenaline levels and blood pressure responses to pindolol. Nor was there any significant relationship between the changes in plasma renin or noradrenaline levels and the changes in blood pressure.     

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.     

Haemodynamic and hormonal changes during acute and chronic diuretic treatment in essential hypertension

Summary The short- and long-term effects of diuretic treatment with chlorthalidone 50 mg/day on haemodynamic and hormonal parameters in patients with essential hypertension (WHO grade I) were investigated. After three days of treatment, all patients showed a rise in plasma renin activity (PRA), plasma aldosterone (PA), urinary norepinephrine excretion (UNE) and heart rate (HR), and a decrease in body weight (BW) and extracellular volume (ECV) and blood volume (BV); the change in blood pressure (BP) was variable. The changes in BP were correlated with those in BV. After three months of therapy, the signs of volume depletion tended to fade, but the lower ECV persisted. In contrast to the 4-day study, after three months the change in BP correlated inversely with changes in ECV and renin dependency (saralasin response), and positively with PRA and changes in UNE. It is concluded that the BP response to diuretic treatment is determined by the adaptation with time of the haemodynamic reactions to the volume-depleted state. Whether this adaptation will take place cannot be predicted from the control values of the parameters studied, or from acute changes observed during the first days of treatment.     

Time course of blood pressure,pulse rate,plasma renin and metoprolol during treatment of hypertensive patients

Summary Eleven patients were treated for essential hypertension with metoprolol (Selokén^®) for more than three months. The time course of changes in blood pressure, pulse rate and plasma renin activity was studied during treatment with an oral maintenance dose of 100 mg twice daily. Significant decreases in pulse rate, diastolic blood pressure and plasma renin activity were observed even after the first dose. The plasma concentration of metoprolol reached equilibrium after the second dose. After the third dose there was no further significant change in blood pressure. There was a significant correlation (p<0.001) between the initial (after three doses) and final (after >90days) effect of metoprolol on blood pressure (r=0.86 and 0.91 for systolic and diastolic blood pressure change, respectively).     

Postprandial changes in supine and erect heart rate,systemic blood pressure and plasma noradrenaline and renin activity in normal subjects

Summary The haemodynamic effects of a standard meal were assessed in a balanced cross-over study in eight normal fasting subjects, investigated under conditions applicable to many drug tests.Both the supine and erect diastolic blood pressure were reduced on average by 10 mmHg over the 4 h following the meal.The supine systolic pressure was increased on average by 2 mmHg, a difference of no biological relevance. Erect systolic blood pressure was not affected by eating.Supine heart rate was slightly but significantly increased, but the erect heart rate did not change.Postprandial plasma renin activity was increased. Venous plasma noradrenaline levels in the supine position were not affected by eating and after standing erect, and immobile for 5 min they were only slightly and not-significantly increased.A food-induced vasodepressor response combined with baroreceptor resetting is considered to have occurred in this population. The changes had a gradual onset, reaching their maximum about 2 h after eating and they were still evident after 3 h. Eating should be considered as an important potential source of bias in cardiovascular studies.     

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.     

Effects of once daily indapamide and pindolol on blood pressure,plasma aldosterone concentration and plasma renin activity in a general practice setting

Summary Sixteen patients with essential hypertension completed a double blind factorial trial comparing the effects of indapamide (2.5 mg daily) and pindolol (10 mg daily) on blood pressure, heart rate, plasma renin activity and plasma aldosterone concentration. There were four randomised test phases of eight weeks each during which patients received indapamide alone, pindolol alone, indapamide plus pindolol and no active treatment (placebo). Blood pressure and heart rate were measured every two weeks. Supine mean arterial pressure fell from 117 mm Hg in the placebo phase to 111 mm Hg in the indapamide phase, 106 mm Hg in the pindolol phase and 103 mm Hg in the combined indapamide plus pindolol phase. Factorial analysis confirmed that the hypotensive effects of the two drugs were additive, without evidence of potentiation or antagonism. Indapamide caused significant reductions in plasma potassium and chloride, and increases in plasma bicarbonate and urate concentrations; it also caused increases in plasma renin activity and aldosterone concentration. These changes are similar to those observed with thiazide diuretics.     

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.     

Effects of acute and long-term beta-adrenoceptor blockade with propranolol on haemodynamics,plasma catecholamines and renin in essential hypertension

Summary The effect of an acute intravenous and repeated oral doses of propranolol on haemodynamics, plasma and urinary catecholamines and plasma renin activity was studied in patients with essential hypertension. Intravenous injection of propranolol 5 mg produced a fall in cardiac output but had no consistent effect on blood pressure. Treatment with oral propranolol for 24 weeks lowered cardiac output and blood pressure; total peripheral resistance did not differ from the pretreatment values. Neither acute intravenous nor chronic oral administration of the beta-blocker affected the resting plasma levels of noradrenaline and adrenaline. Long-term treatment with propranolol reduced urinary excretion of vanilmandelic acid without affecting urinary catecholamine excretion. Acute intravenous injection of propranolol decreased plasma renin activity less than did chronic oral treatment with the drug. The observed time course of plasma renin activity was compatible with the view that suppression of this enzyme contributed to the antihypertensive effect of propranolol.     

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.     

Effect of intravenous ketanserin on plasma catecholamines and renin activity in normal volunteers

Summary In a placebo controlled, single blind, randomized cross over study catecholamines (CA) and renin activity (PRA) in plasma were measured in 2 female and 4 male healthy volunteers, at rest in the supine position, following a single intravenous injection of 0.15 mg/kg ketanserin (K) and placebo (P, 10 ml saline). K caused a significant increase in the area under the plasma norepinephrine (NE) time curve (AUC_NE) from 13,200 to 18,100 ng × 1^–1 × min for 1 hour after the injection. The area under the plasma epinephrine (E) time curve (AUC_E) was also increased but to a lesser extent; it was significantly elevated from 54 to 68 ng × 1^–1 × min for 1 minute after the injection. Dopamine (DA) and PRA did not show any significant response to ketanserin. Following the P injection, none of the four parameters showed any significant change.     

Effect of nifedipine on plasma catecholamines in man at rest and during exercise

Summary Blood pressure, heart rate, and plasma catecholamine concentrations were measured in 9 normotensive volunteers during a randomized cross-over study of oral nifedipine (10 mg×5) and placebo; measurements were made at rest and during maximal anaerobic exercise. At rest nifedipine reduced blood pressure and increased heart rate and plasma noradrenaline, whereas plasma adrenaline did not change. During exercise, the blood pressure response was similar in nifedipine and placebo treated subjects; however, heart rate was significantly higher with nifedipine. Plasma noradrenaline increased more during exercise in nifedipine-treated subjects. By contrast, nifedipine inhibited the increase in plasma adrenaline induced by exercise.The results suggest that peripheral vasodilatation induced by nifedipine is responsible for increased sympathetic nerve activity, both at rest and during exercise, and that nifedipine inhibits adrenaline secretion in man.The data were presented in part at the Symposium: Calcium entry blockers and tissue protection, Rome, 1984     

Effect of nifedipine on plasma renin,aldosterone and catecholamines in arterial hypertension

Summary Acute sublingual administration of nifedipine 10–20 mg to 13 hypertensive patients caused a rapid decrease in blood pressure (BP) and a concomitant increase in heart rate (HR), plasma noradrenaline (NA) and plasma renin activity (PRA); there was no significant change in plasma adrenaline (A) or aldosterone (ALDO). Basal PRA was the major determinant of the rise in PRA, as a close correlation was present between the basal value and the increase caused by nifedipine (r=0.92, p<0.001). The rise in PRA was also correlated with the plasma concentration of nifedipine after 60 min (r=0.80, p<0.01), but it was not correlated with the decrease in BP, the rise in HR or the increase in NA. Nifedipine 30–60 mg daily for 6 weeks caused a reduction in mean BP from 133 to 113 mmHg (p<0.001). Body weight and serum potassium decreased but no consistent change was noted in NA, PRA, ALDO or 24 h-excretion of catecholamines. A significant correlation was present between the change in NA and that in PRA (r=0.74, p<0.01). The alterations in the various parameters in the acute and chronic studies were not correlated. The findings indicate that different regulatory mechanisms are activated during acute and chronic administration of nifedipine. It is suggested that an initial rise in sympathetic activity gradually decreases during prolonged therapy, but it still remains a determinant of PRA.     

Influence of dobutamine and dopamine on hemodynamics and plasma concentrations of noradrenaline and renin in patients with low cardiac output following acute myocardial infarction

Summary The comparative hemodynamic effects of dobutamine and dopamine were studied in 6 patients with low cardiac output resulting from acute myocardial infarction. Plasma levels of noradrenaline and renin were measured before and during a 5 µg/kg/min infusion of each of the drugs. Dobutamine had a more pronounced chronotropic effect, increased the systolic arterial pressure more and decreased the systemic vascular resistance less than dopamine at doses which had comparable effects on cardiac output. Dobutamine stimulated renin release, which might partly be the cause of the increased systolic arterial pressure. The drug reduced the plasma level of noradrenaline, which might be explained as a reflex reduction in sympathetic tone. Dopamine, however, did not stimulate renin release but it did enhance the plasma level of noradrenaline, which might be due mainly to the release of endogenous noradrenaline.     

Effects of a new long-acting beta-blocker bopindolol (LT 31-200) on blood pressure,plasma catecholamines,renin and cholesterol in patients with arterial hypertension

Summary Bopindolol (LT 31-200), a new, long-acting, non-selective beta-blocker, was given as monotherapy to 13 patients, 12 with essential hypertension and 1 with renovascular hypertension. After a placebo period of 4–6 weeks, bopindolol was given once daily, starting with 1 mg and subsequently increasing at two-weekly intervals to 2 and 4 mg once daily until a diastolic blood pressure⩽90 mmHg was achieved. The effective dose was continued for 12 weeks. In 10 patients plasma levels of renin, noradrenaline, adrenaline and cholesterol were measured during placebo and after 3 months of therapy. Blood pressure and heart rate were lowered significantly during bopindolol treatment. The mean effective dose was 2.2 mg per day. In 10/13 patients a diastolic blood pressure⩽90 mmHg was achieved. Side effects were minimal. Changes in plasma noradrenaline and adrenaline were small and not significant, but renin and cholesterol were significantly reduced. Thus, LT 31-200 is an effective and well tolerated beta-blocker when given in a once daily dosage.     

Acute effects of a new vasodilator,Ro 12-4713, on blood pressure,plasma renin activity,aldosterone and catecholamine levels,and renal function in hypertensive and normal subjects

Summary Selected cardiovascular and endocrine effects of the new oral vasodilator Ro 12-4713 have been evaluated in an acute single dose study. In five patients with essential hypertension, Ro 12-4713 caused a dose-dependent decrease in supine and upright blood pressure and an increase in heart rate. Initial effects occurred one to 2 h after drug ingestion and maximal effects were noted after five hours and persisted for at least 8 h. Blood pressure was normalized, and the antihypertensive and chronotropic effects persisted for 24 h after a dose of about 300 mg/1.73 m². Plasma and urinary norepinephrine and plasma renin levels tended to be raised, whereas plasma and urinary epinephrine and plasma aldosterone did not change. Changes in supine heart rate were inversely correlated with changes in mean blood pressure (r=–0.60; P<0.02), and positively with those in plasma norepinephrine (r=0.55; P<0.05) and renin (r=0.62, P<0.01); changes in supine plasma renin level were also inversely correlated with those in mean blood pressure (r=–0.65; P<0.01), and positively with those in plasma norepinephrine (r=0.58; P<0.05). 24 h-urinary sodium excretion was significantly (P<0.001) decreased; it was positively correlated with mean blood pressure (r=0.51; P<0.05) and inversely with supine plasma renin activity (r=–0.63; P<0.01). In six normal subjects and six patients with essential hypertension, effective renal plasma flow and the renal clearance of sodium, potassium, calcium and uric acid were not significantly altered five hours after a dose of Ro 12-4713 of about 250 mg/1.73 m²; glomerular filtration rate tended to be slightly decreased, and filtration fraction was significantly (P<0.05) reduced in the hypertensive patients. At the same time blood pressure was decreased and plasma norepinephrine (P<0.01) and renin (ns) were slightly increased in both groups. Ro 12-4713 in a single oral dose of about 300 mg appeared to be a potent, long acting, hypotensive vasodilator.     

卡维地洛治疗慢性心衰对外周血浆肾素及利钠肽的影响

目的:探讨β-受体阻滞剂卡维地洛治疗慢性心力衰竭时对外周血中血浆肾素活性(PRA)、心钠肽(ANP)及脑钠肽(NBNP)水平的影响.方法:60例慢性心衰患者随机分为常规治疗组(血管紧张素转换酶抑制 利尿剂 地高辛)和卡维地洛组(常规治疗药物 卡维地洛),随访12周,采用放射免疫法测定二组治疗前后和30例健康体检者(正常对照组)外周血中PRA、ANP及N-BNP水平.同时使用核素心室显像测定心衰患者左心室射血分数(LVEF).结果:心衰患者外周血中PRA、ANP及N-BNP水平较正常对照组显著升高,其中ANP及N-BNP水平在卡维地洛治疗前与LVEF负相关,在卡维地洛治疗后与LVEF密切相关,但PRA水平与LVEF无关.治疗后卡维地洛组外周血中PRA、ANP及N-BNP水平较常规治疗组下降更明显.结论:外周血中ANP及N-BNP水平在慢性心衰的病理生理机制中起着重要作用,甚至在β-受体阻滞剂治疗后仍可用于指导心衰患者的治疗.β-受体阻滞剂能抑制心衰患者神经内分泌的过度激活.     

Long term treatment of moderate hypertension with penbutolol (hoe 893d). II. Effect on the response of plasma catecholamines and plasma renin activity to insulin-induced hypoglycemia

Summary The effect of insulin-induced hypoglycemia on the blood levels of catecholamines and renin activity has been studied in five patients with moderate hypertension before and after treatment for 3 – 8 months with penbutolol (PEN) 20 – 30 mg twice daily. Penbutolol caused no change in fasting blood glucose level. Insulin 0.1 IU per kg body weight i.v. reduced blood glucose concentration by approximately 50 per cent after 30 – 45 min, both before and during treatment with penbutolol. Hypoglycemia prior to medication was accompanied by a marked increase in the production of adrenaline and a minor increase of noradrenaline in all five patients. During treatment the response of adrenaline to hypoglycemia was reduced in four patients and the data was inconclusive in one. Basal renin activity was rather low in three patients, within the normal range in one and relatively high in one. Before penbutolol the hypoglycemia-induced increase in catecholamine production caused no change in plasma renin activity in the three patients with low basal levels, whereas a marked increase was observed in the other two. During medication plasma renin activity remained unchanged on induction of hypoglycemia regardless of the catecholamine response. Despite the marked increase in plasma adrenaline following insulin-induced hypoglycemia, no statistically significant increase in pulse rate was recorded.