The effects of beta-adrenoceptor blockade on renin, angiotensin, aldosterone and catecholamines at rest and during exercise.

1 beta-adrenoceptor blockade with metoprolol provoked, both at rest and during exercise, a decrease of 'active' renin and angiotensin II together with an increase of 'inactive' renin and unchanged 'total' renin. The significant exercise-provoked increases in angiotensin II, plasma renin activity and 'active', 'inactive' and 'total' renin when on placebo, were reduced by metoprolol. 2 No significant change in serum sodium and potassium and in plasma aldosterone was found during beta-adrenoceptor blockade at rest. During exercise plasma aldosterone dropped significantly without any change in serum sodium or potassium. 3 Plasma noradrenaline increased significantly at rest on metoprolol. The increase in plasma noradrenaline and adrenaline during exercise was similar on placebo and on metoprolol.     

Catecholamines, renin-angiotensin-aldosterone, and cardiovascular response during exercise following acute and long-term calcium antagonism with felodipine in essential hypertension

Studies were performed in nine patients with essential hypertension to explore the effect of the calcium antagonist felodipine on the exercise-induced responses of the sympathetic and renin-angiotensin-aldosterone systems as well as of blood pressure and heart rate. The patients were subjected to an individually graded submaximal work test (bicycling) after administration of placebo and a single dose of felodipine (10 mg) in a double-blind design and following long-term (8 weeks) felodipine treatment (10 mg twice daily). After a single dose of felodipine sitting preexercise blood pressure was decreased, whereas heart rate, plasma noradrenaline, adrenaline, renin activity, and angiotensin II increased. After long-term felodipine treatment blood pressure was reduced, heart rate was unchanged, and plasma noradrenaline and renin activity increased. The exercise-induced increases in plasma catecholamines, renin activity, angiotensin II, aldosterone, blood pressure, and heart rate were similar after acute and long-term felodipine administration as compared with placebo. In conclusion, acute and long-term felodipine treatment influences neither reflex activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system nor the cardiovascular responses to physical exercise in patients with essential hypertension.     

Effect of alacepril on blood pressure and neurohumoral factors at rest and during dynamic exercise in patients with essential hypertension.

We assessed blood pressure and neurohumoral factors at rest and during exercise in 10 patients with essential hypertension before and after treatment with the new angiotensin converting enzyme inhibitor, alacepril (25-50 mg day-1). Alacepril significantly lowered mean blood pressure at rest and at the same exercise load as before treatment without affecting heart rate response. The response of plasma renin activity, plasma aldosterone, and plasma adrenaline were not changed by alacepril, but increase of plasma angiotensin II and plasma noradrenaline during exercise were significantly attenuated after alacepril treatment (ANOVA, P = 0.04, both). The change in mean blood pressure during exercise was positively correlated with the decrease in plasma angiotensin II (r = 0.65, P < 0.05). These results demonstrated that alacepril was effective in essential hypertension both at rest and during exercise, suggesting that the antihypertensive effect during exercise might be related to the decrease in pressor hormones, especially in plasma angiotensin II.     

The effect of 8 weeks treatment with the calcium antagonist felodipine on blood pressure, heart rate, working capacity, plasma renin activity, plasma angiotensin II, urinary catecholamines and aldosterone in patients with essential hypertension.

The effect of 8 weeks treatment with the calcium antagonist felodipine--a new long-acting dihydropyridine derivative--in a dose of 10 mg twice daily was studied in 10 male patients with essential hypertension, WHO grade I-II, aged 25-62 years. Diastolic blood pressure was reduced in supine and upright position. Systolic blood pressure was reduced only in the upright position. Heart rate was unchanged in the supine and decreased in the upright position. During dynamic exercise blood pressure was reduced. The maximal working capacity decreased, whereas the maximal heart rate attained was unchanged. Twenty-four hour urinary noradrenaline excretion, plasma renin activity and 24 h urinary aldosterone excretion were increased. Plasma angiotensin II and 24 h urinary adrenaline excretion were unchanged. In conclusion, felodipine is an effective long-acting blood pressure lowering drug with minor side effects. After 8 weeks on felodipine treatment heart rate was not increased, although the activity of the sympathetic nervous system and the renin-aldosterone system seemed enhanced.     

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     

The effect of captopril and propranolol on the responses to posture and isometric exercise in patients with essential hypertension

The effects of captopril and propranolol on blood pressure, heart rate and plasma noradrenaline, renin and aldosterone, and on the responses to changes in posture and to isometric exercise were measured in patients with essential hypertension. During placebo administration blood pressure, heart rate and plasma noradrenaline rose on standing and during isometric exercise. The rise in diastolic blood pressure during isometric exercise correlated significantly with the rise in plasma noradrenaline. During captopril treatment blood pressure was significantly lower than during placebo administration when the patients were lying, standing or sitting, but the reduction during isometric exercise was not significant. Plasma renin increased, but heart rate, plasma noradrenaline and plasma aldosterone remained unchanged. The acute changes in blood pressure, heart rate and plasma noradrenaline produced by standing and isometric exercise during captopril treatment were similar to those during placebo administration. During propranolol treatment diastolic blood pressure was significantly lower than during placebo administration when the patients were lying, standing or sitting and during isometric exercise. Heart rate also fell. Plasma noradrenaline during standing, sitting and isometric exercise was significantly greater than during placebo administration. The changes in plasma noradrenaline measured during propranolol treatment with the patients supine were negatively correlated with noradrenaline values obtained during placebo administration: plasma noradrenaline fell in patients with higher, and increased in those with lower, initial concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

UNEXPECTED INCIDENCE OF LOW BLOOD PRESSURE 2 YEARS AFTER UNILATERAL ADRENALECTOMY FOR PRIMARY ALDOSTERONISM

1. Serial observations of blood pressure after unilateral adrenalectomy for aldosterone-producing adenoma revealed an incidence of hypotension (systolic BP less than fifth percentile for age- and sex-matched normal population) of 27% at 2 years, more than 5 times that predicted. 2. Serial observations of volume regulatory hormones showed significantly raised mean levels of plasma renin activity consistent with hypovolaemia. Significantly reduced mean aldosterone levels despite significantly raised mean plasma renin activity levels may reflect reduced responsiveness of the remaining adrenal. 3. Reduction of significantly elevated preoperative ANP levels to significantly reduced levels postoperatively is also in keeping with postoperative hypovolaemia. 4. A 50% reduction in plasma adrenaline after unilateral adrenalectomy might contribute to reduced noradrenergic activity (prejunctional beta-receptor) and reduced blood pressure, but plasma noradrenaline did not fall significantly postoperatively. 5. Postoperative levels of renin, aldosterone, adrenaline and noradrenaline were not significantly different between those who did, and those who did not, become hypotensive.     

Acute haemodynamic and humoral responses to felodipine and metoprolol in mild hypertension

Summary Oral administration of felodipine to 10 patients with mild essential hypertension acutely reduced systemic vascular resistance (SVR) by 40% after 30 min. The change in SVR was significantly related to age (r=–0.74). The reduction in the intraarterially measured brachial artery pressure was limited to 15/13 mmHg, due to a rise in cardiac output (CO). The tachycardia was sustained for 90 min, as was an elevation of plasma noradrenaline. There was a transient increase in stroke volume, associated with a reduction in pulmonary capillary wedge pressure, which was at least partly due to a reduced intravascular volume. In contrast to SVR, pulmonary vascular resistance was not affected by felodipine. Addition of intravascular metoprolol after 90 min decreased HR and CO and augmented SVR. The felodipine-induced rise in plasma renin activity (PRA) of 100% was completely reversed by metoprolol. Plasma angiotensin II (PA II) rose by 15% during felodipine, whereas plasma aldosterone concentration (PAC) was not affected. Thus, actuely administered felodipine was a potent dilator of systemic but not of pulmonary arterioles, it stimulated the sympathetic nervous system, and reduced left ventricular filling pressure. The rise in plasma renin did not result in a higher plasma aldosterone level, due partly to reduced generation of angiotensin II.     

Effects of intravenous endralazine in essential hypertension.

The effects of endralazine, administered intravenously, on blood pressure, heart rate, forearm blood flow, plasma renin activity, aldosterone, adrenaline and noradrenaline were studied in five patients with essential hypertension. Endralazine reduced peripheral vascular resistance, resulting in decrease in mean arterial pressure from 141 to 116 mm Hg and increase in heart rate from 67 to 92 beats/min. Plasma renin activity, adrenaline and noradrenaline increased significantly after endralazine infusion. All effects observed are consistent with endralazine acting as a peripheral vasodilating drug.     

Effects of felodipine on atrial natriuretic peptide in hypertensive non-insulin dependent diabetes mellitus.

Eighteen patients with non-insulin dependent diabetes mellitus and hypertension were treated during two 4 week periods with the calcium antagonist felodipine or placebo in a double-blind, randomised, cross-over study. Mean systemic blood pressure was significantly lower on felodipine, without producing a deleterious effect on diabetic control. Felodipine was associated with an increment in plasma renin concentration but plasma aldosterone and the renal outputs of sodium and dopamine were similar on both treatments. Plasma atrial natriuretic peptide levels were significantly reduced following felodipine treatment.     

Comparison of the effects of felodipine and cilazapril on exercise performance in patients with mild to moderate hypertension. A crossover study

This double-blind crossover study was designed to compare the effects of felodipine and cilazapril on exercise performance in hypertensive patients. After a 2-week placebo run-in period, 40 patients with mild to moderate hypertension were randomized into two parallel groups to receive either felodipine (10 mg) or cilazapril (5 mg) for 4 weeks. After another 2-week washout period, treatments were then crossed over for a further 4-week study period. All patients were given an extensive rest and exercise evaluation at the end of the placebo period. Extensive rest and exercise evaluations were repeated after a 4-week treatment period and again after the second washout period and after the second 4-week treatment period. Before each exercise test, epinephrine, norepinephrine and dopamine plasma levels and plasma renin activity were measured. Two groups were similar at baseline for systolic and diastolic blood pressure and heart rate as well as for laboratory and hormonal variables and duration of exercise test. At the end of treatment diastolic blood pressure was significantly reduced in the felodipine group (p = 0.019). Duration of exercise test was longer than at baseline (p = 0.031) in the felodipine group. Plasma dopamine levels were significantly increased in the cilazapril group. Plasma renin activity significantly increased in the felodipine group. In conclusion, our data show that the two drugs have the same effectiveness in resting conditions but that felodipine is more effective in lowering maximum exercise diastolic blood pressure and in improving exercise time with an double product increase (not significant); it has no statistically significant effect on maximal exercise systolic blood pressure.     

The level of plasma neuroendocrine activity and the concentration of digoxin in the serum of patients with mild chronic heart failure

The concentrations of adrenaline, noradrenaline, dopamine, aldosterone, the atrial natriuretic hormone, and plasma renin activity were investigated in 50 patients with mild chronic heart failure. The patients received oral digoxin chronically in a daily dose of 0.125 mg. On the basis of the estimate of the dosing of digoxin these patients were divided into two groups: the first with therapeutic and the second with subtherapeutic concentrations of digoxin in serum. The therapeutic concentration of digoxin in serum was found in 23 patients (46%), while subtherapeutic levels were found in 27 patients (54%). The concentrations of noradrenaline, dopamine, the renin activity of plasma, aldosterone and the atrial natriuretic hormone in the blood serum in the group of patients in whom the presence of subtherapeutic concentrations of digoxin was found, did not differ essentially from the concentration that was observed in the group with therapeutic concentrations. Only the concentration of adrenaline was higher (p < 0.05) in the group of patients with therapeutic concentrations of digoxin. The above results reveal that the neuroendocrine activity of plasma (except for the concentration of adrenaline) is alike in both ranges of digoxin concentrations in serum.     

Effect of felodipine,a new calcium channel antagonist,on platelet function and fibrinolytic activity at rest and after exercise

Summary Fourteen healthy male volunteers (age 21–29 years, mean 23.7 years) were given placebo for 14 days followed immediately by felodipine 5 mg b.d. for a further 14 days. After each period of treatment blood for analysis was taken at rest and after exercise on a cycle ergometer. Platelet aggregation, plasma beta-thromboglobulin (B-TG), platelet factor 4 (PF-4), adrenaline and noradrenaline, and serum thromboxane B₂ (TXB₂), 6-keto-prostaglandin (F₁ (6-keto-PGF₁), and euglobulin clot lysis time (ECLT), were measured on each occasion. The ECG, heart rate and blood pressure were monitored during the exercise tests.After felodipine therapy there was a significant decrease in the plasma level of PF-4 and B-TG at rest. This effect was maintained during exercise. There was no significant change in platelet aggregation, ECLT, TXB₂ or 6-keto-PGF₁ at rest or during exercise. Irrespective of therapy, the plasma levels of adrenaline and noradrenaline were increased and the ECLT was decreased when measured immediately after exercise.Thus, felodipine in modest therapeutic dosage decreases the plasma levels of B-TG and PF-4, indicating an inhibitory effect on platelet on release. The effect also occurred during exercise. Felodipine did not change fibrinolytic activity or the production of TXB₂ or 6-keto-PGF₁.     

Effect of beta-adrenergic receptor blockade with propranolol on the response of plasma catecholamines and renin activity to upright tilting in normal subjects.

1 Relationship between plasma catecholamines (measured as noradrenaline and adrenaline) and plasma renin activity (PRA) were examined at rest and during passive head-up tilting for 30 min in nine normal subjects, before and after treatment with propranolol 160 mg daily for 7 days. 2 Noradrenaline (NA) and adrenaline (A) increased substantially after tilting for 15 min. There were no changes in PRA. After 30 min tilting, NA remained elevated, whereas A had returned to resting levels. A significant increase in PRA was apparent at 30 min. Pulse rate and diastolic blood pressure increased progressively during tilting. Systolic pressure did not change. 3 Treatment with propranolol reduced pulse rate and systolic blood pressure at rest and during tilting. Resting catecholamine concentrations and the response of NA to tilting were unaffected. In contrast, treatment prolonged the A response leading to significantly higher levels after 30 min tilting. Propranolol reduced PRA in six of the nine subjects and prevented the increase with tilting observed before treatment.     

Increased plasma adrenaline concentrations in benign essential hypertension

Plasma adrenaline, noradrenaline, and dopamine concentrations and plasma renin activity were measured in the supine position and after standing for 10 minutes in 14 patients with sustained benign essential hypertension and in five patients with labile hypertension. Results were compared with values obtained in 11 normotensive control subjects. In controls plasma noradrenaline concentrations increased with age, while plasma adrenaline values tended to decrease with age. No significant difference in mean plasma noradrenaline was found between hypertensive and control subjects, but plasma noradrenaline seemed slightly increased in a proportion of hypertensive patients aged less than 50. Plasma adrenaline was considerably raised in both supine and standing positions in eight patients with sustained hypertension and in two with labile hypertension. Dopamine concentrations and plasma renin activity were similar in all groups studied. The finding of significantly raised plasma adrenaline concentrations in a large proportion of hypertensive patients supports the hypothesis that the activity of the sympathetic nervous system is increased in essential hypertension. Measurement of plasma adrenaline seems to be a more sensitive index of this activity than that of plasma noradrenaline.     

Effects of single and repeated doses of the calcium antagonist felodipine on blood pressure, renal function, electrolytes and water balance, and renin-angiotensin-aldosterone system in hypertensive patients

Doses of 10 mg b.i.d. of the new dihydropyridine calcium antagonist, felodipine, were tested for seven consecutive days in 11 hospitalized hypertensive patients. A significant reduction of both systolic and diastolic blood pressures, with patients in both the supine and upright positions, occurred immediately after the first dose and was maintained (daily average 15%) throughout the following days. An increase in heart rate was observed after the first dose (15 and 23 beats/min, in supine and upright postures), and subsequently declined to average values of 8 and 14 beats/min on the seventh day. There was a marked natriuretic response during the first and second day, during which an average negative sodium balance of 95 mmol developed; on the following days sodium output was not significantly different from control, but a negative balance averaging 135 mmol was still present on the seventh day of felodipine administration. A moderate negative potassium balance also progressively developed and reached -48 mmol on the seventh day. Glomerular filtration rate was unchanged, but renal plasma flow increased significantly during administration of felodipine. Plasma renin activity and plasma aldosterone were also increased very moderately by felodipine. Compared with previous observations by our group with higher doses of felodipine (12.5, 25, and 50 mg t.i.d.), 10 mg b.i.d. of this new calcium antagonist appear to exert a marked and prolonged blood pressure reduction, accompanied by a definite natriuretic instead of an antinatriuretic effect.     

Effect of indomethacin on hydralazine-induced renin and catecholamine release in the conscious rabbit.

1. The effects of hydralazine on mean arterial pressure (MAP) heart rate (HR), plasma renin activity (PRA) and plasma catecholamines were examined in conscious rabbits before and after prostaglandin synthesis inhibition with indomethacin. 2. Hydralazine (3 mg/kg. i.v.) produced a 12% decrease in MAP and significant increases in HR, PRA and plasma noradrenaline and adrenaline. 3. Indomethacin (5 mg/kg, s.c.) failed to alter significantly the control MAP, HR, PRA or plasma catecholamines but inhibited renal venous prostaglandin E2 by 56% (P less than 0.02). 4. Indomethacin inhibited the hydralazine-induced tachycardia by 24% and augmented its hypotensive effects by 6%. 5. The hydralazine-stimulated increase in PRA was also inhibited 75% (P less than 0.001) by indomethacin whereas noradrenaline and adrenaline concentrations were not significantly reduced. 6. Indomethacin inhibits hydralazine-induced renin release in the presence of elevated concentrations of plasma catecholamines; these findings suggest that renal prostaglandins function as important mediators of sympathetically-induced renin release.     

Long term treatment of moderate hypertension with the beta1-receptor blocking agent metoprolol

Summary The effect of submaximal work and insulin-induced hypoglycaemia on plasma catecholamines and renin activity was studied in nine males with moderate hypertension before treatment, after one month on placebo and after three months of metoprolol treatment. The maintenance dose used was 50–150 mg three times daily. The placebo caused no change in blood glucose, blood pressure, pulse rate, plasma catecholamines and renin activity, neither under basal conditions nor following submaximal work or insulin-induced hypoglycaemia. Metoprolol significantly reduced blood pressure, pulse rate and plasma renin activity under basal conditions whereas plasma catecholamines were unchanged. During metoprolol treatment the increase in blood pressure and pulse rate in response to submaximal work was reduced, but the plasma noradrenaline response was enhanced and plasma adrenaline unaltered. The decrease in pulse rate after work was positively correlated with the mean plasma metoprolol concentration. The fall in blood glucose after insulin 0.1 IU/kg body weight i. v. and its return to normal was unaffected by metoprolol. Before metoprolol, hypoglycaemia was followed by a pronounced increase in plasma adrenaline, with a maximum after 45 min. During metoprolol the adrenaline increase was even more pronounced. Hypoglycaemia was also followed by a two-fold increase in plasma noradrenaline, both before and during treatment with metoprolol. Plasma renin activity during submaximal work and insulin-induced hypoglycaemia varied as much before as during treatment with metoprolol.     

Catecholamines and the renin-angiotensin-aldosterone system during treatment with felodipine ER or hydrochlorothiazide in essential hypertension.

The neurohumoral responses after 10 mg of felodipine extended release (ER), a new dihydropyridine calcium antagonist, and 25 mg of hydrochlorothiazide (HCTZ) were compared in a randomized, double-blind, crossover trial in 28 mild to moderate hypertensives. Antihypertensive drugs were gradually discontinued. Felodipine ER, 10 mg was given once daily for 2 weeks; after another washout period of 1 week, patients were switched to 25 mg of HCTZ once daily and vice versa. Blood pressure (BP) was measured at baseline, 2.5 h after medication, and after 2 weeks of treatment (24 h postdosing) using an oscillometric device. Felodipine ER and HCTZ both lowered BP effectively. However, felodipine ER was superior in reducing systolic and diastolic BP during the short term and medium term. Treatment with felodipine ER over 2 weeks increased sympathetic outflow as indicated by elevated plasma norepinephrine levels, whereas plasma epinephrine was mainly unaffected, as were plasma renin and aldosterone levels. On the other hand, 25 mg of HCTZ increased plasma renin and aldosterone, but left catecholamines unchanged. Despite persistent increased sympathetic activity, the reduction in BP in this study was more pronounced after felodipine ER as compared to HCTZ. The lack of a difference between heart rates under both medications after 2 weeks of treatment suggests a resetting of the baroreflex by felodipine ER and furthermore that the increased norepinephrine levels may not be clinically relevant, but demonstrate the maintained baroreflex activity. HCTZ, in doses as low as 25 mg, is still capable of stimulating the renin-angiotensin-aldosterone system.     

Effects of chronic antihypertensive treatment with acebutolol and pindolol on blood pressures, plasma catecholamines, and oxygen uptake at rest and during submaximal and maximal exercise

The effects of 4-week periods of treatment, with equivalent doses of acebutolol (500 mg daily) and pindolol (15 mg daily), on plasma noradrenaline, adrenaline, and dopamine, and oxygen uptake at rest, during submaximal steady-state exercise and maximal exercise, and 5 min after exercise, were studied in 11 moderately hypertensive men aged 26-40 years, using a single, crossover design. The two agents had similar effects on heart rate and arterial pressures. Neither the noradrenaline nor the dopamine response to exercise was affected by acebutolol or pindolol. However, 5 min after exercise, nor adrenaline was significantly lower after pindolol. Plasma adrenaline concentration was significantly raised only by pindolol during maximal exercise (from 3.9 +/- 2.3 to 5.0 +/- 3.3 nmol/L, p less than 0.05). Neither oxygen uptake, nor ventilation during steady-state exercise were significantly different from control conditions. Maximal oxygen uptake tended to be slightly lower after acebutolol (5%), and distinctly lower after pindolol (14%). The maximal oxygen pulse was significantly increased only after acebutolol. The absence of a noradrenaline enhancement during the action of pindolol and acebutolol suggests that the increased plasma noradrenaline levels observed after some Beta-receptor blockers during work, do not reflect a compensatory response to lower blood pressure or restricted physical work capacity. The differential effects of Beta-receptor blockers appear to be due to differences in their pharmacological properties.