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.     

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.     

Acute effects of prizidilol on blood pressure,heart rate,catecholamines, renin and aldosterone in essential hypertension

Summary Prizidilol is a new antihypertensive agent reported to possess combined precapillary vasodilator and betareceptor-blocking properties. To clarify the profile of the acute effects of prizidilol in man, a variable dose study was performed in 8 patients with benign essential hypertension. Blood pressure, heart rate, plasma renin activity, aldosterone, plasma and urinary catecholamines and electrolytes were determined at short intervals before and up to 23 h after oral administration of placebo and prizidilol 150, 300 and 600 mg. The 4 studies were performed at weekly intervals according to a Latin square design. Prizidilol produced dose-dependent decreases in supine and upright blood pressure, with an initial change after about 2 h and maximal effects from 4 to 8 h after drug ingestion. Following a high dose of prizidilol, supine mean blood pressure (average 128 mmHg prior to treatment) was normalised (<107 mmHg) from 3 to 7 h and was still below predose levels 23 h after ingestion. The only reported side effects were postural dizziness in 2 cases (corresponding to a fall in systolic upright blood pressure to <95 mmHg) and headache in one case. A biphasic variation in heart rate and plasma renin activity, with an early drop and a subsequent tendency to a slight rise, was observed after an intermediate or high dose of prizidilol. Plasma norepinephrine levels were increased by a high dose of prizidilol, while plasma epinephrine, aldosterone and plasma and urinary electrolytes were not consistently changed. Prizidilol in a single oral dose appeared to be a potent antihypertensive agent. The profile of heart rate and plasma renin point to early dominance of beta-blockade followed by appearance of the concomitant vasodilator properties of prizidilol.     

Acute and long-term effects of labetalol on systemic and pulmonary haemodynamics in hypertensive patients

Summary The effects of the combined adrenergic alpha- and beta-receptor blocking compound labetalol on the systemic and pulmonary circulation were studied after its acute and long-term administration to patients with essential hypertension (WHO grade I–II). Nine men and one woman (mean age 46 years) participated in the acute study. Cardiac index, systemic blood pressure, pulmonary artery pressure and heart rate were measured at rest in the supine and upright positions, and during supine exercise at two work loads (50 and 100 watt), before and after intravenous administration of labetalol 50 mg. Eight of the men were re-examined after three months oral treatment with labetalol 600–900 mg daily. In the acute study cardiac index was unchanged by labetalol, except at the work load of 100 watt, when it decreased by 18.7%. The mean blood pressure decreased under all conditions; 11.6 mm Hg at supine rest, 22.3 mm Hg in the upright position, and by 15.9 mm Hg and 16.9 mm Hg at the two work loads. Heart rate was unchanged at supine rest, but was reduced in the upright position 9,0% and during exercise — at 50 watt by 9.3%, and at 100 watt by 10.3%. Systemic vascular resistance decreased at rest in the supine and upright positions, but not during exercise. The pulmonary artery pressure remained unchanged both at rest and during exercise. In the long-term study cardiac index was unchanged except at the heavy work load, when it decreased by 11.4%. Mean blood pressure was reduced significantly under all circumstances, by 14.6 mm Hg at supine rest, 16.8 mm Hg in the upright positions, and by 13.9 mm and 13.4 mm, respectively, at the two work loads. Heart rate was reduced both at rest 13.6% and during exercise at the two work loads 9.6% and 12.4%. Systemic vascular resistance decreased at rest, but not during exercise. The pulmonary artery pressure were unchanged. Thus, the haemodynamic patterns after acute and long-term administration of labetalol were essentially similar, which suggests that the agent is suitable both for acute and long-term treatment of hypertension, at least from a haemodynamic point of view.     

Treatment of essential hypertension with felodipine in combination with a diuretic

Summary In a double-blind cross-over study, the effect on blood pressure (BP), heart rate (HR) and plasma noradrenaline concentration (pNA) of placebo or felodipine given in addition to hydrochlorothiazide was studied in 12 male patients with essential hypertension, not satisfactorily controlled with the diuretic alone. The first dose of felodipine decreased BP and increased HR for about 6 h. After 4 weeks of treatment with felodipine, BP was reduced for 24 h, whereas HR was only transiently increased. The elimination half-life of felodipine was about 23 h. The plasma noradrenaline concentration increased after felodipine and serum uric acid decreased. Side-effects were few and usually mild.     

Felodipine extended release in mild to moderate hypertension

A multi-centre study was carried out to examine the antihypertensive effect and adverse event profile of felodipine in an extended-release (ER) formulation given once daily as monotherapy. Doses of 5 mg, 10 mg or 20 mg felodipine ER were compared with placebo in 183 patients with mild or moderate hypertension. All antihypertensive medication was discontinued on entering a 4-week placebo run-in period. If, at the end of the run-in period, supine diastolic blood pressure was in the range greater than 95 less than 120 mmHg, patients were randomly allocated to double-blind treatment with felodipine, 5 mg, 10 mg or 20 mg, or placebo, to be taken once daily for 4 weeks. Supine and standing blood pressure, heart rate and body weight were measured every 2 weeks during the trial. Assessments were made 24 hours after intake of the study drug. Adverse events were recorded at each review. Over the 4-week treatment period, a dose-related decrease in supine diastolic blood pressure was observed, this reduction occurring already during the first 2 weeks of active treatment. In the placebo group and the felodipine 5 mg, 10 mg and 20 mg groups, supine blood pressure (systolic/diastolic) decreased by 7/6 mmHg, 9/8 mmHg, 12/10 mmHg and 14/11 mmHg, respectively. Supine diastolic blood pressure reduction in the felodipine 10 mg group and both systolic and diastolic blood pressure reductions in the 20 mg group were significantly greater than with placebo. Standing diastolic blood pressure reduction was significantly greater in all three dose groups on felodipine compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-dependent effects of felodipine on diuresis and natriuresis in healthy subjects

We compared the effects of various acute doses of felodipine and placebo on diuresis and natriuresis in healthy men. The subjects were given felodipine, 1 and 3 mg as an intravenous infusion, and 5, 15, and 40 mg as an oral solution on 5 separate days. On each day blood pressure and heart rate were recorded and urine was collected for analysis of volume and sodium for 24 h. Felodipine induced a dose-dependent increase in heart rate and a dose-dependent decrease in diastolic blood pressure. These effects were maximal within 30 min of drug administration. Felodipine induced a maximal increase in diuresis of about 150% compared with placebo and a maximal increase in natriuresis of about 240%. The renal effects were most pronounced during the first 4 h after dose intake. During the 8-24 h interval, diuresis and natriuresis were lower than after placebo, but when the whole 24-h period was considered, no significant differences were found between felodipine and placebo in regard to sodium and water excretion. The most pronounced effects on diuresis and natriuresis were seen after moderate doses (3 mg i.v. and 15 mg orally). The response to the highest dose (40 mg orally) was somewhat less probably due to the excessive drop in diastolic blood pressure.     

Baroreceptor activity in man during administration of the calcium channel blocker felodipine

The mechanisms responsible for the resetting of the baroreceptor reflex during long-term administration of 1,4 dihydropyridine calcium channel blockers are incompletely understood. The present study investigated the effect of 10 mg per day of felodipine on arterial blood pressure (BP), heart rate (HR), urinary norepinephrine, and cardiac beta-1-receptor sensitivity in 10 healthy volunteers. Blood pressure heart rate and urinary norepinephrine were determined during control and on days 1,4, and 14 of felodipine administration. Dose response curves of intravenous bolus injections of isoproterenol were performed on the same days to measure cardiac beta-1-receptor sensitivity. Felodipine significantly reduced the blood pressure from 131 +/- 6/74 +/- 3 mm Hg (mean +/- s.e.m.) to 123 +/- 6/65 +/- 2 mm Hg on day 1 (p less than 0.01). The blood pressure remained decreased during the entire protocol. The initial increase in the heart rate (62 +/- 5 to 67 +/- 4 min-1) remained elevated on day 4 and returned within the control range by day 14 (63 +/- 4 min-1) in spite of unchanged felodipine plasma levels (1.71 +/- 1.13 ng/ml (day 1) and 1.66 +/- 0.66 ng/ml (day 14). Urinary norepinephrine rose significantly with short-term felodipine administration (62 +/- 12 versus 50 +/- 6 micrograms/24 h; p less than 0.01). With long-term felodipine administration this value returned to pretreatment levels (55 +/- 12 micrograms/24 h). Cardiac beta-1-receptor sensitivity was not changed at any point of the protocol.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of felodipine in angina pectoris

Summary The clinical response to felodipine, in addition to a beta-blocker, was evaluated and compared with placebo in this double-blind cross-over study. Twenty patients with exertional angina pectoris completed the study. Felodipine reduced the number of angina attacks and the Glyceryl Trinitrate (GTN) consumption. The median exercise capacity was increased 33% after 4 weeks' felodipine treatment compared with placebo. At maximal exercise, systolic blood pressure and rate pressure product were reduced by felodipine while no change was seen in heart rate or ST-depression. Felodipine reduced both supine and erect blood pressure. The mean supine blood pressure at rest was 138/82 mm Hg after four weeks' placebo treatment compared with 114/71 mm Hg after felodipine 5–10 mg b.i.d. Felodipine has overall a modest but significant antianginal benefit when combined with a beta-blocker.     

Acute renal effects of oral felodipine in normal man

Summary The acute renal effects of a single oral dose of felodipine 0.15 mg/kg were studied in 8 healthy males. Thirty minutes after administration the mean plasma concentration was 25.7 nmol/l. There was a significant reduction in diastolic blood pressure (24%) and a concomitant rise in heart rate (38%), leaving the systolic pressure unchanged. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion technique using the clearance of¹²⁵I-iothalamate and¹³¹I-hippuran respectively. GFR was unchanged and the filtration fraction (FF) was reduced, whilst there was a decrease in renal vascular resistance (RVR). The glomerular filter characteristics were unchanged, as estimated by the unchanged excretion rate of albumin. There was a significant rise in the clearance of sodium (176%) but only a small and insignificant increase in urine volume. Clearance of potassium was decreased. An increase in the clearance of uric acid and a rise in the beta-2-microglobulin excretion rate were found, both suggesting a proximal tubular effect of felodipine. The excretion rate of calcium was increased.     

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.     

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.     

Antihypertensive efficacy and tolerability of a fixed combination of metoprolol and felodipine in comparison with the individual substances in monotherapy. The Swedish/United Kingdom Study Group.

In this double-blind, randomized, parallel-group study, the aim was to compare the efficacy and tolerability of a new fixed combination of felodipine and metoprolol with the individual components in monotherapy. After a placebo period of 4 weeks, 159 patients with mild to moderate essential hypertension were randomized to extended-release formulations of either felodipine plus metoprolol 10 + 100 mg (FM), felodipine 10 mg (F), or metoprolol 100 mg (M) once daily if supine diastolic blood pressure greater than 95 mm Hg. After 12 weeks of active treatment, the reductions in supine blood pressure (24 h after dosing) were 20/14, 13/10, and 11/8 mm Hg for FM, F, and M, respectively. The difference in change was 7/4 mm Hg (p = 0.004/p = 0.006) and 8/5 mm Hg (p = 0.0002/p less than 0.0001) for the fixed combination and F or M, respectively. Blood pressure control (diastolic blood pressure less than 90 mm Hg after 12 weeks) was significantly better for the combination than for F and M, i.e., 71%, 49% (p = 0.008), and 34% (p = 0.004), respectively. Adverse experiences were those to be expected from previous studies with felodipine and metoprolol and did not differ in frequency between groups. It can be concluded that a fixed combination of metoprolol and felodipine has a clinically relevant and significantly better blood pressure reduction 24 h postdose than the individual substances in monotherapy, without decreased tolerability.     

Ketanserin, a novel 5-hydroxytryptamine antagonist: monotherapy in essential hypertension

Blood pressure and heart rate, supine and standing, were studied in patients with essential hypertension during 8 weeks of oral therapy with two dosage schedules of ketanserin, 40 mg once and twice daily. Ketanserin caused significant reductions in both supine and standing blood pressure but no significant alterations in heart rate in both groups of patients. Measurements of blood pressure and heart rate over a 24 h period during steady state conditions revealed that maximal blood pressure reduction was correlated with time to peak plasma concentrations. Steady state plasma concentrations of ketanserin were significantly higher in the patients receiving 40 mg twice daily compared to 40 mg once daily. In the group with once daily treatment, tmax was 1.2 +/- 0.17 h, Css 13 +/- 4.3 ng/ml, Cmax 137 +/- 19.6 ng/ml and t1/2, z h. 9.6 +/- 1.27 h.     

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.     

Antihypertensive and hypouricaemic effects of nitrendipine in chronic renal failure

Summary To evaluate the potential therapeutic value of calcium antagonists in hypertension associated with impaired renal function, blood pressure (BP), certain regulatory factors, and metabolic correlates of cardiovascular risk have been assessed in 15 patients with mild to marked chronic renal failure before and after 6 weeks of therapy with nitrendipine.Compared to placebo, nitrendipine (mean final dose 55 mg/day) decreased supine BP from 173/102 to 146/81 mm Hg and upright BP from 170/105 to 145/86 mm Hg. Heart rate, body weight (+0.8 kg) and exchangeable sodium (+176 mmol, not significant) were minimally increased, and plasma and whole blood volume, plasma angiotensin II and creatinine concentrations, and urinary electrolyte and creatinine excretion were not significantly changed.Nitrendipine increased uric acid excretion and lowered plasma uric acid by 24%; glucose, insulin, serum total lipids, and lipoprotein fractions were unchanged.     

Cardiovascular regulation during administration of co-dergocrine to normal subjects

Summary Whether and to what extent activation of peripheral presynaptic dopamine₂-receptors may modulate the release of norepinephrine (NE) and so affect blood pressure (BP) in normal or hypertensive man is not clear. The hydrogenated ergotoxine derivative, co-dergocrine, given in effective antihypertensive rather than excessive experimental doses, has recently been shown to act predominantly as a peripheral dopamine₂-receptor agonist in several species. Accordingly, BP regulation assessed has been in 8 normal men on placebo and after 3 weeks on co-dergocrine 4 mg/day. Co-dergocrine significantly reduced urinary NE excretion from 43 to 33 µg/24 h, supine and upright plasma NE 21 to 16 and 49 to 36 ng/dl, respectively, heart rate (–8 and –5%, respectively) and upright systolic BP, 115 to 102 mm Hg; upright diastolic BP also tended to be lower. A standard pressor dose of infused NE was lowered from 131 to 102 ng/kg/min, and the relationship between NE-induced changes in BP and concomitant NE infusion rate or plasma NE concentration was displaced to the left. Exchangeable sodium and plasma volume tended to be slightly decreased. Plasma and urinary electrolytes and epinephrine, plasma renin activity and aldosterone levels, pressor responsiveness to angiotensin II, the chronotropic responses to isoproterenol, and the NE-induced rise in BP, plasma clearance of NE, glomerular filtration rate and effective renal plasma flow were not consistently modified. The findings are consistent with effective peripheral dopamine₂-receptor agonism by co-dergocrine in humans. Peripheral presynaptic dopaminergic activation may modulate sympathetic activity and BP in normal man.     

Effect of labetalol on plasma noradrenaline and adrenaline in hypertensive man

Summary Injection i. v. of labetalol, a new adrenergic alpha- and beta-blocking agent, decreased arterial blood pressure in 9 hypertensive subjects resting in the supine position, when standing and during supine exercise. Heart rate after labetalol was unchanged in the resting supine position, and it fell in the latter two conditions. Plasma noradrenaline concentration was higher after labetalol in all three experiments as compared to a control study. Plasma adrenaline after labetalol was increased only in the standing position, when the highest plasma noradrenaline concentrations were observed. Blood glucose concentration tended to increase after labetalol, but the difference was not statistically significant. The changes in plasma noradrenaline and blood glucose after labetalol mimic findings observed after alpha-adrenergic receptor blockade. The beta-adrenergic receptor blocking property of labetalol is responsible for the reduced heart rate and it is likely to contribute to the higher plasma noradrenaline concentration observed when standing and during supine exercise.     

The pharmacodynamics and dose-response relationships of the angiotensin converting enzyme inhibitor, cilazapril, in essential hypertension.

In a double-blind, placebo controlled, crossover study 12 patients with essential hypertension received single doses of 5, 10 and 20 mg of cilazapril, a new angiotensin converting enzyme (ACE) inhibitor. All doses similarly and significantly (P less than 0.05) reduced supine and erect blood pressure without increasing heart rate. The hypotensive effect was evident within 1 h, maintained for up to 8 h, with a maximal effect at 6 h. There was no discernible effect on blood pressure at 24 h after dosing. Plasma ACE activity was markedly inhibited to the same extent after all doses, with a peak inhibition of 94-96% at 2-3 h. At 24 h residual inhibition of ACE was 49-54%. Plasma renin activity increased in a dose-dependent manner with a peak at 6 h, and returned to baseline at 24 h. No correlation was found between the reduction in blood pressure and plasma renin activity, either at baseline or following cilazapril. There were no significant changes in plasma noradrenaline and the responses to upright posture and to dynamic exercise were preserved. There was no evidence of impaired exercise performance. Cilazapril is a potent ACE inhibitor with a rapid onset and a prolonged duration of action. These results suggest that peak ACE inhibition is achieved by 5 mg and that lower doses may be useful in clinical practice.     

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.