Cardiovascular and renal effects of single administration of three different doses of isradipine in hypertensive patients. Dose-response curves of the different effects.

The antihypertensive, humoral, and renal effects of acute single oral administration of placebo and isradipine, a new dihydropyridine calcium antagonist, at doses of 2.5 mg, 5.0 mg, and 7.5 mg once daily were investigated in 11 patients with mild-to-moderate uncomplicated essential hypertension. The patients maintained a constant daily intake of 100 mmol of sodium and 40 mmol of potassium. Placebo and isradipine were randomly administered to each patient, according to a Latin-square design, at intervals of at least 48 hours. The antihypertensive effect was dose-dependent and peaked at two hours after oral administration; changes at the lowest dose were already statistically significant (p less than 0.01). Increases in heart rate were mild and similar with all isradipine doses. Glomerular filtration rate and renal plasma flow showed a trend towards a dose-dependent rise; plasma renin activity was statistically increased (p less than 0.05) following the highest isradipine dose, whereas plasma aldosterone was unmodified. Isradipine resulted in a statistically significant rise (p less than 0.05) in sodium excretion and urine volume, which was similar with all active doses. In conclusion, the antihypertensive efficacy of isradipine is dose-dependent, whereas the natriuretic and diuretic effects are already at maximum following 2.5 mg per day, the lowest dose in this study.

Effects of a low-sodium diet on antihypertensive and natriuretic responses to acute administration of nifedipine.

This study was designed to determine (1) whether different sodium intakes influence the acute antihypertensive effect of a single dose of nifedipine, (2) whether the combination of nifedipine and a low-sodium diet lowers blood pressure to a greater extent than administration of nifedipine alone and (3) whether a reduction in sodium intake can dissociate the antihypertensive from the natriuretic response to nifedipine. We studied 11 hypertensive patients in order to investigate the antihypertensive and natriuretic effects of a single oral dose of 10 mg nifedipine during sodium repletion (100 mmol/day sodium intake) and depletion (20 mmol/day sodium intake), with a constant potassium intake (40 mmol/day). Nifedipine significantly (P less than 0.01) lowered supine blood pressure, from 178 +/- 14/107 +/- 7 to 161 +/- 12/100 +/- 7 mmHg during sodium repletion and from 152 +/- 12/95 +/- 9 to 142 +/- 11/90 +/- 8 mmHg with sodium depletion. The natriuretic and diuretic actions of nifedipine were marked and statistically significant during sodium repletion and almost absent during sodium depletion. We conclude that (1) the acute antihypertensive effect of a single dose of nifedipine is present both in the sodium-replete and in the sodium-depleted states, although during sodium depletion the nifedipine effect is somewhat reduced in extent and duration; (2) the blood pressure reached after administration of nifedipine in the sodium-depleted state is significantly lower than the values reached after nifedipine treatment in the sodium-replete state; (3) the natriuretic action of calcium antagonists is not essential to the acute antihypertensive action of these compounds.

Resting and postexercise hemodynamic effects of carvedilol, a beta-adrenergic blocker and precapillary vasodilator in hypertensive patients.

Carvedilol is a recently developed antihypertensive drug that combines in the same molecule a nonselective beta-adrenoceptor blocking effect and a vasodilating precapillary activity. In our study, we have investigated the effects of carvedilol 25 mg b.i.d. on blood pressure, heart rate, and plasma noradrenaline in hypertensive patients at rest and during exercise after acute and repeated oral administration for 7 days. The daily average supine blood pressure of the 12 patients with essential hypertension was 178 +/- 10/107 +/- 3 mm Hg (means +/- SD of 8 measurements in each patient) after placebo and was significantly (p less than 0.01) reduced to 162 +/- 17/99 +/- 8 mm Hg on the first day and to 158 +/- 15/96 +/- 8 mm Hg on the seventh day of carvedilol treatment. Similar values were found in the upright posture. Heart rate was slightly but significantly lowered during acute and repeated administration. The exercise-induced increase in systolic blood pressure was significantly reduced by carvedilol 25 mg b.i.d., while there was a nonsignificant reduction in the tachycardic response. There was a significantly greater rise in plasma noradrenaline during exercise on the seventh day of carvedilol treatment. Carvedilol significantly lowered blood pressure and heart rate at rest and the exercise-induced rise in systolic blood pressure.

Effects of different sodium intakes on the antihypertensive and renal effects of single oral doses of nifedipine in hypertensive patients.

The aim of this study was to investigate whether the antihypertensive and renal effects of Ca2+ antagonists are related to the sodium state of the patients. For this purpose, in a group of 11 patients with essential hypertension we have compared the blood pressure lowering effects of a single oral dose of nifedipine before (100 mmol Na+/day and 40 mmol K+/day) and after sodium depletion (20 mmol Na+/day and 40 mmol K+/day: each period was of 6-8 day duration). During the normal sodium diet nifedipine significantly lowered supine blood pressure (from 185 +/- 13/107 +/- 7 to 161 +/- 13/100 +/- 7 mm Hg, p less than 0.001) and induced a significant rise in Na+ excretion (from 52 +/- 10 to 94 +/- 13 mmol/6 h) and in urine volume (from 520 +/- 80 to 947 +/- 120 ml/6 h; p less than 0.01). Sodium depletion significantly lowered supine blood pressure (152 +/- 12/95 +/- 9 mm Hg, p less than 0.001); nifedipine caused a further and significant blood pressure reduction (142 +/- 11/90 +/- 8 mm Hg, p less than 0.01), but only a minor and not significant increase in sodium excretion (from 10 +/- 2 to 22 +/- 5 mmol/6 h) and urine volume (from 338 +/- 76 to 463 +/- 94 ml/6 h). Our data suggest that the natriuretic action of calcium antagonists is not relevant to their antihypertensive effect.

Renal effects of felodipine in hypertension.

The results of 2 recent studies on the renal effects of felodipine in hypertensive patients are described. Antihypertensive doses of felodipine (10mg bid) displayed a clear natriuretic and diuretic effect associated with a constant glomerular filtration rate and an increase in renal plasma flow. With higher doses of felodipine (up to 50mg tid), the natriuretic effect was reversed to an antinatriuretic effect, accompanied by a reduction in glomerular filtration rate. The natriuretic effect of felodipine 10mg bid was evident during the first 2 days of administration, but a negative sodium balance was still present at the end of the seventh day. The mechanisms of the renal effects of calcium antagonists are discussed as well as the relevance of the natriuretic effect for the antihypertensive action of these compounds.

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.

Antihypertensive and renal effects of tertatolol, a new beta-blocking agent, in hypertensive patients.

Tertatolol, a new nonselective beta-adrenoceptor blocker, was administered to 11 hypertensive patients in a short-term study. Systolic and diastolic blood pressure and heart rate were significantly decreased when compared to the placebo period: in spite of that glomerular filtration rate and renal plasma flow were unchanged. The administration of metoclopramide (a dopaminergic receptor antagonist) caused a significant reduction of renal plasma flow and a significant rise of renal vascular resistances during placebo, but no change during tertatolol therapy. A possible interference of tertatolol on dopaminergic receptors is discussed as the mechanism responsible for the unmodified renal plasma flow despite the significant blood pressure lowering with tertatolol.

Renal and antihypertensive effects of felodipine in hypertensive patients.

The effects of small doses of felodipine (10 mg twice daily) on blood pressure, renal function and sodium and water balance were studied in 11 patients with arterial hypertension. Felodipine significantly reduced systolic and diastolic blood pressure: most of the antihypertensive effect was already evident on day 1 of administration (-18/-11 mmHg) and only slightly increased during the subsequent week. Heart rate rose moderately only during day 1 of felodipine administration (+7 beats/min). Sodium excretion was increased during days 1 and 2, and no signs of water and electrolyte retention was observed in the week during which the balance study could be performed (Na, -135 +/- 65 mmol/7 days). At relatively low doses felodipine appears to be an effective antihypertensive agent, initially exerting some diuretic and natriuretic action and subsequently being devoid of a water- and sodium-retaining action.

Does beta 1-selective agonistic activity interfere with the antihypertensive efficacy of beta 1-selective blocking agents?

In order to investigate whether addition of beta 1-selective agonism can interfere with the antihypertensive efficacy of beta 1-selective adrenoceptor blockers, two separate studies were carried out to evaluate the effects on blood pressure and heart rate of three beta 1-selective blockers with or without varying degree of beta 1-selective agonism. In hypertensive patients at rest, the greatest blood pressure reduction and bradycardia were found with atenolol, a beta 1-selective blocker without any agonistic activity; a consistently smaller effect on blood pressure and heart rate was observed with Visacor (ICI 141 292), a beta 1-selective blocker with moderate beta 1-selective agonism, whereas no clinically relevant decrease in blood pressure occurred with Corwin (ICI 118 587), the beta 1-selective blocker with high beta 1-selective agonism. In contrast, during exercise-induced sympathetic activation, all three compounds reduced systolic blood pressure and heart rate to a similar degree.

Antihypertensive and water and sodium balance effects of felodipine, a new vasodilating calcium antagonist, in hypertensive patients.

Felodipine, a new dihydropyridine derivative with a selective action on vascular smooth muscle, was investigated in 2 short term studies in hypertensive patients. In the first study, oral administration of felodipine 12.5 mg three times daily in a preliminary tablet formulation for 3 days significantly reduced supine and upright blood pressure with only a slight increase in heart rate and no clinically relevant signs of sodium and water retention. By increasing each dose to 25 and 50 mg three times daily, there was a further, but quite moderate, decrease in blood pressure; however, this was accompanied by an increase in heart rate and a tendency towards a reduction of creatinine clearance and urinary sodium output. In the second study, a new oral formulation containing 10 mg felodipine, administered twice daily for 7 days, was effective in lowering blood pressure without a clinically relevant tachycardia. Following the first dose of felodipine, urinary sodium excretion was slightly increased while potassium excretion showed only minor changes. The new calcium antagonist, felodipine, lowers blood pressure without the clinically relevant adverse reactions commonly related to other direct vasodilator antihypertensive drugs.

Felodipine, a new vasodilating drug: blood pressure, cardiac, renal, and humoral effects in hypertensive patients.

We studied the antihypertensive action of felodipine, a new dihydropyridine vasodilator interfering with intracellular calcium mechanisms, in 11 patients with essential hypertension whose supine blood pressure averaged 181/109 mm Hg after 5 days of placebo administration. Felodipine, 12.5 mg t.i.d., for 3 days, caused a marked reduction (-39/-19 mm Hg) of supine systolic and diastolic pressures. Doses of 25 and 50 mg t.i.d., for three consecutive days, caused only a slight further reduction of blood pressure. At the highest dose tested all patients had their supine blood pressure brought down to values below 150 mm Hg systolic and 90 mm Hg diastolic at all six daily measurements. The antihypertensive effect was of the same magnitude when the patients lay supine or stood upright. Lowering of blood pressure was accompanied by tachycardia, which was quite moderate after the 12.5 mg t.i.d. dose, but more conspicuous with the two higher doses. There was some increase in plasma renin activity and in plasma aldosterone. A significant decrease in renal sodium and water excretion occurred only during administration of the highest dose of 50 mg t.i.d., when reduction in blood pressure was pronounced and there were reflex increases in plasma renin activity and plasma aldosterone.

Modification of arterial baroreflexes by captopril in essential hypertension.

Captopril lowers blood pressure without increasing heart rate and plasma norepinephrine, which suggests that this drug may potentiate arterial baroreflexes. In eight subjects with untreated essential hypertension, blood pressure was monitored intraarterially and the effects of baroreceptor stimulation or deactivation were assessed by measuring (1) the slopes of the relations between increase or reduction in systolic pressure (intravenous phenylephrine or nitroglycerin) and the resulting lengthening or shortening in R-R interval, and (2) the increase or decrease in mean arterial pressure induced by increasing and decreasing carotid transmural pressure (neck chamber). The measurements were made before and after a hypotensive oral dose of captopril (50 mg). Before captopril, the slopes of the R-R interval changes with increase and reduction in systolic pressure were 8 and 4 ms/mm Hg, respectively. The slopes of the mean arterial pressure changes with increase and reduction in carotid transmural pressure were 0.51 and 0.40 mm Hg, respectively. After captopril, the responses to baroreceptor stimulation were unaltered but those to baroreceptor deactivation were augmented. The pressor and heart rate responses to hand-grip and cold exposure were unchanged by captopril. Administration of captopril is accompanied by a baroreflex potentiation which involves the lower portion of the stimulus-response curve of the reflex. This phenomenon (which may originate at the afferent baroreceptor fibers or centrally) may avoid a reduction in the tonic baroreflex influence during captopril-induced hypotension, thus contributing to the hemodynamic effects of the drug.