Calcium, the renin-aldosterone system, and the hypotensive response to nifedipine.

Abstract

SUMMARY Ionic, hormonal, and blood pressure responses to a single oral dose of the calcium channel blocker nifedipine were assessed in 25 essential hypertensive subjects. When grouped according to their renin-sodium profile, low renin subjects had a greater hypotensive response to nifedipine (change in diastolic blood pressure -20.0± 1.4 vs -6.4 ± 1.0%; p<0.005) than did high renin hypertensive subjects. The initial level of serum ionized calcium predicted the blood pressure response to nifedipine (r = 0.70, p<0.001), as did the initial plasma renin activity (r=0.65, p<0.005). Nifedipine induced a transient rise in serum ionized calcium (from 2.22 ± 0.02 to 2.28 ± 0.02 mEq/L; p<0.01), while plasma renin activity was consistently elevated compared with initial values at 30 (p<0.01), 60 (p<0.01), and 120 (p<0.05) minutes after drug administration. By comparison, plasma aldosterone levels did not rise and even declined at 30 (p<0.01), 60 (p<0.05), and 120 (p < 0.05) minutes after nifedipine. These results suggest that low renin hypertension is more critically dependent on extracellular calcium than are higher renin forms and demonstrate that levels of serum ionized calcium, plasma renin activity, or both may predict the sensitivity of blood pressure to calcium channel blockade. Lastly, calcium may play a pivotal role in vivo in coupling renin stimulation to adrenal aldosterone responses. (Hypertension 10: 254-258, 1987) KEY WORDS hypertension calcium metabolism * renin activity • calcium channel blockade V ARIOUS abnormalities of calcium metabolism have recently been described in both experimental and human forms of hypertension, 1 although the specific manner in which these abnormalities relate to the elevations in pressure remains unknown. We have recently demonstrated consistent relationships between circulating levels of ionized calcium and the concurrent plasma renin activity in human essential hypertension.2 Low renin essential hypertensive subjects had lower average levels of serum ionized calcium compared with both other hypertensive subjects and normotensive control subjects. We hypothesized that lower serum levels of ionized calcium in these subjects reflected an increase in intra- cellular calcium levels, and thus an altered steady state distribution of calcium between intracellular and extracellular compartments. If this hypothesis is correct, one might expect an enhanced dependence of blood pressure on the extracellular calcium pool in the low renin hypertensive state. Therefore, blood pressure in these subjects ought to be more sensitive to blockade of intracellular calcium accumulation from extracellular sites. Indeed, calcium channel blocking agents were found to lower pressure preferentially in lower renin forms of experimental as well as human hypertension. 3 - 4 We would similarly predict that differing initial levels of extracellular calcium would also affect the hypotensive efficacy of calcium blocking drugs. However, no studies to date have related clinical indices of calcium metabolism to ...

Intracellular ionic consequences of dietary salt loading in essential hypertension. Relation to blood pressure and effects of calcium channel blockade.

“…Lastly, this study provides a cellular ionic basis for the enhanced antihypertensive efficacy of calcium channel blockade previously noted in volume-dependent hypertensive states such as DOC-saline and Dahl salt-sensitive rat models and in essential hypertensive subjects with low plasma renin activity and/ or lower serum ionized calcium values (19,20,50). We have previously suggested that the lower average extracellular ionized calcium observed in the low renin state reflects a greater dependence of blood pressure on cytosolic calcium accumulation from the extracellular space vis a vis from internal stores (5 1), hence explaining their greater sensitivity to calcium channel blocking agents such as nifedipine (50).…”

“…We have previously suggested that the lower average extracellular ionized calcium observed in the low renin state reflects a greater dependence of blood pressure on cytosolic calcium accumulation from the extracellular space vis a vis from internal stores (5 1), hence explaining their greater sensitivity to calcium channel blocking agents such as nifedipine (50). This present study provides additional evidence in favor of this hypothesis, by directly demonstrating in RBCs devoid of intracellular calcium stores, the linked blood pressure and cellular calcium elevating effects of salt loading and the reversal of these pressure and calcium effects by nifedipine.…”

Comparative Pharmacodynamics of Olmesartan and Azelnidipine in Patients with Hypertension: a Population Pharmacokinetic/Pharmacodynamic Analysis

“…Resnick et al, however, have reported a negative correlation between the extent of blood pressure reduction after nifedipine administration and pre-treatment PRA. 15) One reason for this disagreement could be the difference in the distribution of pre-treatment PRA between these studies. It was reported that salt intake was high in the Japanese population and low-renin hyperten- Fig.…”

“…3) It has been reported that antihypertensive drugs such as angiotensin receptor blockers (ARB), [8][9][10] angiotensin converting enzyme (ACE) inhibitors, 11,12) and b-blockers 13) reduce blood pressure more in hypertensive patients with a higher pre-treatment PRA. In contrast, diuretics 6,14) and calcium channel blockers (CCB) 15) show a more antihypertensive response in patients with a low-renin state. In these studies, however, the antihypertensive agents were not administered in a crossover fashion, and therefore whether the observed average trends are also reproducible in each individual patient has not yet been clearly demonstrated considering that essential hypertension is a heterogeneous disorder.…”

Effects of Antihypertensive Drugs on the Renin-Angiotensin System in Essential Hypertension

“…Hypertensive subjects with the opposite metabolic profile (high-renin activity, high serum ionized calcium and low 1,25-dihydroxy vitamin D levels) are relatively insensitive to the BP effects of both dietary salt loading and nifedipine, and show no significant hypotensive response to calcium supplements. [10] These results suggest that low-renin hypertension is more critically dependent on extracellular calcium than the highrenin type and demonstrate that both levels of serum ionized calcium and PRA may predict the sensitivity of BP to calcium channel blockade. [10] The CCBs have a wide spectrum of effects on the kidney.…”