Evidence for a tonic inhibitory role of nifedipine-sensitive calcium channels in aldosterone biosynthesis

Abstract

This study investigated the effects of the calcium channel blockers nifedipine (a dihydropyridine) and verapamil (a papaverine derivative), on aldosterone production utilizing isolation of the early and late phases of aldosterone biosynthesis. Pregnenolone production (the early phase of aldosterone biosynthesis) was assessed in trilostane-treated bovine glomerulosa cells, used to inhibit the conversion of pregnenolone onwards to aldosterone. Conversion of exogenous corticosterone to aldosterone, an index of late phase activity, was assessed using aminoglutethimide to inhibit endogenous aldosterone production. Low concentrations of nifedipine, 10 −11−10 −9 M, Stimulated basal total aldosterone biosynthesis by enhancing the late phase although the early phase was inhibited. In the presence of 12 mM potassium (K +), which is less effective in stimulating aldosterone production than lower K + concentrations, aldosterone production was enhanced by nifedipine, 10 −8 M, by an effect on the late phase. At K + 6 and 8 mM, nifedipine, 10 −4 M, inhibited the early phase. Nifedipine 10 −5 inhibited angiotensin II (AII)-stimulated total aldosterone biosynthesis by independent effects on the early and late phases. Verapamil, 10 −4 M, inhibited total and early phase aldosterone production at K +, 4 mM and inhibited both phases at K +, 8 mM, stimulation was not observed using verapamil. Verapamil, 10 −4 M, also inhibited AII-stimulated aldosterone production. Basal and AII-stimulated pregnenolone production were inhibited by verapamil, 10 −4 M (basal) and 10 −6 M (AII-stimulated). These studies using nifedipine have revealed subtle calcium-dependent mechanisms involved in the tonic inhibition of activity in the late phase of aldosterone biosynthesis and the reversal of the inhibitory effect of high K + concentrations also on the late phase. In addition, the data reported indicate that both AII and K + independently enhance activity in the early and late phases of aldosterone production by calcium-dependent mechanisms.