Mechanism of blockade by (+)isradipine of adrenal catecholamine release

Abstract

Cat adrenal glands were perfused at a high rate with various modified Krebs solutions containing different concentrations of K + but no Ca 2+. Catecholamine release was tested by applying brief Ca 2+ pulses (10 s of a solution containing 120 mM K + and 2.5 mM Ca 2+). Under polarizing conditions (10 min perfusion with 1.4 mM K + with no Ca 2+), the total catecholamines released by the Ca 2+ pulse amounted to 5 μg; in depolarizing conditions (10 min perfusion with a solution containing 70 mM K + but no Ca 2+, secretion was somewhat less (4–4.5 μg). (+)Isradipine, a 1,4-dihydropyridine Ca 2+ channel blocker, did not affect the secretory response under polarizing conditions at 10 −8M; at 10 −6 M, the secretory response was halved. When present under depolarizing conditions (70 mM K + in 0 Ca 2+), (+)isradipine (10 −8 M) blocked catecholamine release by 90%. In contrast, the inorganic Ca 2+ channel blocker, Co 2+, inhibited secretion equally well under polarizing or depolarizing conditions. Since 45Ca 2+ uptake into adrenal medullary chromaffin cells was also inhibited by (+)isradipine (10 −8 M) in a voltage-dependent manner, it seems likely that blocking effects of the drug on catecholamine release are associated with inhibition of Ca 2+ entry into cells through L-type Ca 2+ channels. The association of (+)israpidine to its receptor is very rapid under polarizing conditions; dissociation is very slow in depolarized cells and very rapid upon polarization of such cells. Since chromaffin cells are being depolarized during stressful situations to secrete catecholamines into the circulation, (+)israpidine is likely to bind better to dihydropyridine receptors in this state; in this manner, the ensuing blockade of adrenal secretion could serve as a protective mechanism of cardiovascular tissues against massive increases in circulating catecholamines. If this suggestion is correct this mechanism could have additional therapeutic value in the treatment of hypertensive patients with (+)isradipine.