(+)‐Isradipine but not (−)‐Bay‐K‐8644 exhibits voltage‐dependent effects on cat adrenal catecholamine release

Abstract

1 Catecholamine release from cat adrenal glands perfused at a high rate (4mlmin-1) at 37°C with polarizing (1.2 or 5.9 mm K+) or depolarizing (17.7, 35, 59 6 Potentiation of secretion by (-)-Bay K 8644 was concentration-dependent from 10-8 to 10-6 M. At 10-5M, such potentiation largely disappeared in both polarized and depolarized glands. However, this dual effect of (-)Bay K 8644 was better seen in depolarizing conditions, suggesting that using the same enantiomer, the voltage-dependence is only seen when blockade of secretion dominates. 7 In the presence of increasing concentrations of (-)Bay K 8644 (3 x 10-9, 3 x 10-8 and 3 x 10-7M), the concentration-response curves for (+)isradipine to inhibit secretion were displaced to the right. However, a Schild plot of (dose ratio -1) against (-)-Bay K 8644 concentrations gave a slope of 0.6, suggesting that the interactions between (+)-isradipine and (-)Bay K 8644 were non-competitive in nature. The pA2 for (-)-Bay K 8644 was 9.13. 8 Overall, the results suggest that potentiation of secretion by (-)Bay K 8644 (a voltage-independent phenomenon), and blockade by (+)-isradipine or (+-Bay K 8644 (a voltage-dependent phenomenon) might be exerted through binding of the dihydropyridines activators and blockers to separate sites on chromaffin cell L-type Ca2 + channels.