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(+)‐Isradipine but not (−)‐Bay‐K‐8644 exhibits voltage‐dependent effects on cat adrenal catecholamine release
Author(s) -
López Manuela G.,
Michelena Pedro,
Gandía Luis,
García Antonio G.
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12168.x
Subject(s) - isradipine , catecholamine , endocrinology , chemistry , pharmacology , medicine , calcium , dihydropyridine
1 Catecholamine release from cat adrenal glands perfused at a high rate (4 ml min −1 ) at 37°C with polarizing (1.2 or 5.9 m m K + ) or depolarizing (17.7, 35, 59 or 118 m m K + ) solutions, was triggered by 5 or 10 s pulses of Ca 2+ (0.5 or 2.5 m m ) in the presence of various concentrations of K + . 2 In polarized glands, secretion was greater the higher the K + concentration present during the secretory K + /Ca 2+ test pulse. Thus, in 17.7 m m K + , catecholamine released was 162 ± 27 ng per pulse, while in 118 m m K + secretion rose to 1839 ± 98 ng per pulse. In depolarized glands, secretion reached a peak of around 1000 ng per pulse in 35–59 m m K + ; in 118 m m K + , secretion did not increase further, suggesting that voltage changes are implicated in the control of the secretory process. 3 Blockade of secretion by increased concentrations of (+)‐isradipine was much more manifest in polarized glands. The higher the degree of depolarization was (35, 59 or 118 m m K + ), the lower the IC 50 s were. So, the ratios between the IC 50 s in polarized and depolarized glands rose from 3.92 in 35 m m K + to 26.7 in 118 m m K + . 4 In contrast, the Ca 2+ channel activator (−)‐Bay K 8644 potentiated catecholamine release evoked by K + /Ca 2+ pulses equally well in polarized or depolarized glands. The ratios between EC 50 s in polarized or depolarized glands were, respectively, 0.30,0.59 and 0.69 for 17.7, 35 and 118 m m K + . 5 In simultaneous experiments, the two enantiomers of Bay K 8644 exhibited opposite effects on secretion. (+)‐Bay K 8644 (a Ca 2+ channel blocker) inhibited secretion better in depolarized than in polarized glands, whilst (−)‐Bay K 8644 potentiated secretion in a voltage‐independent manner. 6 Potentiation of secretion by (−)‐Bay K 8644 was concentration‐dependent from 10 −8 to 10 −6 m . At 10 −5 m , 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 × 10 −9 , 3 × 10 −8 and 3 × 10 −7 m ), 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 pA 2 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 Ca 2+ channels.