Calcium antagonists stimulate prostaglandin synthesis by cultured rat cardiac myocytes and prevent the effects of hypoxia

Abstract

The effect of three calcium antagonists on the synthesis of prostacyclin (PGI2, assayed as 6-Keto-PGF1alpha) and PGE2 by cultured rat cardiac myocytes and fibroblasts was investigated. In myocytes only, bepridil, diltiazem and verapamil (10 −9 to 10 −7 M) stimulated PGs synthesis by two- to three-fold, dose-dependently. At a concentration of 10 −6 or 10 −5 M the intensity of the stimulation of PGI2 and PGE2 decreased. Cobalt chloride (2 × 10 −3 M) did not change PGs synthesis (pg/mg of protein/30 min; means ± SE, N = 10; PGE2: 365 ± 59 and 463 ± 89 treated vs controls; PGI2: 824 ± 214 and 799 ± 143 treated vs controls). After 30 min exposure of myocytes to hypoxic conditions (glucose-free medium and low PO2), the glycogen content was half that of the controls (P <0.001),ATP content did not change and PGI2 and PGE2 synthesis increased (×1.5, P < 0.05). When applied to myocytes 30 min before inducing hypoxia, the three calcium antagonists stimulated PGs synthesis by three- to seven-fold at maximal effect, and bepridil (10 −8 M) or diltiazem (10 −7 M) prevented the hypoxia-induced decrease in glycogen content. With 10 −5 M drug concentration, the effect on PGs was not significant, except for the effect of bepridil on PGI2 (P < 0.05). It is concluded that therapeutic concentrations of calcium antagonists simultaneously prevent the decrease in myocyte glycogen induced by hypoxia and stimulate PGs synthesis by myocytes.