A re-evaluated role for cyclic AMP in uterine relaxation. Differential effect of isoproterenol and forskolin

Abstract

Our previous observations suggested that beta adrenergic-mediated relaxation of the rat myometrium could not be ascribed solely to cyclic AMP. The present study examines the relationships between relaxation and cyclic AMP accumulation in the myometrium in response to isoproterenol, forskolin and the combination of both. The diterpene enhanced cyclic AMP generation and potentiated the rises in cyclic AMP due to isoproterenol and prostaglandin (PG) E2. Isoproterenol-induced relaxation of a carbachol-contracted myometrium was associated with modest increments in cyclic AMP (6-12 pmol/mg of protein) in contrast to forskolin whose relaxing effect could be expressed only when associated with large increases in cyclic AMP (80-180 pmol/mg of protein). PGE2, although elevating cyclic AMP to the same extent as isoproterenol, caused contractions which were antagonized by isoproterenol and forskolin, respectively, associated with low and high cyclic AMP concentrations. Both PGE2 and forskolin, by virtue of their stimulatory effect on cyclic AMP generation, enhanced the efficiency of isoproterenol to cause relaxation. Likewise, the greater efficacy of forskolin to relax a PGE2- as opposed to a carbachol-contracted myometrium, was ascribed to its potentiated cyclic AMP response when combined with PGE2. It is proposed that the beta adrenoceptor-linked relaxation results from the concerted effects of both a cyclic AMP-dependent (sensitive to low cyclic AMP) and a cyclic AMP-independent process; the latter is postulated to operate at the membrane level with an ultimate reduction in cytosolic Ca++. On the other hand, cyclic AMP, provided it reached a critical concentration essential to mediate intracellular Ca++ sequestration, would be the sole determinant for forskolin-elicited relaxation.