Forskolin modulates cyclic AMP generation in the rat myometrium. Interactions with isoproterenol and prostaglandins E2 and I2.

Abstract

In the intact rat myometrium, forskolin stimulated cyclic AMP generation and markedly potentiated increases in cyclic AMP caused by isoproterenol, prostaglandin E2 and prostacyclin. The diterpene increased the maximal responses and lowered the EC50 for both isoproterenol- and prostaglandin-stimulated cyclic AMP accumulation. Forskolin did not modify the Ki for the beta-adrenergic antagonist propranolol. Activation of cyclic AMP generation by forskolin was biphasic with respect to concentration; the major response being mediated by a low affinity interaction (Kapp 28 microM) and a minor effect being due to an interaction with a high affinity site (Kapp 0.5 microM). By contrast, the synergistic effect of the diterpene with isoproterenol, prostaglandin E2 as well as with cholera toxin, involved a single component of high affinity (Kapp 0.5 to 2 microM), which was thus considered to be associated with the activated complex of the cyclase catalytic subunit and the guanine nucleotide regulatory protein. Forskolin could further partially maintain isoproterenol-mediated synergism in a beta-adrenergic desensitized tissue. In myometrial membrane preparations, forskolin stimulated adenylate cyclase activity but failed to potentiate isoproterenol- and prostaglandin E2-mediated activation.