Involvement of cyclic AMP in vasodilatation by amrinone: a comparative study with 3-isobutyl-methyl-xanthine (IBMX).

We investigated the effect of amrinone, a non-glycosidic, non-adrenergic cardiotonic drug, on rabbit aortic strips and vascular smooth muscle cells cultured from rabbit aorta. Amrinone relaxed the strips precontracted by KCl, norepinephrine, serotonin or STA2 in a dose-dependent manner, and it shifted the dose-response curves downward. A similar mode of relaxation was noted with IBMX, an inhibitor of cyclic AMP phosphodiesterase (cAMPPDE). Although propranolol did not affect the relaxation induced by amrinone, W-7, a calmodulin antagonist, slightly potentiated and IBMX attenuated the response. In intact smooth muscle cells in culture, amrinone increased basal levels of cAMP and markedly potentiated cAMP accumulation in response to 10(-6) M isoproterenol. The effect on cAMP accumulation mimicked that of IBMX but the effects were not additive. Inhibition of cAMPPDE was also demonstrated in a cell-free system, IC50 values for amrinone and IBMX being 2.1 X 10(-5) M and 1.2 X 10(-6) M, respectively, using a preparation of cAMPPDE partially purified from the cells by DEAE cellulose chromatography. Amrinone seems to exert a direct effect on vascular smooth muscle cells by potently inhibiting cAMPPDE. This inhibition would to some extent explain the vasodilatory property.