Pharmacologic analysis of papaverine-induced positive chronotropic and inotropic effects

Effects of papaverine on sinus rate and atrial contractility were investigated using the isolated atrium preparation of the dog perfused with heparinized arterial blood led from a support dog. When papaverine was injected into the cannulated sinus node artery, positive chronotropic and inotropic responses were dose-relatedly produced from about 3 mug. At a dose level above 100 mug, papaverine induced initially slightly negative chronotropic and inotropic effects followed by marked positive ones. Papaverine-induced positive chronotropic and inotropic effects (P-PCIE) were not influenced by treatment with tetrodotoxin which blocked the action of nicotine. P-PCIE were slightly suppressed by an adrenergic beta-blocking agent, alprenolol, which blocked the action of norepinephrine. They were however potentiated by treatment with desmethylimipramine which completely blocked the action of tyramine. A large amount of MnCl2 suppressed the actions of both papaverine and norepinephrine. Papaverine-induced negative chronotropic and inotropic effects were not influenced by atropine treatment. In addition, papaverine slightly potentiated the negative chronotropic and inotropic responses to adenosine. From these results, it appears that papaverine has a direct stimulating property on sinus rate and atrial contractility which may be due to inhibition of phosphodiesterase and successive accumulation of cyclic AMP. Moreover, papaverine may partially cause catecholamine release from adrenergic nerve fibers and it may inhibit the adenosine uptake mechanism.