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HEMODYNAMIC RESPONSES TO PAPAVERINE: DO NITRIC OXIDE, CYCLIC GMP, OR CALCIUM MEDIATE THE VASODILATION?

Papaverine is a commonly used vasodilator of the internal mammary artery in cardiac surgery. The effects of papaverine with and without Nω-L-arginine methyl ester (L -NAME) (a nitric oxide production inhibitor) and/or zaprinast (a cyclic GMP inhibitor) or verapamil (calcium channel antagonist) on systemic vascular resistance in vivo have not been well documented. This study examines the hemodynamic responses to papaverine and attempts to identify the role of nitric oxide, cyclic guanosine monophosphate (GMP), and calcium in the vasodilation. The effects of varying doses of papaverine were evaluated with and without L-NAME and/or zaprinast or verapamil on the hindlimb vascular resistance in the male rat. With institutional approval, 40 male Sprague-Dawley rats (400–450 g) were anesthetized with intraperitoneal pentobarbital (50 mg kg−1). The carotid artery, jugular vein, and abdominal aorta were cannulated by cutdown; mean arterial pressure (MAP) and hindlimb perfusion pressure (HPP) were recorded. Rats were heparinized (1000 U kg−1). Papaverine (1,3,10,30, and 100 μg) was injected into the hindlimb, whereas MAP was maintained constant, and the HPP was recorded. Both L-NAME (25 mg kg−1) and/or verapamil and then papaverine (1, 3, and 10 μg) were injected into the hindlimb, and changes in HPP were recorded. A Student's t-test was used for statistical analysis, with a p < 0.05 considered significant. Papaverine, in increasing doses, decreased HPP incrementally. L-NAME partially blocked the effects of papaverine (p < 0.05), as did verapamil (p < 0.05). The combination of L-NAME and verapamil further decreased papaverine's vasodilation to almost eliminate it (p < 0.05). We demonstrated the effect of papaverine on the hindlimb vasculature is similar to its effects noted in the internal mammary artery. Nitric oxide is known to be an agent causing vasodilation. It was demonstrated that papaverine vasodilation in the hindlimb vascular bed is modified by L-NAME, which suggests that nitric oxide production inhibition is partially responsible for this effect. It was demonstrated that there is an effect of calcium channel blockade on the vasodilation caused by papaverine. Both L-NAME and verapamil together appear to modify further the vasodilation caused by papaverine, suggesting both calcium channel and nitric oxide mechanisms for vasodilation. Zaprinast, a specific cyclic GMP phosphodiesterase inhibitor, did not affect the vasodilation caused by papaverine, acetylcholine, nitroglycerin, or verapamil.