Interactions of sildenafil with various coronary vasodilators in isolated porcine coronary artery

Abstract

There are reports of serious hypotension or circulatory shock when sildenafil citrate, a selective cyclic nucleotide phosphodiesterase type 5 inhibitor, which was developed for the treatment of erectile dysfunction, is given to patients taking certain coronary vasodilators. We thus examined the interaction of sildenafil with various coronary vasodilators including nitric oxide (NO) donors in isolated porcine coronary artery. Sildenafil caused concentration-dependent relaxations of the artery precontracted with U46619 (9,11-dideoxy-9α,11α-methanoepoxy-prostaglandin F 2α). Incubation with the NO synthase inhibitor N G-nitro- l-arginine or the soluble guanylate cyclase inhibitor ODQ (1 H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one) significantly shifted the concentration–response curve for sildenafil to the right without affecting the maximum response, indicating that some part of the relaxant response to sildenafil may be the result of the inhibition of phosphodiestrase type 5-induced degradation of cyclic GMP (cGMP) that is produced through guanylate cyclase activation by NO released spontaneously. The relaxant effects of the vasodilators with an NO donor property, isosorbide dinitrate, sodium nitroprusside, nicorandil and nipradilol, were significantly enhanced by sildenafil, as shown by a significant leftward shift of their concentration–response curves. In contrast, the relaxant responses to the drugs without a property as an NO donor, diltiazem, celiprolol and pinacidil, were not affected by sildenafil. The cGMP level of the tissue was elevated after adding sildenafil, and the cGMP-generating effect of a combination of sildenafil and sodium nitroprusside was higher than that of each drug alone. The cyclic AMP level determined simultaneously was not changed by sildenafil. These results suggest that sildenafil potentiates specifically the relaxant responses of porcine coronary artery to the drugs which behave as an NO donor, providing basic evidence that the benefit of sildenafil in the treatment of erectile dysfunction can be limited by a risk of marked vasodilation when used together with NO-related coronary vasodilators.