Inhibition of cADP-Ribose Formation Produces Vasodilation in Bovine Coronary Arteries

Abstract

cADP-ribose (cADPR) induces the release of Ca(2+) from the intracellular stores of coronary artery smooth muscle cells. However, little is known about the role of cADPR-mediated intracellular Ca(2+) release in the control of vascular tone. The present study examined the effects of nicotinamide, a specific inhibitor of ADP-ribosylcyclase, on the vascular tone of bovine coronary arteries. A bovine coronary artery homogenate stimulated the conversion of nicotinamide guanine dinucleotide into cGDP-ribose, which is a measure of ADP-ribosylcyclase activity. Nicotinamide significantly inhibited the formation of cGDP-ribose in a concentration-dependent manner: at a concentration of 10 mmol/L, it reduced the conversion rate from 3.34+/-0.11 nmol. min(-1). mg(-1) of protein in control cells to 1.42+/-0.11 nmol. min(-1). mg(-1) of protein in treated cells, a 58% reduction. In U46619-precontracted coronary artery rings, nicotinamide produced concentration-dependent relaxation. Complete relaxation with nicotinamide occurred at a dose of 8 mmol/L; the median inhibitory concentration (IC(50)) was 1.7 mmol/L. In the presence of a cell membrane-permeant cADPR antagonist, 8-bromo-cADPR, nicotinamide-induced vasorelaxation was markedly attenuated. Pretreatment of the arterial rings with ryanodine (50 micromol/L) significantly blunted the vasorelaxation response to nicotinamide. However, iloprost- and adenosine-induced vasorelaxation was not altered by 8-bromo-cADPR. Moreover, nicotinamide significantly attenuated KCl- or Bay K8644-induced vasoconstriction by 60% and 70%, respectively. These results suggest that the inhibition of cADPR formation by nicotinamide produces vasorelaxation and blunts KCl- and Bay K8644-induced vasoconstriction in coronary arteries and that the cADPR-mediated Ca(2+) signaling pathway plays a role in the control of vascular tone in coronary circulation.