Inhibition of cADP-ribose formation produces vasodilation in bovine coronary arteries

cADP-ribose (cADPR) induces the release of Ca2+ from the intracellular stor es of coronary artery smooth muscle cells. However, little is known about t he role of cADPR-mediated intracellular Ca2+ release in the control of vasc ular tone. The present study examined the effects of nicotinamide, a specif ic 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 forma tion 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 p rotein in treated cells, a 58% reduction. In U46619-precontracted coronary artery rings, nicotinamide produced concentration-dependent relaxation. Com plete relaxation with nicotinamide occurred at a dose of 8 mmol/L; the medi an inhibitory concentration (IC50) was 1.7 mmol/L. In the presence of a cel l membrane-permeant cADPR antagonist, 8-bromo-cADPR, nicotinamide-induced v asorelaxation was markedly attenuated. Pretreatment of the arterial rings w ith ryanodine (50 mu mol/L) significantly blunted the vasorelaxation respon se to nicotinamide. However, iloprost- and adenosine-induced vasorelaxation was not altered by 8-bromo-cADPR. Moreover, nicotinamide significantly att enuated KCl- or Bay K8644-induced vasoconstriction by 60% and 70%, respecti vely. These results suggest that the inhibition of cADPR formation by nicot inamide produces vasorelaxation and blunts KCl- and Bay K8644-induced vasoc onstriction in coronary arteries and that the cADPR-mediated Ca2+ signaling pathway plays a role in the control of vascular tone in coronary circulati on.