THE SYDNONIMINE C87-3754 EVOKES ENDOTHELIUM-INDEPENDENT RELAXATIONS AND PREVENTS ENDOTHELIUM-DEPENDENT CONTRACTIONS IN BLOOD-VESSELS OF THEDOG

Experiments were designed to compare the relaxing activities of the ne w sydnonimine C87-3754 with SIN-1 in arteries and veins of the dog, an d to determine whether C87-3754 can prevent endothelium-dependent cont ractions. Rings of coronary and femoral arteries, and saphenous veins were suspended in organ chambers for the measurement of changes in iso metric tension. SIN-1 and C87-3754 evoked concentration-dependent rela xations in all rings of blood vessels contracted with a submaximal con centration of either prostaglandin F2alpha, endothelin-1, phenylephrin e, or norepinephrine. In both arteries and veins, the concentration re laxation curves to C87-3754 were shifted significantly to the right (b y two to three logarithmic units) of that to SIN-1. The presence of en dothelium significantly inhibited the relaxations to SIN-1 but did not affect those to C87-3754. The treatment of coronary arteries with met hylene blue or oxyhemoglobin significantly impaired the relaxations to SIN-1 and C87-3754. Neither C87-3754 nor its prodrug pirsidomine (CAS 936) affected the membrane potential in coronary arteries. The endoth elium-dependent contractions evoked by nitro L-arginine, arachidonic a cid, and the calcium ionophore A23187 in basilar arteries of the dog w ere inhibited by C87-3754. These results indicate that the sydnonimine C87-3754 is a dilator of both arterial and venous smooth muscle, and can prevent endothelium-mediated contractions in cerebral arteries of the dog. The inhibition of vascular tone is likely to involve the acti vation of soluble guanylate cyclase, causing enhanced production of cy clic guanosine monophosphate in the smooth muscle without a change in membrane potential.