The sydnonimine C87-3754 evokes endothelium-independent relaxations and prevents endothelium-dependent contractions in blood vessels of the dog

Abstract

Experiments were designed to compare the relaxing activities of the new sydnonimine C87-3754 with SIN-1 in arteries and veins of the dog, and to determine whether C87-3754 can prevent endothelium-dependent contractions. Rings of coronary and femoral arteries, and saphenous veins were suspended in organ chambers for the measurement of changes in isometric tension. SIN-1 and C87-3754 evoked concentration-dependent relaxations in all rings of blood vessels contracted with a submaximal concentration of either prostaglandin F2 alpha, endothelin-1, phenylephrine, or norepinephrine. In both arteries and veins, the concentration-relaxation curves to C87-3754 were shifted significantly to the right (by two to three logarithmic units) of that to SIN-1. The presence of endothelium significantly inhibited the relaxations to SIN-1 but did not affect those to C87-3754. The treatment of coronary arteries with methylene blue or oxyhemoglobin significantly impaired the relaxation to SIN-1 and C87-3754. Neither C87-3754 nor its prodrug pirsidomine (CAS 936) affected the membrane potential in coronary arteries. The endothelium-dependent contractions evoked by nitro L-arginine, arachidonic acid, and the calcium ionophore A23187 in basilar arteries of the dog were 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 activation of soluble guanylate cyclase, causing enhanced production of cyclic guanosine monophosphate in the smooth muscle without a change in membrane potential.