Selective inhibition of endothelium-dependent dilation in resistance-sized vessels in vivo

Abstract

In vivo experiments were performed in autoperfused hindlimbs of rabbits to investigate the role of endothelium-mediated vasomotion in resistance-sized vessels. The flow responses to the vasodilators acetylcholine (ACh), ATP, and substance P (SP), all of which have been shown to act in an endothelium-dependent manner in large conduit arteries, were studied before and after exposure of the hindleg vasculature to gossypol (a potent inhibitor of endothelium-mediated vasodilation in vitro). The flow responses to adenosine (ADO), nitroglycerin (GTN), and prostaglandin E2 (PGE2), which induce relaxation by a direct effect on vascular smooth muscle, were tested in the same manner. All vasodilators induced dose-dependent increases in femoral flow up to two- to threefold when administered intra-arterially. After gossypol, the flow responses to the endothelium-dependent compounds (ACh, ATP, and SP) were severely reduced (by 88 +/- 3%, P less than 0.01) or sometimes were converted to constrictions (ATP). The flow increases induced by ADO, PGE2, and GTN remained largely unaffected. Sham treatment (gossypol solute only), exposure to indomethacin (10 microM), and ganglionic blockade had no differential effect on the flow responses. The selective action of gossypol in suppressing the flow responses to the endothelium-dependent compounds ACh, ATP, and SP is consistent with a vasomotor role for endothelial cells in resistance-sized vessels in vivo.