Endothelin modulation of choroidal blood flow in the rabbit

Based on the previous finding that locally produced nitric oxide (NO) and endothelin (ET) exert competing effects on choroidal resistance vessels, the present study sought to further characterize the pharmacology of ET in the choroid. The specific goal was to quantify the choroidal blood flow responses to acute changes in perfusion pressure before and after administering endothelin 1 (ET1), a non-selective ET antagonist, and selective antagonists for the endothelin A (ETA) and endothelin B (ETB) receptor subtypes. Anesthetized rabbits were instrumented with an ear artery cannula to measure mean arterial pressure (MAP), occluders on the aorta and vena cava to control MAP, and a vitreous cannula to measure intraocular pressure (IOP). Choroidal blood flow was measured by laser Doppler flowmetry with a vitreous fiber optic probe. The protocol entailed changing the ocular perfusion pressure by varying MAP before and after ET1 (0.9 microg kg(-1), i.v., n = 14), non-selective ET blockade (A-182086, 3 mg kg(-1), i.v., n = 10), selective ETA blockade (FR-139317, 3 mg kg(-1), i.v., n = 12), and selective ETB blockade (A-192621, 3 mg kg(-1), i.v., n = 14). ET1 and ETB blockade shifted the choroidal pressure-flow relation downward, while the non-selective antagonist and the selective ETA antagonist had no effect. The choroid had a biphasic response to exogenous ET1 as seen in other tissues (i.e. initial brief dilation followed by prolonged constriction) that was blocked by the non-selective antagonist whereas the ETA antagonist enhanced the dilation and blocked the constriction, and the ETB antagonist blocked the dilation and enhanced the constriction. These results indicate that ETA and ETB receptors are present and mediate opposing effects on choroidal vascular resistance. The results also suggest that endogenous ET preferentially elicits ETB vasodilation, most likely by stimulating endothelial nitric oxide release.