Functional and Molecular Characterization of the Endothelin System in Retinal Arterioles

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Abstract
Purpose. Activation of the endothelin (ET) system has been implicated in the pathogenesis of retinal ischemic disease. Although ET-1, the predominant endogenous isoform of ET, has been shown to cause constriction of retinal vessels, the expression and functional significance of its synthesis and the involved specific ET receptors in retinal arterioles remain unknown. The authors examined the roles of ETA and ETB receptors and of endothelin-converting enzyme (ECE)-1 in ET-1–induced vasomotor responses of single retinal arterioles. methods. To exclude systemic confounding effects, porcine retinal arterioles were isolated for vasoreactivity and molecular studies. results. Isolated and pressurized retinal arterioles developed basal tone and constricted in a manner dependent on concentration to ET-1. ET-1 precursor big ET-1 elicited time-dependent vasoconstriction over 20 minutes, which was blocked by the ECE-1 inhibitor phosphoramidon. ETA receptor antagonist BQ123 inhibited most (approximately 90%) of vasoconstrictions to ET-1 and big ET-1. ETB receptor agonist sarafotoxin also elicited concentration-dependent constriction of retinal arterioles but with significantly less potency than ET-1. ETB receptor antagonist BQ788 abolished vasoconstriction to sarafotoxin but only slightly reduced responses to ET-1 and big ET-1. Protein and mRNA expressions of ETA, ETB, and ECE-1 were detected in retinal arterioles. Immunohistochemistry revealed ETA and ETB receptors predominantly in smooth muscle and ECE-1 predominantly in endothelium and smooth muscle. conclusions. ET-1 elicits constriction of retinal arterioles predominantly through the activation of smooth muscle ETA receptors. Endogenous production of ET-1 from vascular ECE-1 is sufficient to evoke ETA receptor–dependent constriction in retinal arterioles.

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