6533b861fe1ef96bd12c561d

RESEARCH PRODUCT

The α1B-adrenoceptor subtype mediates adrenergic vasoconstriction in mouse retinal arterioles with damaged endothelium

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Background and Purpose The α1-adrenoceptor family plays a critical role in regulating ocular perfusion by mediating responses to catecholamines. The purpose of the present study was to determine the contribution of individual α1-adrenoceptor subtypes to adrenergic vasoconstriction of retinal arterioles using gene-targeted mice deficient in one of the three adrenoceptor subtypes (α1A-AR−/−, α1B-AR−/− and α1D-AR−/− respectively). Experimental Approach Using real-time PCR, mRNA expression for individual α1-adrenoceptor subtypes was determined in murine retinal arterioles. To assess the functional relevance of the three α1-adrenoceptor subtypes for mediating vascular responses, retinal vascular preparations from wild-type mice and mice deficient in individual α1-adrenoceptor subtypes were studied in vitro using video microscopy. Key Results Retinal arterioles expressed mRNA for all three α1-adrenoceptor subtypes. In functional studies, arterioles from wild-type mice with intact endothelium responded only negligibly to the α1-adrenoceptor agonist phenylephrine. In endothelium-damaged arterioles from wild-type mice, phenylephrine evoked concentration-dependent constriction that was attenuated by the α1-adrenoceptor blocker prazosin. Strikingly, phenylephrine only minimally constricted endothelium-damaged retinal arterioles from α1B-AR−/− mice, whereas arterioles from α1A-AR−/− and α1D-AR−/− mice constricted similarly to arterioles from wild-type mice. Constriction to U46619 was similar in endothelium-damaged retinal arterioles from all four mouse genotypes. Conclusions and Implications The present study is the first to demonstrate that α1-adrenoceptor-mediated vasoconstriction in murine retinal arterioles is buffered by the endothelium. When the endothelium is damaged, a vasoconstricting role of the α1B-adrenoceptor subtype is unveiled. Hence, the α1B-adrenoceptor may represent a target to selectively modulate retinal blood flow in ocular diseases associated with endothelial dysfunction.