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

Br. J. Pharmacol.2014 Aug;171(16):3858-67. doi:10.1111/bph.12743
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摘要


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.

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