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

ABSTRACT: BACKGROUND AND PURPOSE: The ??-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 ??-adrenoceptor subtypes to adrenergic vasoconstriction of retinal arterioles using gene-targeted mice deficient in one of the three adrenoceptor subtypes (??A-AR(-/-), ??B-AR(-/-) and ??D-AR(-/-) respectively). EXPERIMENTAL APPROACH: Using real-time PCR, mRNA expression for individual ??-adrenoceptor subtypes was determined in murine retinal arterioles. To assess the functional relevance of the three ??-adrenoceptor subtypes for mediating vascular responses, retinal vascular preparations from wild-type mice and mice deficient in individual ??-adrenoceptor subtypes were studied in vitro using video microscopy. KEY RESULTS: Retinal arterioles expressed mRNA for all three ??-adrenoceptor subtypes. In functional studies, arterioles from wild-type mice with intact endothelium responded only negligibly to the ??-adrenoceptor agonist phenylephrine. In endothelium-damaged arterioles from wild-type mice, phenylephrine evoked concentration-dependent constriction that was attenuated by the ??-adrenoceptor blocker prazosin. Strikingly, phenylephrine only minimally constricted endothelium-damaged retinal arterioles from ??B-AR(-/-) mice, whereas arterioles from ??A -AR(-/-) and ??D-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 ??-adrenoceptor-mediated vasoconstriction in murine retinal arterioles is buffered by the endothelium. When the endothelium is damaged, a vasoconstricting role of the ??B-adrenoceptor subtype is unveiled. Hence, the ??B-adrenoceptor may represent a target to selectively modulate retinal blood flow in ocular diseases associated with endothelial dysfunction.

SUBMITTER: Bohmer T

PROVIDER: S-EPMC4128048 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Böhmer Tobias T Manicam Caroline C Steege Andreas A Michel Martin C MC Pfeiffer Norbert N Gericke Adrian A

British journal of pharmacology 20140801 16

<h4>Background and purpose</h4>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).<h4>Experimental approach</h4>Using real-time PCR, mRNA ...[more]

PMID: 24749494

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Project description:AIM:Sphingosine-1-phosphate (S1P) influences resistance vessel function and is implicated in renal pathological processes. Previous studies revealed that S1P evoked potent vasoconstriction of the pre-glomerular microvasculature, but the underlying mechanisms remain incompletely defined. We postulated that S1P-mediated pre-glomerular microvascular vasoconstriction involves activation of voltage-dependent L-type calcium channels (L-VDCC) and the rho/rho kinase pathway. METHODS:Afferent arteriolar reactivity was assessed in vitro using the blood-perfused rat juxtamedullary nephron preparation, and diameter was measured during exposure to physiological and pharmacological agents. RESULTS:Exogenous S1P (10-9 -10-5 mol L-1 ) evoked concentration-dependent vasoconstriction of afferent arterioles. Superfusion with nifedipine, a L-VDCC blocker, increased arteriolar diameter by 39 ± 18% of baseline and significantly attenuated the S1P-induced vasoconstriction. Superfusion with the rho kinase inhibitor, Y-27632, increased diameter by 60 ± 12% of baseline and also significantly blunted vasoconstriction by S1P. Combined nifedipine and Y-27632 treatment significantly inhibited S1P-induced vasoconstriction over the entire concentration range tested. In contrast, depletion of intracellular Ca2+ stores with the Ca2+ -ATPase inhibitors, thapsigargin or cyclopiazonic acid, did not alter the S1P-mediated vasoconstrictor profile. Scavenging reactive oxygen species (ROS) or inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity significantly attenuated S1P-mediated vasoconstriction. CONCLUSION:Exogenous S1P elicits potent vasoconstriction of rat afferent arterioles. These data also demonstrate that S1P-mediated pre-glomerular vasoconstriction involves activation of L-VDCC, the rho/rho kinase pathway and ROS. Mobilization of Ca2+ from intracellular stores is not required for S1P-mediated vasoconstriction. These studies reveal a potential role for S1P in the modulation of renal microvascular tone.

Project description:AimPeripheral vasoconstriction has long been described as a vascular adverse effect of ?-adrenoceptor blockers. Whether ?-adrenoceptor blockers should be avoided in patients with peripheral vascular disease depends on pharmacological properties (e.g. preferential binding to ?1 -adrenoreceptors or intrinsic sympathomimetic activity). However, this has not been confirmed in experimental studies. We performed a network meta-analysis in order to assess the comparative risk of peripheral vasoconstriction of different ?-adrenoceptor blockers.MethodWe searched for randomized controlled trials (RCTs) including ?-adrenoceptor blockers that were published in core clinical journals in the Pubmed database. All RCTs reporting peripheral vasoconstriction as an adverse effect of ?-adrenoceptor blockers and controls were included. Sensitivity analyses were conducted including possibly confounding covariates (latitude, properties of the ?-adrenoceptor blockers, e.g. intrinsic sympathomimetic activity, vasodilation, drug indication, drug doses). The protocol and the detailed search strategy are available online (PROSPERO registry CRD42014014374).ResultsAmong 2238 records screened, 38 studies including 57?026 patients were selected. Overall, peripheral vasoconstriction was reported in 7% of patients with ?-adrenoceptor blockers and 4.6% in the control groups (P < 0.001), with heterogeneity among drugs. Atenolol and propranolol had a significantly higher risk than placebo, whereas pindolol, acebutolol and oxprenolol had not.ConclusionOur results suggest that ?-adrenoceptor blockers have variable propensity to enhance peripheral vasoconstriction and that it is not related to preferential binding to ?1 -adrenoceptors. These findings challenge FDA and European recommendations regarding precautions and contra-indications of use of ?-adrenoceptor blockers and suggest that ?-adrenoceptor blockers with intrinsic sympathomimetic activity could be safely used in patients with peripheral vascular disease.

Dataset Information

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

Publications

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

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