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A polymorphism in the protein kinase C gene PRKCB is associated with ?2-adrenoceptor-mediated vasoconstriction.

ABSTRACT: ?2-Adrenoceptors (?2-AR) mediate both constriction and dilatation of blood vessels. There is considerable interindividual variability in dorsal hand vein (DHV) constriction responses to ?2-AR agonist activation. Genetic factors appear to contribute significantly to this variation. The present study was designed to identify the genetic factors contributing toward the interindividual variability in ?2-AR-mediated vascular constriction induced by the selective ?2-AR agonist dexmedetomidine.DHV constriction responses to a local infusion of dexmedetomidine were assessed by measuring changes in vein diameter with a linear variable differential transformer. The outcome variable for constriction was log-transformed dexmedetomidine ED50. A genome-wide association study (GWAS) of 433 378 single-nucleotide polymorphisms (SNPs) was carried out for determining the sensitivity of DHV responses in 64 healthy Finnish individuals. Twenty SNPs were selected on the basis of the GWAS results and their associations with the ED50 of dexmedetomidine were tested in an independent North American study population of 68 healthy individuals.In both study populations (GWAS and replication samples), the SNP rs9922316 in the gene for protein kinase C type ? was consistently associated with dexmedetomidine ED50 for DHV constriction (unadjusted P=0.00016 for the combined population).Genetic variation in protein kinase C type ? may contribute toward the interindividual variation in DHV constriction responses to ?2-AR activation by the agonist dexmedetomidine.

SUBMITTER: Posti JP

PROVIDER: S-EPMC3912740 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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A polymorphism in the protein kinase C gene PRKCB is associated with α2-adrenoceptor-mediated vasoconstriction.

Posti Jussi P JP Salo Perttu P Ruohonen Saku S Valve Laura L Muszkat Mordechai M Sofowora Gbenga G GG Kurnik Daniel D Stein C Michael CM Perola Markus M Scheinin Mika M Snapir Amir A

Pharmacogenetics and genomics 20130301 3

<h4>Objectives</h4>α2-Adrenoceptors (α2-AR) mediate both constriction and dilatation of blood vessels. There is considerable interindividual variability in dorsal hand vein (DHV) constriction responses to α2-AR agonist activation. Genetic factors appear to contribute significantly to this variation. The present study was designed to identify the genetic factors contributing toward the interindividual variability in α2-AR-mediated vascular constriction induced by the selective α2-AR agonist dexme ...[more]

PMID: 23337848

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Project description:AimPeripheral vasoconstriction has long been described as a vascular adverse effect of β-adrenoceptor blockers. Whether β-adrenoceptor blockers should be avoided in patients with peripheral vascular disease depends on pharmacological properties (e.g. preferential binding to β1 -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 β-adrenoceptor blockers.MethodWe searched for randomized controlled trials (RCTs) including β-adrenoceptor blockers that were published in core clinical journals in the Pubmed database. All RCTs reporting peripheral vasoconstriction as an adverse effect of β-adrenoceptor blockers and controls were included. Sensitivity analyses were conducted including possibly confounding covariates (latitude, properties of the β-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 β-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 β-adrenoceptor blockers have variable propensity to enhance peripheral vasoconstriction and that it is not related to preferential binding to β1 -adrenoceptors. These findings challenge FDA and European recommendations regarding precautions and contra-indications of use of β-adrenoceptor blockers and suggest that β-adrenoceptor blockers with intrinsic sympathomimetic activity could be safely used in patients with peripheral vascular disease.

Project description:Background and purposeThe 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 approachUsing 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 resultsRetinal 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 implicationsThe 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.

Dataset Information

A polymorphism in the protein kinase C gene PRKCB is associated with ?2-adrenoceptor-mediated vasoconstriction.

Publications

A polymorphism in the protein kinase C gene PRKCB is associated with α2-adrenoceptor-mediated vasoconstriction.

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