Dataset Information

Genetic variation in the ?1A-adrenergic receptor and phenylephrine-mediated venoconstriction.

ABSTRACT: There is large interindividual variability and ethnic differences in phenylephrine-mediated vasoconstriction. We tested the hypothesis that genetic variation in ADRA1A, the ?1A adrenergic receptor gene, contributes to the variability and ethnic differences. We measured local dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 42 African-Americans and genotyped for 32 ADRA1A single nucleotide polymorphisms. The ED50 ranged from 11 to 5442?ng?min(-1), and the Emax ranged from 13.5-100%. The rs574647 variant was associated with a trend towards lower logED50 in each race and in the combined cohort (P=0.008). In addition, rs1079078 was associated with a trend to higher logED50 in each race and in the combined cohort (P=0.011). Neither variant accounted for the ethnic differences in response. None of the ADRA1A haplotypes was associated with the outcomes. In conclusion, ADRA1A variants do not contribute substantially to the marked interindividual variability or ethnic differences in phenylephrine-mediated venoconstriction.

SUBMITTER: Adefurin A

PROVIDER: S-EPMC4442768 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic variation in the α1A-adrenergic receptor and phenylephrine-mediated venoconstriction.

Adefurin A A Ghimire L V LV Kohli U U Muszkat M M Sofowora G G GG Li C C Paranjape S Y SY Stein C M CM Kurnik D D

The pharmacogenomics journal 20141125 4

There is large interindividual variability and ethnic differences in phenylephrine-mediated vasoconstriction. We tested the hypothesis that genetic variation in ADRA1A, the α1A adrenergic receptor gene, contributes to the variability and ethnic differences. We measured local dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 42 African-Americans and genotyped for 32 ADRA1A single nucleotide polymorphisms. The ED50 ranged from 11 to 5442 ng min(-1), and the Emax ...[more]

PMID: 25421140

Similar Datasets

Project description:ObjectiveStimulation of cardiac α1A-adrenergic receptors (α1A-AR) has been proposed for treatment of heart failure, since it increases myocardial contractility. We investigated a different mechanism, induction of angiogenesis.Approach and resultsFour to 6 weeks after permanent coronary artery occlusion, transgenic rats with cardiomyocyte-specific α1A-adrenergic receptor overexpression had less remodeling than their nontransgenic littermates, with less fibrosis, hypertrophy and lung weight, and preserved left ventricular ejection fraction and wall stress (all P<0.05). Coronary blood flow, measured with microspheres, increased in the infarct zone in transgenic rats compared with nontransgenic littermates (1.4±0.2 versus 0.5±0.08 mL min(-1) g(-1); P<0.05), which is consistent with angiogenesis, as reflected by a 20% increase in capillary density in the zone adjacent to the infarct. The question arose, how does transgenic overexpression of a gene in cardiomyocytes induce angiogenesis? We identified a paracrine mechanism, whereby vascular endothelial growth factor-A mRNA and protein were increased in isolated transgenic cardiomyocytes and also by nontransgenic littermate cardiomyocytes treated with an α1A-agonist, resulting in angiogenesis. Conditioned medium from cultured cardiomyocytes treated with an α1A agonist enhanced human umbilical vein endothelial cell tubule formation, which was blocked by an anti-vascular endothelial growth factor-A antibody. Moreover, improved cardiac function, blood flow, and increased capillary density after chronic coronary artery occlusion in transgenic rats were blocked by either a mitogen ERK kinase (MEK) or a vascular endothelial growth factor-A inhibitor.ConclusionCardiomyocyte-specific overexpression of the α1A-adrenergic receptors resulted in enhanced MEK-dependent cardiomyocyte vascular endothelial growth factor-A expression, which stimulates angiogenesis via a paracrine mechanism involving heterocellular cardiomyocyte/endothelial cell signaling, protecting against remodeling and heart failure after chronic coronary artery occlusion.

Project description:In mammals, increasing evidence supports the generality of cotranscriptional gene regulation and the idea that genetic control often occurs subsequent to RNA polymerase II (Pol II) recruitment. In our recent experiments, we have used Pol II Chromatin Immunoprecipitation (ChIP) to investigate relationships between the mechanistic events that control acute stress response (ASR) gene activation following stimulation of the alpha1a-Adrenergic Receptor expressed in rat-1 fibroblasts. We validate the temporal accuracy of our Pol II ChIP assay by comparison to major transcriptional events assessable by microarray and PCR analysis of precursor and mature mRNA. Initial temporal microarray analysis of gene activation following agonist addition identified genes that were upregulated and provided a temporal profile of changes in polyadenylated mRNA levels. Combined with PCR analysis of pre-mRNA, total RNA, polyadenylated RNA and the Pol II ChIP data, we demonstrate complex multilevel gene regulation including a diverse set of cotranscriptional mechanisms. Given our data, we propose that analysis of a genes regulation must begin with global assessement of changes in transcriptional behavior to identify events that are actually rate limiting if reductionist mechanistic dissection is to distinguish events that are regulated from the larger set of mechanisms available to most genes. This microarray analysis reports on the temporal changes in polyadenylated mRNA levels in proliferating rat-1 fibroblasts following stimulation of the alpha-1a Adrenergic Receptor with filter sterilized 10 uM phenylephrine (PE). Cells were treated and harvested at 70 to 80% confluence. Rat-1 cells under these conditions are still mid-log phase and continue to proliferate for at least another replicative cycle. Message levels in untreated cells were determined for 3 biological replicates, but all other time points are single replicates as sufficiently detailed dissection made replicates expensive and unnecessary, given that clear trending behavior in the expression profiles demonstrates profile accuracy.

Dataset Information

Genetic variation in the ?1A-adrenergic receptor and phenylephrine-mediated venoconstriction.

Publications

Genetic variation in the α1A-adrenergic receptor and phenylephrine-mediated venoconstriction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets