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OtherAUTONOMIC PHARMACOLOGY

Heterologous Desensitization of the Rat Tail Artery Contraction and Inositol Phosphate Accumulation After in VitroExposure to Phenylephrine Is Mediated by Decreased Levels of Gαq and Gαi

Tammy M. Seasholtz, Hakan Gurdal, Hoau-Yan Wang, Guoping Cai, Mark D. Johnson and Eitan Friedman
Journal of Pharmacology and Experimental Therapeutics November 1997, 283 (2) 925-931;
Tammy M. Seasholtz
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Hakan Gurdal
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Hoau-Yan Wang
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Guoping Cai
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Mark D. Johnson
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Eitan Friedman
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Abstract

Desensitization of alpha-1 adrenoceptor (α1AR)-mediated responses in aortic smooth muscle after exposure to catecholamines or α1AR agonists has been widely demonstrated. To determine whether exposure to an α1AR agonist results in desensitization of α1AR-mediated responses in a resistance artery, rat tail artery rings were exposed to 7.5 or 75 μM phenylephrine (PE) for 22 hr in vitro. Norepinephrine-stimulated contraction was significantly reduced in PE-exposed tail artery rings. Contractions mediated by the α2AR agonists, clonidine and UK 14,304, and by serotonin were also reduced in PE-treated tail artery rings. However, the contractile responses to KCl and ionomycin remained unchanged. Norepinephrine-, PE-, endothelin- and serotonin-stimulated inositol phosphate accumulations were reduced in PE-exposed tail artery rings, whereas KCl- and ionomycin-stimulated inositol phosphate accumulation remained unchanged. The density of membrane α1ARs, measured by specific [125I]2-{[β-(4-hydroxyphenyl)ethyl]aminomethyl}-1-etralone binding was not changed in PE-desensitized tail arteries. Further studies were performed to examine if alterations in receptor/G protein interaction accompanies arterial desensitization. In these studies receptor-stimulated increases in [35S]GTPγS binding to G proteins was assessed in membranes obtained from vehicle (control) and PE-treated tail arteries. In control membranes α1AR stimulation increased [35S]GTPγS binding to Gαq and Gαi proteins, whereas the α2AR agonist UK14,304 activated [35S]GTPγS binding to Gαi exclusively. Both PE- and UK14,304-induced responses were reduced in membranes from tail arteries that were exposed to either 7.5 or 75 μM PE for 22 hr. Western blot analyses of G protein alpha andbeta subunits demonstrated that Gαq and Gαi protein levels were decreased in PE-exposed tail artery membranes. These data show that the reduced transmembrane signaling for the α1AR in tail artery after in vitro PE exposure is associated with decreases in Gαq and Gαi protein levels. The reduction in these Gα proteins also appears to mediate the loss of function of α2AR and perhaps of other G protein-coupled receptors.

Footnotes

  • Send reprint requests to: Eitan Friedman, Ph.D., Division of Molecular Pharmacology, Department of Pharmacology, MCP - Hahnemann School of Medicine/EPPI, Allegheny University of the Health Sciences, 3200 Henry Avenue, Philadelphia, PA 19129.

  • ↵1 This work was supported by grants awarded by Allegheny-Singer Research Institute; the American Heart Association, Southeastern Pennsylvania Affiliate; the American Heart Association, Delaware Valley Affiliate and National Institutes of Health, US Public Health Service AG14510.

  • ↵2 Current address: Department of Pharmacology, Medical School of Ankara University, Sihhiye 06100 Ankara Turkey.

  • Abbreviations:
    α1AR
    alpha-1 adrenoceptor
    α2AR
    alpha-2 adrenoceptor
    DPBS
    Dulbecco’s phosphate-buffered saline
    HEAT
    2-{[β-(4-hydroxyphenyl)ethyl]aminomethyl}-1-etralone
    5-HT
    serotonin
    IMP
    immunoprecipitation buffer
    IP
    inositol phosphate
    IP3
    inositol triphosphate
    KRB
    Krebs-Ringer solution
    NE
    norepinephrine
    PE
    phenylephrine
    PLC
    phospholipase C
    PBS
    phosphate buffered saline
    PSS
    physiological saline solution
    SDS
    sodium dodecyl sulfate
    EDTA
    ethylenediaminetetraacetic acid
    EGTA
    ethyleneglycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
    HEPES
    N-2-hydroxyethylpipeerazine-N′-2-ethanesulfonic acid
    ANOVA
    analysis of variance
    • Received March 26, 1997.
    • Accepted July 14, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 2
1 Nov 1997
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OtherAUTONOMIC PHARMACOLOGY

Heterologous Desensitization of the Rat Tail Artery Contraction and Inositol Phosphate Accumulation After in VitroExposure to Phenylephrine Is Mediated by Decreased Levels of Gαq and Gαi

Tammy M. Seasholtz, Hakan Gurdal, Hoau-Yan Wang, Guoping Cai, Mark D. Johnson and Eitan Friedman
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 925-931;

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OtherAUTONOMIC PHARMACOLOGY

Heterologous Desensitization of the Rat Tail Artery Contraction and Inositol Phosphate Accumulation After in VitroExposure to Phenylephrine Is Mediated by Decreased Levels of Gαq and Gαi

Tammy M. Seasholtz, Hakan Gurdal, Hoau-Yan Wang, Guoping Cai, Mark D. Johnson and Eitan Friedman
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 925-931;
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