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Research ArticleArticle

Adenosine A2A Receptors Mediate Coronary Microvascular Dilation to Adenosine: Role of Nitric Oxide and ATP-Sensitive Potassium Channels

Travis W. Hein, Luiz Belardinelli and Lih Kuo
Journal of Pharmacology and Experimental Therapeutics November 1999, 291 (2) 655-664;
Travis W. Hein
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Luiz Belardinelli
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Lih Kuo
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Abstract

Adenosine is a potent vasodilator that plays an important role in the regulation of coronary microvascular diameter. Although multiple adenosine receptor subtypes have been recently cloned, the specific adenosine receptor subtypes and the underlying mechanisms responsible for the vasodilation to adenosine in the coronary microcirculation remain unknown. Therefore, in the present study we determined the receptor subtypes for coronary arteriolar dilation to adenosine and investigated the role of nitric oxide (NO) and ATP-sensitive potassium (KATP) channels in this vasodilatory response. Pig coronary arterioles (50–100 μm in situ) were isolated, cannulated, and pressurized without flow for in vitro study. Arterioles developed basal tone and dilated in a concentration-dependent manner to adenosine and to adenosine receptor agonists (2S)-N6-[2-endo-norbornyl]adenosine (A1), 2-[p-(2-carboxyethyl)]phenylethyl-amino-5′-N-ethylcarboxamidoadenosine (CGS21680; A2A),N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (A3), and N-ethylcarboxamidoadenosine (nonselective adenosine receptor activation). The selective A2A receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-yl amino]ethyl)phenol attenuated vasodilation to adenosine and to all adenosine receptor agonists tested, suggesting that the vasodilatory responses were primarily mediated by A2A receptors. Adenosine- and CGS21680-induced dilations were attenuated in a similar manner by endothelial removal and by the NO synthase inhibitorNG-nitro-l-arginine methyl ester. In denuded vessels, both adenosine- and CGS21680-induced dilations were nearly abolished by the KATP channel inhibitor glibenclamide. The selective A2A agonist CGS21680 mechanistically mimics the vasodilation in response to adenosine. Collectively, our results suggest that the dilation of coronary arterioles to adenosine is mediated predominantly by A2Areceptors. Activation of this receptor subtype elicits vasodilation by endothelial release of NO and by the smooth muscle opening of KATP channels.

Footnotes

  • Send reprint requests to: Lih Kuo, Ph.D., Department of Medical Physiology, Cardiovascular Research Institute, Texas A&M University System Health Science Center, 336 Reynolds Medical Building, College Station, TX 77843-1114. E-mail: lkuo{at}tamu.edu

  • ↵1 This work was supported by National Heart, Lung, and Blood Institute Grants HL48179 and K02-HL03693 (Research Career Award) to L.K.

  • Abbreviations:
    NO
    nitric oxide
    CGS15943
    5-amino-9-chloro-2-(2-furyl)1,2,4-triazolo[1,5-c]quinazoline
    CGS21680
    2-[p-(2-carboxyethyl)]phenylethyl-amino-5′-N-ethylcarboxamidoadenosine
    CPX
    8-cyclopentyl-1,3-dipropylxanthine
    ENBA
    (2S)-N6-[2-endo-norbornyl]adenosine
    AB-MECA
    4-aminobenzyl-5′-N-methylcarboxamidoadenosine
    IB-MECA
    N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide
    KATP
    ATP-sensitive potassium
    L-NAME
    NG-nitro-l-arginine methyl ester
    CCPA
    2-chloro-N6-cyclopentyladenosine
    DMSO
    dimethyl sulfoxide
    MRS1191
    3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate
    NECA
    N-ethylcarboxamidoadenosine
    PSS
    physiological salt solution
    ZM241385
    4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-yl amino]ethyl)phenol
    • Received February 24, 1999.
    • Accepted July 8, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 2
1 Nov 1999
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Research ArticleArticle

Adenosine A2A Receptors Mediate Coronary Microvascular Dilation to Adenosine: Role of Nitric Oxide and ATP-Sensitive Potassium Channels

Travis W. Hein, Luiz Belardinelli and Lih Kuo
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 655-664;

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Research ArticleArticle

Adenosine A2A Receptors Mediate Coronary Microvascular Dilation to Adenosine: Role of Nitric Oxide and ATP-Sensitive Potassium Channels

Travis W. Hein, Luiz Belardinelli and Lih Kuo
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 655-664;
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