Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 33, Issue 2, Pages 271-282Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1006/jmcc.2000.1298
Keywords
adenosine receptor; coronary microcirculation; cAMP; potassium channels
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Funding
- NHLBI NIH HHS [K02 HL-03693, HL-48179] Funding Source: Medline
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Adenosine is a potent vasodilator of the coronary microvessels and is implicated in the regulation of coronary blood flow during metabolic stress. However, the receptor subtypes and the vasodilatory mechanism responsible For the dilation of coronary microvessels to adenosine remain unclear. In the present study, using an isolated-vessel preparation we demonstrated that porcine coronary arterioles (50-100 mum) dilated concentration-dependently to adenosine, CPA (adenosine A(1) receptor agonist) and CGS21680 (adenosine A(2A) receptor agonist). These vasodilations were not altered by the A(1) receptor antagonist CPX, but were abolished by the selective A(2A) receptor antagonist ZM241385, indicating that activation of A(2A) receptors mediates these vasodilatory responses. The protein kinase A inhibitor Rp-8-Br-cAMPS abolished coronary arteriolar dilations to adenylyl cyclase activator forskolin and cAMP analog 8-Br-cAMP but failed to inhibit adenosine-and CGS21680-induced dilations. The calcium-activated potassium channel inhibitor iberiotoxin also did not affect vasodilations to adenosine and CGS21680. In contrast, the ATP-sensitive potassium (K-ATP) channel inhibitor glibenclamide abolished vasodilations to adenosine and CGS21680 but did not affect vasodilations to forskolin and 8-Br-cAMP. In addition, the cAMP level in coronary microvessels was not increased by adenosine or CGS21680, The results from RT/PCR and in situ hybridization indicated that adenosine A(2A) receptor mRNA was encoded in coronary arterioles al-td the left anterior descending (LAD) artery but not in cardiomyocytes, whereas the A(1) receptor transcript was detected in the LAD artery and cardiomyocytes but not in arterioles. Similarly, adenosine A(1) and A(2A) proteins were expressed in the LAD artery but only A(2A) receptors were expressed in coronary arterioles. Collectively, these functional data suggest that coronary arteriolar dilation to adenosine is primarily mediated by the opening of K-ATP channels through activation of A(2A) receptor. This conclusion is corroborated by the molecular data showing that coronary arterioles only express adenosine A(2A) receptors. Furthermore, the dilation of coronary microvessels to adenosine A(2A) receptor activation appears to be independent of cAMP signaling. (C) 2001 Academic Press.
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