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Adenosine receptor subtypes and cardioprotection
Author(s) -
Lee Jang Eun,
Wilcox Karen,
Jacobson Kenneth A.,
Dichter Marc,
Liang Bruce T.
Publication year - 1998
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199811/12)45:3/4<394::aid-ddr40>3.0.co;2-j
Subject(s) - ischemic preconditioning , cardioprotection , ischemia , adenosine , pharmacology , adenosine receptor antagonist , adenosine receptor , adenosine a1 receptor , glibenclamide , medicine , receptor antagonist , antagonist , agonist , receptor , endocrinology , diabetes mellitus
Brief ischemia prior to a sustained period of ischemia reduces myocardial infarct size, a phenomenon known as preconditioning. A cardiac ventricular myocyte model has been developed to investigate the role and signaling mechanism of adenosine receptor subtypes in cardiac preconditioning. A 5‐min exposure of cardiac myocytes to simulated ischemia, termed preconditioning ischemia, prior to a subsequent 90‐min period of ischemia protected them against injury incurred during the 90‐min ischemia. Preconditioning ischemia preserved ATP content, reduced percentage of cells killed, and decreased release of creatine kinase into the medium. Activation of the adenosine A 1 receptor with CCPA or the A 3 receptor with IB‐MECA can replace preconditioning ischemia and mimic the protective effect of preconditioning ischemia. Blockade of the A 1 receptor with its selective antagonist DPCPX or of the A 3 receptor with the A 3 selective antagonist MRS1191 during the preconditioning ischemia resulted in only a partial attenuation of the subsequent protection. Incubation with both DPCPX and MRS1191 or with the nonselective antagonist 8‐SPT during the preconditioning ischemia completely abolished the protective effect of preconditioning ischemia. The K ATP channel opener pinacidil caused a large activation of the K ATP channel current and was able to precondition the myocyte. The K ATP channel antagonist glibenclamide blocked the cardioprotective effect of preconditioning ischemia when it was included during myocyte exposure to the preconditioning ischemia, indicating that K ATP channel is a requisite effector in mediating preconditioning. A receptor‐mediated stimulation of phospholipase C or phospholipase D, with consequent activation of protein kinase C and K ATP channel, appears to be the signaling mechanism linking adenosine A 1 and A 3 receptors to the induction of preconditioning. A model of how ischemic preconditioning is triggered and mediated is proposed. Evidence is accumulating to support its validity. Drug Dev. Res. 45:394–401, 1998. © 1998 Wiley‐Liss, Inc.