Inducible Nitric Oxide Synthase Mediates Delayed Myocardial Protection Induced by Activation of Adenosine A 1 Receptors

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Abstract
Background—The mechanism of delayed preconditioning induced by activation of adenosine A1 receptors (A1ARs) is not fully understood. We determined the role of inducible nitric oxide synthase (iNOS) in mediating adenosine-induced late cardioprotection using pharmacological inhibitors and iNOS gene–knockout mice. Methods and Results—Adult male mice were treated with saline or an A1AR agonist, 2-chloro-N6-cyclopentyladenosine (CCPA). Twenty-four hours later, the hearts were perfused in Langendorff mode and subjected to 30 minutes of global ischemia followed by 30 minutes of reperfusion. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.1 mg/kg IP) and S-methylisothiourea (SMT; 3 mg/kg IP) were used to block A1ARs and iNOS, respectively. Infarct size (IS) was measured by triphenyltetrazolium chloride staining, and iNOS expression was measured by Western blots. Myocardial IS was reduced from 24.0±3.2% in the saline group to 12.2±2.5% in CCPA-treated mice (PConclusions—Selective activation of A1ARs produces delayed cardioprotection against ischemia/reperfusion injury in the mouse. Increased iNOS expression concomitant with the lack of protective effect of A1AR activation in iNOS gene–knockout mice suggests a direct cause-and-effect relationship of iNOS in adenosine-induced late cardioprotection.

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