(Circulation. 2000;102:902.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Inducible Nitric Oxide Synthase Mediates Delayed Myocardial Protection Induced by Activation of Adenosine A1 Receptors
Evidence From Gene-Knockout Mice
From the Division of Cardiology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
Correspondence to Rakesh C. Kukreja, PhD, Eric Lipman Professor of Medicine and Physiology, Box 980281, Division of Cardiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298.
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 (P<0.05). The infarct-reducing effect of CCPA was abrogated by DPCPX (29.3±3.4%) and SMT (32.3±2.6%) and was absent in mice with targeted ablation of iNOS (23.9±1.6%). CCPA produced improvement in postischemic end-diastolic pressure, developed pressure, and rate-pressure product, which was also blocked by DPCPX and SMT. Increased iNOS protein expression observed in CCPA-treated hearts was diminished by DPCPX.
Conclusions—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.
Key Words: adenosine • receptors • ischemia • reperfusion • nitric oxide synthase • myocardial infarction
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