Role of Nitric Oxide in Myocardial Ischemia and Reperfusion via Antibody Neutralization of P-Selectin
Maurer, Peter M.
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Nitric oxide (NO) has been suggested to participate in several mechanisms affecting myocardial ischemia/reperfusion injury including: leukocyte adhesion, free radical production, systemic hemodynamics, and coronary blood flow. The objective of this investigation was to determine a possible cardioprotective role of nitric oxide in myocardial ischemia and reperfusion via administration of a monoclonal antibody to the adhesion molecule, P-selectin, in an anesthetized, open-chest rabbit model. A branch of the left descending coronary artery was reversibly ligated to produce ischemia followed by reperfusion, after which the degree of myocardial necrosis (infarct size as a percent of area at risk) was assessed by tetrazolium staining. New Zealand rabbits were instrumented for measurement of heart rate, arterial and ventricular pressures, myocardial contractility (LV + dP/dtmax), and cardiac demand (pressure rate product). The animals were treated intravenously with a control (P23) or binding (CY1747) antibody (2 mg/kg) to the adhesion molecule P-selectin, or in combination with an infusion of ~- nitro L-arginine methyl ester (L-NAME) intravenously (100 µg/kg/min). Animals were subject to 30 min of coronary occlusion, followed by 120 min of reperfusion. L-NAME infusions were started 60 min prior to occlusion, and the antibody was administered at 25 min of occlusion. Systemic hemodynamics were not significantly different from control in most cases, except for a hemodynamic depression during late reperfusion, occurring in both treatment groups receiving L-NAME. All treatment groups experienced a transient increase in left ventricular end diastolic pressure near the end of occlusion. Myocardial area at risk was not significantly different among treatment groups. Administration of the CY1747 antibody alone significantly reduced infarct size (16±3%, compared to the P23 controls at 38±3% mean±S.E.; p<0.05), as did the treatment of L-NAME plus CY1747 (22±3% ). Treatment of L-NAME plus P23 treatment did not significantly alter infarct size (39±5%). These results suggest that during myocardial ischemia/ reperfusion, endogenous NO may play a primary cardioprotective role in attenuating leukocyte adhesion, and other protective mechanisms affected by this molecule are of secondary importance.