Deletion of endothelial nitric oxide synthase exacerbates myocardial stunning in an isolated mouse heart model.

Abstract

While endothelial nitric oxide synthase (eNOS) is an important regulator of vascular tone, it is also constitutively expressed in cardiac myocytes and contributes to the regulation of myocardial function. The role of eNOS in ischemia-reperfusion is uncertain, however, with some studies showing beneficial effects while other studies demonstrate increased cardiac injury. We hypothesized that the beneficial effects of eNOS would predominate, and thus that targeted deletion of eNOS would exacerbate myocardial dysfunction following ischemia-reperfusion. ENOS knockout and wild-type mouse hearts were Langendorff-perfused using Krebs bicarbonate buffer and subjected to 20 min of global normothermic ischemia followed by 30 min of reperfusion. Myocardial function was measured using a ventricular balloon to determine time to onset of contracture, left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), and rate-pressure product (RPP). RESUKTS: Heart rate and coronary resistance were similar in both groups during baseline and reperfusion periods. Diastolic function as determined by peak LVEDP during ischemia and final LVEDP after reperfusion were worse in the eNOS knockout group vs wild-type (114 and 31 mmHg vs 92 and 18 mmHg, P <.05). Although RPP (heart rate x LVDP), measured as an index of systolic function, was initially better in eNOS knockouts (24216 vs 16353), wild-type hearts recovered more function than did eNOS knockout hearts by the end of 30 min of reperfusion (30892 vs 20522, P <.05). These data suggest that the deletion of eNOS results in increased myocardial dysfunction following ischemia-reperfusion in an isolated heart model.