EFFECTS OF NITRIC-OXIDE SYNTHESIS ON REPERFUSION INJURY AND CATECHOLAMINE RESPONSIVENESS IN A HETEROTOPIC RAT HEART-TRANSPLANTATION MODEL

Global myocardial ischemia and reperfusion injury play a major role in early postoperative graft dysfunction. In this study, the influence o f nitric oxide (NO) on reperfusion injury and catecholamine sensitivit y after ischemia was investigated in a heterotopic rat heart-transplan tation model. After a l-h ischemic preservation, reperfusion was start ed either after application of saline vehicle (control, n = 8) or nitr o-L-arginine methyl ester (L-NAME; 10 mg/kg, n = 8) for inhibition of NO synthesis or NO-precursor L-arginine (L-Arg; 40 mg/kg, n = 8), or L -NAME plus L-Arg (n = 8), respectively. After 60 min of reperfusion, c ontinuous dobutamine infusion (5 mu g/kg/min) was started. Myocardial blood flow was assessed by the hydrogen-clearance method. An intravent ricular balloon was used to measure pressure-volume relations: peak le ft ventricular pressure, the rate of pressure development (dP/dt), end -diastolic pressure, and isovolumic relaxation constant. Myocardial bl ood flow was significantly reduced after L-NAME and increased after L- Arg in comparison with control (p < 0.05). The L-NAME group showed dec reased systolic and diastolic functional recovery in comparison with c ontrol. Simultaneous infusion of L-Arg and L-NAME reversed these effec ts. L-Arg alone led to a further improvement of cardiac functional rec overy. Whereas myocardial blood flow remained unchanged in the L-NAME group with dobutamine infusion, it significantly increased in the cont rol group (p < 0.05). L-Arg antagonized this effect of L-NAME. Dobutam ine increased peak left ventricular pressure and dP/dt and shortened t he isovolumic relaxation constant in all groups; however, the changes of systolic hemodynamic indices were significantly smaller in the L-NA ME group (p < 0.05) and significantly higher in the L-Arg group (p < 0 .05). These results indicate that (a) NO production within the graft d uring reperfusion has a significant beneficial effect on graft functio n, and (b) NO formation may play an important role in beta-adrenergic responses after heart transplantation.