© 1995 by European Society of Cardiology
Copyright © 1995, European Society of Cardiology
Inhibition of nitric oxide synthesis protects the isolated working rabbit heart from ischaemia-reperfusion injury
Departments of Pediatrics and Pharmacology, Cardiovascular Disease Research Group, University of Alberta, 413 Heritage Medical Research Centre, Edmonton, Alta. T6G 2S2, Canada
* Corresponding author. Tel. (+1-403) 492-6581; Fax (+1-403) 492-9753. * rschulz{at}pmcol.med.ualberta.ca
Objectives: Nitric oxide (NO) exerts both protective and detrimental actions in a variety of biological systems. During acute reperfusion following myocardial ischaemia, a rapid overproduction of free radicals, including NO, may occur. We investigated the effects of the NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA), and the substrate for NO synthesis, L-arginine, on heart function during ischaemia and reperfusion injury. Methods: Spontaneously beating, isolated working rabbit hearts, perfused with modified Krebs-Henseleit buffer containing 1.2 mM palmitate bound to 3% bovine serum albumin, were subjected to 15 min of aerobic perfusion followed by 35 min of global, no-flow ischaemia and 30 min of aerobic reperfusion. Results: Throughout the reperfusion period there was a marked impairment in the recovery of mechanical function, measured as the product of heart rate x peak systolic pressure (rate-pressure product). Addition of L-NAME (3 µM) prior to the onset of ischaemia, but not at reperfusion, caused an immediate and significant increase in the recovery of mechanical function throughout the reperfusion period. The protective action of L-NAME was abolished by L- (but not D-) arginine (100 µM). L-NAME did not cause ischaemia as it did not alter glycogen or lactate content of aerobically perfused hearts. Furthermore, it did not prevent glycogen loss or lactate accumulation during 35 min of ischaemia, suggesting that the effects of L-NAME were not due to metabolic alterations during ischaemia itself. L-NMMA (30 µM) added prior to ischaemia, but not at reperfusion, also had a protective effect which was seen later in the reperfusion period. Addition of L- (but not D-) arginine (100 µM) prior to the onset of ischaemia resulted in an improved recovery of mechanical function only at 15 min of reperfusion. Conclusions: These results suggest that: (1) the recovery of mechanical function of hearts subjected to ischaemia-reperfusion injury can be improved by modulation of myocardial NO synthesis, (2) inhibition of NO synthesis (with L-NAME or L-NMMA) may offer prolonged protection whereas its stimulation (with L-arginine) provides only brief protection, and (3) the reasons for the pharmacological effectiveness of these divergent strategies may be due to the formation of peroxynitrite from NO and superoxide anion during reperfusion.
KEYWORDS L-NAME NG-nitro-L-arginine methyl ester; L-NMMA NG-monomethyl-L-arginine
A portion of these results was presented at the American Heart Association Scientific Sessions, Atlanta, GA, November 8–11, 1993.
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