(Circulation. 1995;91:1545-1551.)
© 1995 American Heart Association, Inc.
Articles |
Inhibition of Nitric Oxide Synthesis Reduces Infarct Size by an Adenosine-Dependent Mechanism
From the Department of Nephrology (R.G.W., G.H.N.), Institute of Urology and Nephrology; and The Hatter Institute for Cardiovascular Studies (V.C.P., D.M.Y.), Department of Academic Cardiology, University College London Medical School, London, UK.
Correspondence to Professor D.M. Yellon, The Hatter Institute for Cardiovascular Studies, Department of Academic Cardiology, University College London Medical School, Gower St, London, UK WC1E 6AU.
Background Nitric oxide (NO) is both a potent endogenous vasodilator with potential to attenuate ischemia-reperfusion injury and a mediator of tissue injury. The aim of the present study was to investigate the mechanism by which prior inhibition of NO synthesis can lessen ischemia-reperfusion injury in the isolated rabbit heart.
Methods and Results We examined the effects of inhibition of NO synthesis on infarct size using a model of coronary artery ligation in isolated rabbit hearts perfused at a constant flow rate of 35 mL/min. Infarct size averaged 65% of the zone at risk after 45 minutes of ischemia and 180 minutes of reperfusion. The addition of 30 µmol/L NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, to the perfusate reduced the infarct-to-risk (I/R) ratio to an average of 41% (P<.05 versus control). This effect was abolished by pretreatment with 75.5 µmol/L 8-p-sulfophenyl theophylline (SPT), an adenosine receptor antagonist (I/R ratio, 63%). Ischemic preconditioning (5 minutes of ischemia and 10 minutes of reperfusion) before 45 minutes of ischemia and 3 hours of reperfusion reduced the I/R ratio to an average of 21%, and this was not augmented by pretreatment with L-NAME (I/R ratio, 20%). However, all protection due to preconditioning and L-NAME was lost in hearts pretreated with SPT (I/R ratio, 59%). In a separate set of experiments, adenosine concentration in the coronary perfusate and myocardial lactate concentrations were measured. Treatment with L-NAME increased the average adenosine concentration in the perfusate from 5.7 µmol/L per 100 g of heart (control) to a peak of 24.0 µmol/L per 100 g of heart; however, there was no effect on average myocardial lactate concentration (control, 4.6 µmol/g dry wt; L-NAME, 5.5 µmol/g dry wt). In contrast, after 5 minutes of global ischemia, the average adenosine concentration peaked at 139.0 µmol/L per 100 g of heart, and the average myocardial lactate concentration increased to 27.1 µmol/g dry wt.
Conclusions Infarct size limitation after inhibition of NO synthesis shares a common mechanism with that of ischemic preconditioning and is dependent on the release of adenosine. However, in this model, adenosine release after inhibition of NO synthesis is not secondary to myocardial ischemia. The protection of the heart against ischemic injury by adenosine appears to be concentration dependent.
Key Words: nitric oxide • adenosine • reperfusion • ischemia
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