Ann. N.Y. Acad. Sci. 962: 402–414 (2002). © 2002 New York Academy of Sciences. Nitric Oxide Triggers Classic Ischemic Preconditioning AMANDA LOCHNER, a,b ERNA MARAIS, b EUGENE DU TOIT, b AND JOHAN MOOLMAN b a Diabetes Research Group, MRC of South Africa, Republic of South Africa b Department of Medical Physiology, University of Stellenbosch, Tygerberg, Republic of South Africa ABSTRACT: The role of NO in the classic ischemic preconditioning phenome- non of the myocardium is not well defined, and was investigated by using the isolated perfused rat heart as a model. Hearts were preconditioned with 3  5 minute ischemia in the presence and absence of the NOS inhibitors L-NAME (50 M) and L-NNA (50 M), and the guanylyl cyclase inhibitor ODQ (20 M). These inhibitors significantly attenuated the protective effect of pre- conditioning against 25-min global ischemia (as measured by functional recov- ery), specifically if administered during the triggering phase. Cyclic infusions (3  5 min) of the NO-donors SNAP (50 M) and SNP (100 M) elicited pro- tection against both 25-min global or low-flow ischemia. Hearts precondi- tioned with NO donors displayed significantly superior functional reserve, if stimulated with adrenaline, compared to hearts preconditioned with ischemia. Although the NO donors SNAP and SNP both activated p38 MAPK during the preconditioning protocol, protection was accompanied by significantly decreased p38 MAPK activity during sustained ischemia, as was the case in ischemic preconditioning. We conclude that (1) NO is a trigger for classic pre- conditioning, (2) cGMP generation plays an important role in its protection, (3) attenuation of p38 MAPK during sustained ischemia accompanies NO pre- conditioning and may mediate cardiac protection, and (4) preconditioning with NO may be more advantageous than using ischemia. KEYWORDS: nitric oxide; classic ischemic preconditioning INTRODUCTION The phenomenon of ischemic preconditioning, by which a short episode of ischemia and reperfusion protects the tissue of that organ against a subsequent pro- longed episode of ischemia, offers both short and long term protection. The imme- diate protection by ischemic preconditioning (i.e., within minutes to a few hours following a short episode of ischemia/reperfusion) is called classic preconditioning, whereas the protection that can be observed 24 hours after the preconditioning inci- dent is called late preconditioning or second window of protection. Preconditioning is the most potent form of myocardial protection against ischemia that has yet been described, 1 and because of its potential clinical use its mechanism has been the Address for correspondence: A. Lochner, P.O. Box 19063, 7505 Tygerberg, Republic of South Africa. alo@gerga.sun.ac.za