Nitric oxide triggers classic ischemic preconditioning.
The role of NO in the classic ischemic preconditioning phenomenon 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 x 5 minute ischemia in the presence and absence of the NOS inhibitors L-NAME (50 microM) and L-NNA (50 microM), and the guanylyl cyclase inhibitor ODQ (20 microM). These inhibitors significantly attenuated the protective effect of preconditioning against 25-min global ischemia (as measured by functional recovery), specifically if administered during the triggering phase. Cyclic infusions (3 x 5 min) of the NO-donors SNAP (50 microM) and SNP (100 microM) elicited protection against both 25-min global or low-flow ischemia. Hearts preconditioned 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 preconditioning, (2) cGMP generation plays an important role in its protection, (3) attenuation of p38 MAPK during sustained ischemia accompanies NO preconditioning and may mediate cardiac protection, and (4) preconditioning with NO may be more advantageous than using ischemia.
Lochner
Amanda
A
Diabetes Research Group, MRC of South Africa, Republic of South Africa. alo@gerga.sun.ac.za
Marais
Erna
E
Du Toit
Eugene
E
Moolman
Johan
J
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester