AI Article Synopsis
- Nitric oxide (NO) plays a key role in delayed ischemic preconditioning, but its involvement in pharmacological protection via iNOS remains uncertain.
- The study tested the effect of the adenosine A(1) receptor agonist (CCPA) on iNOS knockout mice and wild-type mice to evaluate its potential in heart protection after ischemia.
- Results showed that CCPA reduced infarct size in both types of mice, indicating that endothelial NOS (eNOS) might mediate delayed protection, suggesting new pharmacological targets for heart protection during ischemia.
Article Abstract
Background: Nitric oxide (NO), synthesised from the inducible isoform of nitric oxide synthase (iNOS), is implicated in mediating second window of protection (SWOP)/delayed ischemic preconditioning. However the role of NO and iNOS in delayed pharmacological protection remains unclear and is the subject of this investigation.
Methods: To test the hypothesis that iNOS is necessary for delayed pharmacological preconditioning, the adenosine A(1) receptor agonist, 2-chloro N(6) cyclopentyl adenosine (CCPA) (25 microg/kg i.v.) or saline was administered to wild type (WT) or iNOS gene knockout mice (KO). Twenty-four hours later, the hearts were isolated, Langendorff perfused and subjected to 35 min ischemia/30 min reperfusion prior to infarct size determination.
Results: WT and KO control hearts had identical infarct sizes of 37 +/- 3% and 37 +/- 2%, respectively. CCPA significantly reduced infarct size in WT hearts to 22 +/- 2% and also, unexpectedly, in KO hearts (27 +/- 2%). This protection was abrogated with the non-specific NOS inhibitor, N(omega) nitro L-arginine methyl ester (L-NAME, 100 microM), and could be mimicked in naïve hearts with the NO donor, donor S-nitroso N-acetyl DL penicillamine (SNAP, 1 microM). Delayed protection appeared to be mediated by NO synthesis in both WT and KO hearts. Additional studies using Western blot analysis demonstrated endothelial NOS (eNOS) upregulation and increased NO(x) release in both WT and KO hearts.
Conclusions: This is the first study to demonstrate a role for eNOS in delayed A(1) receptor triggered (pharmacological) preconditioning, potentially representing a new pharmacological target for protecting the ischemic heart.
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| http://dx.doi.org/10.1016/s0008-6363(01)00472-2 | DOI Listing |
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