Pivotal role of nitric oxide in delayed pharmacological preconditioning against myocardial infarction

The phenomenon of 'ischemic preconditioning' (TP) has been vigorously inves tigated during the past 15 years. As our knowledge on the possible protecti ve mechanisms of IP has been increasingly expanded, novel approaches based on preconditioning with pharmacological agents have recently emerged. Two d rugs have been used to induce delayed preconditioning against myocardial in farction caused by ischemia/reperfusion. One of the drugs was monophosphory l lipid A (MLA) - a detoxified derivative of lipopolysaccharide from gram-n egative strains; and another drug was RC552 - a novel synthetic glycolipid that mimics the chemical structure of MLA. We have shown that pretreatment of adult mice with MLA or RC552 (350 mug/kg) 24 h prior to the global ische mia and reperfusion in the isolated perfused heart attenuated myocardial in jury. Infarct size was significantly reduced in MLA or RC552-treated groups as compared with the vehicle-treated group. The delayed cardioprotection w as associated with a moderate but significant increase of nitric oxide leve l in the ischemic myocardium. Treatment with S-methylisothiourea (3 mg/kg), a selective inhibitor of inducible nitric oxide synthase (iNOS) abolished MLA or RC552-induced delayed protection. In addition, neither MLA nor RC552 reduced infarct size in iNOS knockout mice. Our findings suggest that both MLA and RC552 are able to induce delayed myocardial preconditioning via iN OS-dependent pathway. (C) 2000 Elsevier Science Ireland Ltd. All rights res erved.