BAY 58-2667, a nitric oxide-independent guanylyl cyclase activator, pharmacologically post-conditions rabbit and rat hearts

T. Krieg, Y. Liu, T. Rutz, C. Methner, X.-M. Yang, T. Dost, S. B. Felix, J.-P. Stasch, M. V. Cohen, J. M. Downey
2009 European Heart Journal  
Aims BAY 58-2667 (BAY-58) directly activates soluble guanylyl cyclase without tolerance in a nitric oxide (NO)independent manner, and its haemodynamic effect is similar to that of nitroglycerin. We tested whether BAY-58 could make both rabbit and rat hearts resistant to infarction when given at the end of an ischaemic insult. Methods and results All hearts were exposed to 30 min regional ischaemia followed by 120-(isolated hearts) or 180-(in situ hearts) min reperfusion. BAY-58 (1-50 nM)
more » ... 58 (1-50 nM) infused for 60 min starting 5 min before reperfusion significantly reduced infarction from 33.0 + 3.2% in control isolated rabbit hearts to 9.5 -12.7% (P , 0.05). In a more clinically relevant in situ rabbit model, infarct size was similarly reduced with a loading dose of 53.6 mg/kg followed by a 60 min infusion of 1.25 mg/ kg/min (41.1 + 3.1% infarction in control hearts to 16.0 + 4.4% in treated hearts, P , 0.05). BAY-58 similarly decreased infarction in the isolated rat heart, and protection was abolished by co-treatment with a protein kinase G (PKG) antagonist, or a mitochondrial K ATP channel antagonist. Conversely, N v -nitro-L-arginine-methyl-esterhydrochloride, a NO-synthase inhibitor, failed to block BAY-58's ability to decrease infarction, consistent with the latter's putative NO-independent activation of PKG. Finally, BAY-58 increased myocardial cGMP content in reperfused hearts while cAMP was unchanged. Conclusion When applied at reperfusion, BAY-58 is an effective cardioprotective agent with a mechanism similar to that of ischaemic pre-conditioning and, hence, should be a candidate for treatment of acute myocardial infarction in man. ---
doi:10.1093/eurheartj/ehp143 pmid:19406872 fatcat:uq2br7vffzajhhcfdhxd57hede