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European Heart Journal Advance Access published online on April 30, 2009
European Heart Journal, doi:10.1093/eurheartj/ehp143
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

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

Thomas Krieg1,*, Yanping Liu4, Thomas Rütz1, Carmen Methner1, Xi-Ming Yang4, Turhan Dost4, Stephan B. Felix1, Johannes-Peter Stasch2, Michael V. Cohen3,4 and James M. Downey4

1 Department of Cardiology, Ernst-Moritz-Arndt University, Loefflerstr. 23, 17487 Greifswald, Germany
2 Institute of Cardiovascular Research, Bayer HealthCare AG, Wuppertal, Germany
3 Department of Medicine, University of South Alabama College of Medicine, Mobile, AL, USA
4 Department of Physiology, University of South Alabama College of Medicine, Mobile, AL, USA

Received 2 November 2008; revised 30 January 2009; accepted 13 March 2009 * Corresponding author. Tel: +49 3834 865658, Tel: +49 3834 866657, Email: krieg{at}uni-greifswald.de

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) 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 µg/kg followed by a 60 min infusion of 1.25 µg/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 KATP channel antagonist. Conversely, N{omega}-nitro-L-arginine-methyl-ester-hydrochloride, 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.

Key Words: BAY 58-2667 • Cardioprotection • Guanylyl cyclase • Protein kinase G • Reperfusion


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