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

Abstract

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 microg/kg followed by a 60 min infusion of 1.25 microg/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(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.

• Authors: Thomas Krieg, Yanping Liu, Thomas Rütz, Carmen Methner, Xi-Ming Yang, Turhan Dost, Stephan B Felix, Johannes-Peter Stasch, Michael V Cohen, James M Downey
• Journal: European heart journal (Eur Heart J) Vol. 30 Issue 13 Pg. 1607-13 (Jul 2009) ISSN: 1522-9645 [Electronic] England
• PMID: 19406872 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoates
• Cardiotonic Agents
• BAY 58-2667
• Cyclic AMP
• Guanylate Cyclase
• Cyclic GMP

Topics

• Animals
• Benzoates (administration & dosage, therapeutic use)
• Cardiotonic Agents (administration & dosage, therapeutic use)
• Cyclic AMP (metabolism)
• Cyclic GMP (metabolism)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical (methods)
• Enzyme Activation (drug effects)
• Guanylate Cyclase (metabolism)
• Male
• Myocardial Infarction (etiology, metabolism, pathology, prevention & control)
• Myocardial Reperfusion Injury (complications, metabolism)
• Myocardium (metabolism)
• Rabbits
• Rats
• Rats, Wistar