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BAY 58-2667, a Nitric Oxide-Independent Guanylyl Cyclase Activator, Pharmacologically Post-Conditions Rabbit and Rat Hearts

BAY 58-2667, a Nitric Oxide-Independent Guanylyl Cyclase Activator, Pharmacologically Post-Conditions Rabbit and Rat Hearts

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

Eur Heart J. 2009 Jul;30(13):1607-13.

PMID: 19406872

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP646995359	Cinaciguat hydrochloride		646995-35-9	Price

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