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BAY 58-2667, an NO-independent guanylyl cyclase activator, pharmacologically post-conditions rabbit and rat hearts

Background

BAY 58-2667 (cinaciguat) directly activates soluble guanylyl cyclase without tolerance in a NO-independent manner, and its hemodynamic effect is similar to that of nitroglycerin. We tested whether BAY 58-2667 could make both rabbit and rat hearts resistant to infarction when given at the end of an ischemic insult.

Methods and results

All hearts were exposed to 30-min regional ischemia followed by 120-(isolated hearts) or 180-(in situ hearts) min reperfusion. BAY 58-2667 (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 58-2667 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, Nω-nitro-L-arginine-methyl-ester-hydrochloride, a NO-synthase inhibitor, failed to block BAY 58-2667's ability to decrease infarction, consistent with the latter's putative NO-independent activation of PKG. Finally, BAY 58-2667 increased myocardial cGMP content in reperfused hearts while cAMP was unchanged.

Conclusion

When applied at reperfusion BAY 58-2667 is an effective cardioprotective agent with a mechanism similar to that of ischemic preconditioning and, hence, should be a candidate for treatment of acute myocardial infarction in man.

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Correspondence to Thomas Krieg.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Krieg, T., Liu, Y., Rütz, T. et al. BAY 58-2667, an NO-independent guanylyl cyclase activator, pharmacologically post-conditions rabbit and rat hearts. BMC Pharmacol 9, P36 (2009). https://doi.org/10.1186/1471-2210-9-S1-P36

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Keywords

  • KATP Channel
  • Ischemic Precondition
  • Guanylyl Cyclase
  • Soluble Guanylyl Cyclase
  • Isolate Rabbit Heart