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BAY 58-2667, an NO-independent guanylyl cyclase activator, pharmacologically post-conditions rabbit and rat hearts
BMC Pharmacology volume 9, Article number: P36 (2009)
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.
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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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
- KATP Channel
- Ischemic Precondition
- Guanylyl Cyclase
- Soluble Guanylyl Cyclase
- Isolate Rabbit Heart