Pharmacological Activation of Soluble Guanylate Cyclase Protects the Heart Against Ischemic Injury

Abstract

Background-The role of the nitric oxide/cGMP/cGMP-dependent protein kinase G pathway in myocardial protection and preconditioning has been the object of intensive investigations. The novel soluble guanylate cyclase activator cinaciguat has been reported to elevate intracellular [cGMP] and activate the nitric oxide/cGMP/cGMP-dependent protein kinase G pathway in vivo. We investigated the effects of cinaciguat on myocardial infarction induced by isoproterenol in rats. Methods and Results-Rats were treated orally twice a day for 4 days with vehicle or cinaciguat (10 mg/kg). Isoproterenol (85 mg/kg) was injected subcutaneously 2 days after the first treatment at an interval of 24 hours for 2 days to produce myocardial infarction. After 17 hours, histopathological observations and left ventricular pressure-volume analysis to assess cardiac function with a Millar microtip pressure-volume conductance catheter were performed, and levels of biochemicals of the heart tissues were measured. Gene expression analysis was performed by quantitative real-time polymerase chain reaction. Isolated canine coronary arterial rings exposed to peroxynitrite were investigated for vasomotor function, and immunohistochemistry was performed for cGMP and nitrotyrosine. The present results show that cinaciguat treatment improves histopathological lesions, improves cardiac performance, improves impaired cardiac relaxation, reduces oxidative stress, ameliorates intracellular enzyme release, and decreases cyclooxygenase 2, transforming growth factor-␤, and ␤-actin mRNA expression in experimentally induced myocardial infarction in rats.In vitro exposure of coronary arteries to peroxynitrite resulted in an impairment of endothelium-dependent vasorelaxation, increased nitro-oxidative stress, and reduced intracellular cGMP levels, which were all improved by cinaciguat. A cardioprotective effect of postischemic cinaciguat treatment was shown in a canine model of global ischemia/reperfusion. Conclusion-Pharmacological soluble guanylate cyclase activation could be a novel approach for the prevention and treatment of ischemic heart disease. (Circulation. 2009;120:677-686.) Key Words: contractility Ⅲ genes Ⅲ myocardial infarction Ⅲ nitric oxide M yocardial infarction (MI) is the rapid development of myocardial necrosis that occurs when a coronary artery is severely blocked so that there is a significant imbalance between the oxygen supply and the demand of the myocardium, causing damage or death of a portion of the myocardium. A better understanding of the processes involved in myocardial injury has stimulated the search for new drugs that could limit the myocardial damage. It has been proposed that the nitric oxide (NO)/soluble guanylate cyclase (sGC)/ cGMP/cGMP-dependent protein kinase G pathway may play a pivotal role in myocardial protection and preconditioning. In the healthy endothelium, vascular NO binds to the ferrous heme iron (Fe 2ϩ ) and activates a key signal transduction enzyme, sGC, resulting in cGMP generation. This activation promotes...

Evaluation of Cardioprotective Activity of Fulvic Acid Against Isoproterenol Induced Oxidative Damage in Rat Myocardium

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Sesamol Attenuates Isoproterenol-induced Acute Myocardial Infarction via Inhibition of Matrix Metalloproteinase-2 and -9 Expression in Rats

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Acute ethanol exposure increases the susceptibility of the donor hearts to ischemia/reperfusion injury after transplantation in rats

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