Pharmacological activation of soluble guanylate cyclase protects the heart against ischemic injury

Sevil Korkmaz, Tamás Radovits, Eniko Barnucz, Kristóf Hirschberg, Philipp Neugebauer, Sivakkanan Loganathan, Gábor Veres, Szabolcs Páli, Beatrice Seidel, Stefan Zöllner, Matthias Karck, Gábor Szabó

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

BackgroundThe role of the nitric oxide/cGMP/cGMPdependent 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/cGMPdependent protein kinase G pathway in vivo. We investigated the effects of cinaciguat on myocardial infarction induced by isoproterenol in rats. Methods and ResultsRats 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-β, and β-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. ConclusionPharmacological soluble guanylate cyclase activation could be a novel approach for the prevention andtreatment of ischemic heart disease.

Original languageEnglish
Pages (from-to)677-686
Number of pages10
JournalCirculation
Volume120
Issue number8
DOIs
Publication statusPublished - Aug 25 2009

    Fingerprint

Keywords

  • Contractility
  • Genes
  • Myocardial infarction
  • Nitric oxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Korkmaz, S., Radovits, T., Barnucz, E., Hirschberg, K., Neugebauer, P., Loganathan, S., Veres, G., Páli, S., Seidel, B., Zöllner, S., Karck, M., & Szabó, G. (2009). Pharmacological activation of soluble guanylate cyclase protects the heart against ischemic injury. Circulation, 120(8), 677-686. https://doi.org/10.1161/CIRCULATIONAHA.109.870774