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


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-beta, and beta-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.


CONCLUSIONS
Pharmacological soluble guanylate cyclase activation could be a novel approach for the prevention and treatment of ischemic heart disease.
Korkmaz
Sevil
S
Department of Cardiac Surgery, University of Heidelberg, Germany. korkmaz_sevil@hotmail.com
Radovits
Tamás
T
Barnucz
Eniko
E
Hirschberg
Kristóf
K
Neugebauer
Philipp
P
Loganathan
Sivakkanan
S
Veres
Gábor
G
Páli
Szabolcs
S
Seidel
Beatrice
B
Zöllner
Stefan
S
Karck
Matthias
M
Szabó
Gábor
G
D000318:Adrenergic beta-Agonists / Q000633:toxicity; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D051546:Cyclooxygenase 2 / Q000235:genetics; D004285:Dogs; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism; D006334:Heart Function Tests / Q000187:drug effects; D007545:Isoproterenol / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D009203:Myocardial Infarction / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D015996:Survival Rate; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics
D000318:Adrenergic beta-Agonists; D001565:Benzoates; D002316:Cardiotonic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D017392:Thiobarbituric Acid Reactive Substances; D053773:Transforming Growth Factor beta1; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C480588:BAY 58-2667; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D007545:Isoproterenol