Cinaciguat, a novel activator of soluble guanylate cyclase, protects against ischemia/reperfusion injury: role of hydrogen sulfide

Salloum FN, Das A, Samidurai A, Hoke NN, Chau VQ, Ockaili RA, Stasch JP, Kukreja RC. Cinaciguat, a novel activator of soluble guanylate cyclase, protects against ischemia/reperfusion injury: role of hydrogen sulfide. Am J Physiol Heart Circ Physiol 302: H1347-H1354, 2012. First published January 20, 2012; doi:10.1152/ajpheart.00544.2011.-Cinaciguat (BAY 58-2667) is a novel nitric oxide (NO)-independent activator of soluble guanylate cyclase (sGC), which induces cGMP-generation and vasodilation in diseased vessels. We tested the hypothesis that cinaciguat might trigger protection against ischemia/reperfusion (I/R) in the heart and adult cardiomyocytes through cGMP/protein kinase G (PKG)-dependent generation of hydrogen sulfide (H2S). Adult New Zealand White rabbits were pretreated with 1 or 10 mu g/kg cinaciguat (iv) or 10% DMSO (vehicle) 15 min before I/R or with 10 mu g/kg cinaciguat (iv) at reperfusion. Additionally, adult male ICR mice were treated with either cinaciguat (10 mu g/kg ip) or vehicle 30 min before I/R or at the onset of reperfusion (10 mu g/kg iv). The PKG inhibitor KT5283 (KT; 1 mg/kg ip) or DL-propargylglycine (PAG; 50 mg/kg ip) the inhibitor of the H2S-producing enzyme cystathionine-gamma-lyase (CSE) were given 10 and 30 min before cinaciguat. Cardiac function and infarct size were assessed by echocardiography and tetrazolium staining, respectively. Primary adult mouse cardiomyocytes were isolated and treated with cinaciguat before simulated ischemia/reoxygenation. Cinaciguat caused 63 and 41% reduction of infarct size when given before I/R and at reperfusion in rabbits, respectively. In mice, cinaciguat pretreatment caused a more robust 80% reduction in infarct size vs. 63% reduction when given at reperfusion and preserved cardiac function following I/R, which were blocked by KT and PAG. Cinaciguat also caused an increase in myocardial PKG activity and CSE expression. In cardiomyocytes, cinaciguat (50 nM) reduced necrosis and apoptosis and increased H2S levels, which was abrogated by KT. Cinaciguat is a novel molecule to induce H2S generation and a powerful protection against I/R injury in heart.