title: Cinaciguat, a novel activator of soluble guanylate cyclase, protects against ischemia/reperfusion injury: role of hydrogen sulfide.
abstract: 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 (H(2)S). Adult New Zealand White rabbits were pretreated with 1 or 10 μg/kg cinaciguat (iv) or 10% DMSO (vehicle) 15 min before I/R or with 10 μg/kg cinaciguat (iv) at reperfusion. Additionally, adult male ICR mice were treated with either cinaciguat (10 μg/kg ip) or vehicle 30 min before I/R or at the onset of reperfusion (10 μg/kg iv). The PKG inhibitor KT5283 (KT; 1 mg/kg ip) or dl-propargylglycine (PAG; 50 mg/kg ip) the inhibitor of the H(2)S-producing enzyme cystathionine-γ-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 H(2)S levels, which was abrogated by KT. Cinaciguat is a novel molecule to induce H(2)S generation and a powerful protection against I/R injury in heart.
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, USA.
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.forename: Anindita
authors.initials: A
authors.lastname: Das
authors.forename: Arun
authors.initials: A
authors.lastname: Samidurai
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Hoke
authors.forename: Vinh Q
authors.initials: VQ
authors.lastname: Chau
authors.forename: Ramzi A
authors.initials: RA
authors.lastname: Ockaili
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009336:Necrosis; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D014463:Ultrasonography; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D001565:Benzoates; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C480588:BAY 58-2667; D017869:Cyclic GMP-Dependent Protein Kinases; D003542:Cystathionine gamma-Lyase; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D006862:Hydrogen Sulfide