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.