Novel soluble guanylyl cyclase stimulator BAY 41-2272 attenuates ischemia-reperfusion-induced lung injury.
The protective effects of nitric oxide (NO), a physiological activator of soluble guanylyl cyclase (sGC), have been reported in ischemia-reperfusion (I/R) syndrome of the lung. Therefore, we studied the effects of BAY 41-2272, a novel sGC stimulator, on I/R injury of the lung in an isolated intact organ model. Lung injury was assessed by measuring weight gain and microvascular permeability (capillary filtration coefficient, K(fc)). Release of reactive oxygen species (ROS) into the perfusate was measured during early reperfusion by electron spin resonance (ESR) spectroscopy. Rabbit lungs were treated with BAY 41-2272, N(G)-monomethyl-L-arginine (L-NMMA), or NO to evaluate the effects on I/R-induced lung injury. In untreated lungs, a dramatic rise in K(fc) values and weight gain during reperfusion were observed, and these results were associated with increased ROS production. Both, BAY 41-2272 and L-NMMA significantly attenuated vascular leakage and suppressed ROS release. Additional experiments showed that BAY 41-2272 diminished PMA-induced ROS production by NADPH oxidase. A pharmacological inhibition of the enzyme with consequent reduction in ROS levels decreased I/R injury. NO had only marginal effect on I/R injury. Thus BAY 41-2272 protects against I/R-induced lung injury by interfering with the activation of NADPH oxidases.
Egemnazarov
Bakytbek
B
Departments of Internal Medicine II, University Hospital Giessen and Marburg, Giessen, Germany.
Sydykov
Akylbek
A
Schermuly
Ralph T
RT
Weissmann
Norbert
N
Stasch
Johannes-Peter
JP
Sarybaev
Akpai S
AS
Seeger
Werner
W
Grimminger
Friedrich
F
Ghofrani
Hossein A
HA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D055370:Lung Injury / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000517:prevention & control*; D012995:Solubility; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D011720:Pyrazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019255:NADPH Oxidases; D006162:Guanylate Cyclase; D013755:Tetradecanoylphorbol Acetate