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.