Submitted on July 9, 2008
Revised on November 5, 2008
Accepted on December 8, 2008
Novel soluble guanylyl cyclase stimulator BAY 41-2272 attenuates ischemia/reperfusion induced lung injury
Bakytbek Egemnazarov1, Akylbek Sydykov1, Ralph Theo Schermuly2, Norbert Weissmann3, Johannes-Peter Stasch4, Akpai S. Sarybaev5, Werner Seeger6, Friedrich Grimminger7, and Hossein Ardeschir Ghofrani8*
1 University of Giessen Lung Center (UGLC)
2 Max-Planck-Institute for Heart and Lung Research
3 Justus-Liebig-University Giessen
4 Bayer AG
5 National Center for Cardiology and Internal Medicine
6 University of Giessen, Germany
7 Justus-Liebig University
8 University Hospital Giessen and Marburg GmbH
* To whom correspondence should be addressed. E-mail: ardeschir.ghofrani{at}innere.med.uni-giessen.de.
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, Kfc). Release of reactive oxygen species (ROS) into the perfusate was measured during early reperfusion by ESR spectroscopy. Rabbit lungs were treated with BAY 41-2272, L-NMMA 400, or NO to evaluate the effects on I/R induced lung injury. In untreated lungs a dramatic rise in Kfc values and weight gain during reperfusion were observed, 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 phorbol-12-myristrate-13-acetate induced ROS production by NADPH-oxidase. A pharmacological inhibition of the enzyme with consequent reduction in ROS levels decreased I/R injury. Nitric oxide 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.
