Submitted on February 25, 2009
Revised on April 17, 2009
Accepted on May 17, 2009
Cinaciguat, a Soluble Guanylate Cyclase Activator, Causes Potent and Sustained Pulmonary Vasodilation in the Ovine Fetus
Marc A Chester1*, Pierre Tourneux2, Gregory Seedorf3, Theresa R Grover4, Jason Gien5, and Steven H. Abman6
1 Pediatric Heart Lung Center, Sections of Neonatology and Pulmonary Medicine, Department of Pediatrics, University of Colorado School of Medicine, Aurora CO., USA
2 Pediatric Heart Lung Center, University of Colorado, Aurora CO., USA and Neonatal Intensive Care Unit, University Hospital & PériTox (UM 4285 INERIS), Amiens, Picardie, France
3 University of Colorado School of Medicine
4 The Children's Hospital
5 Pediatric Heart Lung Center, University of Colorado, Aurora CO., USA
6 University of Colorado at Denver
* To whom correspondence should be addressed. E-mail: chester.marc{at}tchden.org.
Impaired nitric oxide (NO)-cGMP signaling contributes to severe pulmonary hypertension after birth, which may in part be due to decreased soluble guanylate cyclase (sGC) activity. Cinaciguat (BAY 58-2667) is a novel sGC activator that causes vasodilation even in the presence of oxidized heme or heme-free sGC but its hemodynamic effects have not been studied in the perinatal lung. We performed surgery on 8 fetal lambs (126 ± 2 days gestation; term = 147 days) and placed catheters in the main pulmonary artery (MPAP), aorta, and left atrium (LAP) to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery (LPA) to measure blood flow, and a catheter was placed in the LPA for drug infusion. Cinaciguat (0.1 to 100 mcg over 10 min) caused dose-related increases in pulmonary blood flow greater than 4-fold above baseline and reduced PVR by 80%. Treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an sGC oxidizing inhibitor, enhanced cinaciguat-induced pulmonary vasodilation by over 120%. The pulmonary vasodilator effect of cinaciguat was prolonged, decreasing PVR for more than 1.5 hours after brief infusion. In vitro stimulation of ovine fetal pulmonary artery smooth muscle cells with cinaciguat after ODQ treatment demonstrated a 14-fold increase in cGMP in comparison without ODQ. We conclude that cinaciguat causes potent and sustained fetal pulmonary vasodilation that is augmented in the presence of oxidized sGC and speculate that cinaciguat may have therapeutic potential for severe neonatal pulmonary hypertension.
