title: Effects of BAY 41-2272, a soluble guanylate cyclase activator, on pulmonary vascular reactivity in the ovine fetus.
abstract: Nitric oxide (NO)-cGMP signaling plays a critical role during the transition of the pulmonary circulation at birth. BAY 41-2272 is a novel NO-independent direct stimulator of soluble guanylate cyclase that causes vasodilation in systemic and local circulations. However, the hemodynamic effects of BAY 41-2272 have not been studied in the perinatal pulmonary circulation. We hypothesized that BAY 41-2272 causes potent and sustained fetal pulmonary vasodilation. We performed surgery on 14 fetal lambs (125-130 days gestation; term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium 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. Pulmonary vascular resistance (PVR) was calculated as pulmonary artery pressure minus left atrial pressure divided by LPA blood flow. BAY 41-2272 caused dose-related increases in pulmonary blood flow up to threefold above baseline and reduced PVR by 75% (P < 0.01). Prolonged infusion of BAY 41-2272 caused sustained pulmonary vasodilation throughout the 120-min infusion period. The pulmonary vasodilator effect of BAY 41-2272 was not attenuated by N(omega)-nitro-l-arginine, a NO synthase inhibitor. In addition, compared with sildenafil, a phosphodiesterase 5 inhibitor, the pulmonary vasodilator response to BAY 41-2272 was more prolonged. We conclude that BAY 41-2272 causes potent and sustained fetal pulmonary vasodilation independent of NO release. We speculate that BAY 41-2272 may have therapeutic potential for pulmonary hypertension associated with failure to circulatory adaptation at birth, especially in the setting of impaired NO production.
authors.affiliation: Pediatric Heart Lung Center, University of Colorado School of Medicine, Denver, CO 80218-1088, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Deruelle
authors.forename: Theresa R
authors.initials: TR
authors.lastname: Grover
authors.forename: Laurent
authors.initials: L
authors.lastname: Storme
authors.forename: Steven H
authors.initials: SH
authors.lastname: Abman
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006325:Heart Atria / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D011687:Purines; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012756:Sheep; D000068677:Sildenafil Citrate; D013450:Sulfones; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D004791:Enzyme Inhibitors; D010879:Piperazines; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; D013450:Sulfones; D019335:Nitroarginine; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase