Published ahead of print on September 13, 2007, doi:10.1164/rccm.200707-1121OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200707-1121OC
Inhaled Agonists of Soluble Guanylate Cyclase Induce Selective Pulmonary Vasodilation1 Department of Anesthesia and Critical Care and Anesthesia Center for Critical Care Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; 2 Department of Anesthesiology and Laboratory for Biomaterials and Drug Delivery, Children's Hospital, Boston, Massachusetts; 3 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts; 4 Pharma Research Center, Bayer HealthCare, Wuppertal, Germany; 5 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and 6 Department of Respiratory Care, Massachusetts General Hospital and Department of Anesthesia, Harvard Medical School, Boston, Massachusetts Correspondence and requests for reprints should be addressed to Oleg V. Evgenov, M.D., Ph.D., Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit Street, Gray/Bigelow 444, Boston, MA 02114. E-mail: evgenov{at}etherdome.mgh.harvard.edu; oevgenov{at}partners.org Rationale: Nitric oxide–independent agonists of soluble guanylate cyclase (sGC) have been developed. Objectives: We tested whether inhalation of novel dry-powder microparticle formulations containing sGC stimulators (BAY 41-2272, BAY 41-8543) or an sGC activator (BAY 58-2667) would produce selective pulmonary vasodilation in lambs with acute pulmonary hypertension. We also evaluated the combined administration of BAY 41-8543 microparticles and inhaled nitric oxide (iNO). Finally, we examined whether inhaling BAY 58-2667 microparticles would produce pulmonary vasodilation when the response to iNO is impaired. Methods: In awake, spontaneously breathing lambs instrumented with vascular catheters and a tracheostomy tube, U-46619 was infused intravenously to increase mean pulmonary arterial pressure to 35 mm Hg. Measurements and Main Results: Inhalation of microparticles composed of either BAY 41-2272, BAY 41-8543, or BAY 58-2667 and excipients (dipalmitoylphosphatidylcholine, albumin, lactose) produced dose-dependent pulmonary vasodilation and increased transpulmonary cGMP release without significant effect on mean arterial pressure. Inhalation of microparticles containing BAY 41-8543 or BAY 58-2667 increased systemic arterial oxygenation. The magnitude and duration of pulmonary vasodilation induced by iNO were augmented after inhaling BAY 41-8543 microparticles. Intravenous administration of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which oxidizes the prosthetic heme group of sGC, markedly reduced the pulmonary vasodilator effect of iNO. In contrast, pulmonary vasodilation and transpulmonary cGMP release induced by inhaling BAY 58-2667 microparticles were greatly enhanced after treatment with ODQ. Conclusions: Inhalation of microparticles containing agonists of sGC may provide an effective novel treatment for patients with pulmonary hypertension, particularly when responsiveness to iNO is impaired by oxidation of sGC.
Key Words: pulmonary hypertension • soluble guanylate cyclase • BAY 41-2272 • BAY 41-8543 • BAY 58-2667
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