Inhaled agonists of soluble guanylate cyclase induce selective pulmonary vasodilation.
BACKGROUND
Nitric oxide-independent agonists of soluble guanylate cyclase (sGC) have been developed.


OBJECTIVE
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.


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.
Evgenov
Oleg V
OV
Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit Street, Gray/Bigelow 444, Boston, MA 02114, USA. evgenov@etherdome.mgh.harvard.edu
Kohane
Daniel S
DS
Bloch
Kenneth D
KD
Stasch
Johannes-Peter
JP
Volpato
Gian P
GP
Bellas
Evangelia
E
Evgenov
Natalia V
NV
Buys
Emmanuel S
ES
Gnoth
Mark J
MJ
Graveline
Amanda R
AR
Liu
Rong
R
Hess
Dean R
DR
Langer
Robert
R
Zapol
Warren M
WM
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage* / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006162:Guanylate Cyclase; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000008:administration & dosage* / Q000494:pharmacology; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology; D010069:Oxadiazoles / Q000008:administration & dosage / Q000494:pharmacology; D010316:Particle Size; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011208:Powders; D011652:Pulmonary Circulation / Q000187:drug effects*; D011688:Purinones / Q000008:administration & dosage / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D012756:Sheep; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation / Q000187:drug effects
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D000336:Aerosols; C450679:BAY 41-8543; D001565:Benzoates; D004338:Drug Combinations; D009025:Morpholines; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D011208:Powders; D011688:Purinones; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; C480588:BAY 58-2667; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; C011145:zaprinast; D006152:Cyclic GMP