Soluble guanylate cyclase activator reverses acute pulmonary hypertension and augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs.
BACKGROUND
Inhaled nitric oxide (NO) is a potent and selective pulmonary vasodilator, which induces cGMP synthesis by activating soluble guanylate cyclase (sGC) in ventilated lung regions. Carbon monoxide (CO) has also been proposed to influence smooth muscle tone via activation of sGC. We examined whether direct stimulation of sGC by BAY 41-2272 would produce pulmonary vasodilation and augment the pulmonary responses to inhaled NO or CO.


RESULTS
In awake, instrumented lambs, the thromboxane analogue U-46619 was intravenously administered to increase mean pulmonary arterial pressure to 35 mm Hg. Intravenous infusion of BAY 41-2272 (0.03, 0.1, and 0.3 mg x kg(-1) x h(-1)) reduced mean pulmonary arterial pressure and pulmonary vascular resistance and increased transpulmonary cGMP release in a dose-dependent manner. Larger doses of BAY 41-2272 also produced systemic vasodilation and elevated the cardiac index. N(omega)-nitro-l-arginine methyl ester abolished the systemic but not the pulmonary vasodilator effects of BAY 41-2272. Furthermore, infusing BAY 41-2272 at 0.1 mg x kg(-1) x h(-1) potentiated and prolonged the pulmonary vasodilation induced by inhaled NO (2, 10, and 20 ppm). In contrast, inhaled CO (50, 250, and 500 ppm) had no effect on U-46619-induced pulmonary vasoconstriction before or during administration of BAY 41-2272.


CONCLUSIONS
In lambs with acute pulmonary hypertension, BAY 41-2272 is a potent pulmonary vasodilator that augments and prolongs the pulmonary vasodilator response to inhaled NO. Direct pharmacological stimulation of sGC, either alone or in combination with inhaled NO, may provide a novel approach for the treatment of pulmonary hypertension.
Evgenov
Oleg V
OV
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, CLN 309, Boston, Mass 02114, USA. evgenov@etherdome.mgh.harvard.edu
Ichinose
Fumito
F
Evgenov
Natalia V
NV
Gnoth
Mark J
MJ
Falkowski
George E
GE
Chang
Yuchiao
Y
Bloch
Kenneth D
KD
Zapol
Warren M
WM
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000633:toxicity; D000280:Administration, Inhalation; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000819:agonists* / Q000502:physiology; D002245:Carbon Dioxide / Q000097:blood; D002248:Carbon Monoxide / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D051604:Guanylate Cyclase-Activating Proteins; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D007262:Infusions, Intravenous; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010100:Oxygen / Q000097:blood; D011651:Pulmonary Artery; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012756:Sheep; D014655:Vascular Resistance / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014851:Wakefulness
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D002135:Calcium-Binding Proteins; D051604:Guanylate Cyclase-Activating Proteins; D011720:Pyrazoles; D011725:Pyridines; D014665:Vasodilator Agents; D002245:Carbon Dioxide; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D002248:Carbon Monoxide; D006152:Cyclic GMP; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester