Circulation (New York, N.Y.), 2004, Vol.110 (15), p.2253-2259
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.
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.
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.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - toxicity ; Administration, Inhalation ; Animals ; Biological and medical sciences ; Blood and lymphatic vessels ; Blood Pressure - drug effects ; Calcium-Binding Proteins - agonists ; Calcium-Binding Proteins - physiology ; Carbon Dioxide - blood ; Carbon Monoxide - pharmacology ; Cardiology. Vascular system ; Coronary heart disease ; Cyclic GMP - biosynthesis ; Cyclic GMP - secretion ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Drug Evaluation, Preclinical ; Drug Interactions ; Guanylate Cyclase-Activating Proteins ; Heart ; Hypertension, Pulmonary - chemically induced ; Hypertension, Pulmonary - drug therapy ; Hypertension, Pulmonary - physiopathology ; Infusions, Intravenous ; Medical sciences ; NG-Nitroarginine Methyl Ester - administration & dosage ; NG-Nitroarginine Methyl Ester - pharmacology ; Nitric Oxide - administration & dosage ; Nitric Oxide - pharmacology ; Nitric Oxide - therapeutic use ; Oxygen - blood ; Pneumology ; Pulmonary Artery ; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases ; Pyrazoles - administration & dosage ; Pyrazoles - pharmacology ; Pyrazoles - therapeutic use ; Pyridines - administration & dosage ; Pyridines - pharmacology ; Pyridines - therapeutic use ; Sheep ; Vascular Resistance - drug effects ; Vasodilator Agents - administration & dosage ; Vasodilator Agents - pharmacology ; Vasodilator Agents - therapeutic use ; Wakefulness
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