Abstract | BACKGROUND: METHODS AND RESULTS: Both Bay41-2272 and Bay58-2667 dose-dependently inhibited the pressor response of acute hypoxia in the isolated perfused lung system. When wild-type (NOS3(+/+)) or NOS3(-/-) mice were housed under 10% oxygen conditions for 21 or 35 days, both strains developed pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, demonstrated by an increase in fully muscularized peripheral pulmonary arteries. Treatment of wild-type mice with the activator of sGC, Bay58-2667 (10 mg/kg per day), or the stimulator of sGC, Bay41-2272 (10 mg/kg per day), after full establishment of pulmonary hypertension from day 21 to day 35 significantly reduced pulmonary hypertension, right ventricular hypertrophy, and structural remodeling of the lung vasculature. In contrast, only minor efficacy of chronic sGC activator therapies was noted in NOS3(-/-) mice. In monocrotaline-injected rats with established severe pulmonary hypertension, both compounds significantly reversed hemodynamic and structural changes. CONCLUSIONS:
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Authors | Rio Dumitrascu, Norbert Weissmann, Hossein Ardeschir Ghofrani, Eva Dony, Knut Beuerlein, Harald Schmidt, Johannes-Peter Stasch, Mark Jean Gnoth, Werner Seeger, Friedrich Grimminger, Ralph Theo Schermuly |
Journal | Circulation
(Circulation)
Vol. 113
Issue 2
Pg. 286-95
(Jan 17 2006)
ISSN: 1524-4539 [Electronic] United States |
PMID | 16391154
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
- Benzoates
- Pyrazoles
- Pyridines
- BAY 58-2667
- Nitric Oxide Synthase Type II
- Nitric Oxide Synthase Type III
- Nos3 protein, mouse
- Guanylate Cyclase
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Topics |
- Animals
- Benzoates
(administration & dosage, pharmacology)
- Cardiomegaly
(enzymology)
- Disease Models, Animal
- Enzyme Activation
(drug effects)
- Guanylate Cyclase
(metabolism)
- Humans
- Hypertension, Pulmonary
(drug therapy, enzymology, etiology)
- Hypertrophy, Right Ventricular
(enzymology)
- Hypoxia
(complications)
- Male
- Mice
- Mice, Knockout
- Nitric Oxide Synthase Type II
(deficiency)
- Nitric Oxide Synthase Type III
- Pulmonary Circulation
- Pyrazoles
(administration & dosage, pharmacology)
- Pyridines
(administration & dosage, pharmacology)
- Rats
- Rats, Sprague-Dawley
- Solubility
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