E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats
| Autor: | Mayu Nishino, Hideyuki Adachi, Masahiko Oka, Yoshinosuke Fukuchi, Masashi Muramatsu, Norihisa Hanasato |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Pulmonary and Respiratory Medicine
Male medicine.medical_specialty Time Factors medicine.drug_mechanism_of_action Physiology Phosphodiesterase Inhibitors Hypertension Pulmonary Rats Sprague-Dawley Piperidines Oral administration Physiology (medical) Internal medicine Nitriles medicine Animals Hypoxia Cyclic GMP Lung Aorta biology business.industry Respiratory disease Hemodynamics Phosphodiesterase Cell Biology Hypoxia (medical) medicine.disease Pulmonary hypertension Rats Endocrinology medicine.anatomical_structure Enzyme inhibitor biology.protein medicine.symptom business Phosphodiesterase 5 inhibitor |
| Zdroj: | The American journal of physiology. 277(2) |
| ISSN: | 0002-9513 |
| Popis: | The purpose of this study was to determine whether E-4010, a newly synthesized potent and selective orally active phosphodiesterase (PDE) 5 inhibitor, would prevent the development of chronic hypoxia-induced pulmonary hypertension in rats. In conscious, pulmonary hypertensive rats, a single oral administration of E-4010 (1.0 mg/kg) caused an acute, long-lasting reduction in mean pulmonary arterial pressure (PAP), with no significant effects on systemic arterial pressure, cardiac output, and heart rate. In rats that received food containing 0.01 or 0.1% E-4010 during the 3-wk exposure to hypoxia, mean PAP was significantly decreased (mean PAP 24.0 ± 0.9, 16.2 ± 0.8, and 12.8 ± 0.5 mmHg in rats treated with 0, 0.01, and 0.1% E-4010-containing food, respectively), whereas mean systemic arterial pressure was unchanged and cardiac output was slightly increased compared with chronically hypoxic control rats. Right ventricular hypertrophy, medial wall thickness in pulmonary arteries corresponding to the respiratory and terminal bronchioles, and the degree of muscularization of more distal arteries were less severe in E-4010-treated rats. Long-term treatment with E-4010 caused an increase in cGMP levels in lung tissue and plasma but not in aortic tissue and no significant change in cAMP levels in either lung, aorta, or plasma. These results suggest that long-term oral treatment with E-4010 reduced the increase in PAP, right ventricular hypertrophy, and pulmonary arterial remodeling induced by exposure to chronic hypoxia, probably through increasing cGMP levels in the pulmonary vascular smooth muscle. |
| Databáze: | OpenAIRE |
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