pd-180988 and Hypertension--Pulmonary

Phenotypic and contractile changes in pulmonary arterial smooth muscle cells (PASMCs) were examined in rats with pulmonary hypertension induced by hypoxia. Exposure to hypoxia induced pulmonary hypertension within 1-4 weeks. Staining with BrdU revealed that proliferative activities of PASMCs peaked at 1 week of hypoxic exposure, and then moderate proliferative activity was maintained for the next 2-4 weeks. The beta-actin/alpha-actin ratio also increased at 1-2 weeks of exposure to hypoxia. Absolute contractility of the pulmonary arterial ring continuously decreased during hypoxia, whereas the basal active tonus of the pulmonary artery increased at 1-3 weeks. Nicardipine, the ETA-receptor antagonis, CI-1034 and the rho-kinase inhibitor Y27632 partially inhibited the elevated active tonus. Endothelin-1 content in the pulmonary hypertensive lung was continuously increased during exposure to hypoxia. In conclusion, the hypoxia-induced proliferative activity of PASMCs comprised a transient phase followed by a sustained phase. The change in PASMCs from a contractile to a synthetic phenotype also correlated with proliferative activity, which subsequently decreased PASMC contractility. The continuous production of endothelin-1 upon hypoxic exposure might contribute to the increased basal tonus of the pulmonary arterial wall, which might subsequently increase pulmonic arterial pressure, resulting in accelerated pulmonary hypertension.

Topics: Actins; Amides; Animals; Cell Proliferation; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Immunohistochemistry; Male; Muscle Contraction; Muscle, Smooth; Nicardipine; Phenotype; Pulmonary Artery; Pyridines; Rats; Rats, Sprague-Dawley; Thiazines; Time Factors