CONTRIBUTION OF ENDOGENOUS ENDOTHELIN-1 TO THE PROGRESSION OF CARDIOPULMONARY ALTERATIONS IN RATS WITH MONOCROTALINE-INDUCED PULMONARY-HYPERTENSION

Endothelin-1 (ET-1) is known to have potent contractile and proliferat ive effects on vascular smooth muscle cells and is known to induce myo cardial cell hypertrophy. We studied the pathophysiological role of en dogenous ET-1 in rats with monocrotaline-induced pulmonary hypertensio n. Four-week-old rats were given a single subcutaneous injection of 60 mg/kg monocrotaline (MCT rats) or saline (control rats) and were kill ed after 6, 10, 14, 18, and 25 days. In the MCT rats, right ventricula r systolic pressure progressively increased and right ventricular hype rtrophy developed in a parallel fashion. The venous plasma ET-1 concen tration also progressively increased, and this increase preceded the d evelopment of pulmonary hypertension. The isolated pulmonary artery ex hibited a significantly weaker response to ET-1 in the MCT rats on day 25 but not on days 6 and 14. In the MCT rats, the expression of prepr o ET-1 mRNA as measured by Northern blot analysis significantly increa sed in the heart on days 18 and 25, whereas it gradually decreased in the lungs. The peptide level of ET-1 in the lungs also significantly d ecreased in the pulmonary hypertensive stage. The expression of prepro ET-1 mRNA had increased by day 6 only in the kidneys. Continuous infu sion of BQ-123, a selective ETA receptor antagonist, by an osmotic min ipump (14.3 mg per day per rat for 18 days) significantly inhibited th e progression of both pulmonary hypertension (right ventricular systol ic pressure, 77.8 +/- 4.2 [mean +/- SEM] mm Hg [n=10] versus 52.3 +/- 2.4 mm Hg [n = 7]; P < .01) and right ventricular hypertrophy (right v entricle/[left ventricle +/- septum], 0.56 +/- 0.03 [n=10] versus 0.41 +/- 0.02 [n = 71; P < .01). Histological examination revealed that BQ -123 also effectively prevented pulmonary arterial medial thickening. The inhibition of right ventricular hypertrophy by BQ-123 may be partl y ascribed to the blockade of excessive stimulation of the heart by ET -1, in addition to the prevention of pulmonary hypertension. The prese nt findings suggest that endogenous ET-1 contributes to the progressio n of cardiopulmonary alterations in rats with MCT-induced pulmonary hy pertension.