Angiotensin II and monocrotaline-induced pulmonary hypertension: effect of losartan (DuP 753), a nonpeptide angiotensin type 1 receptor antagonist.

Administration of the pyrrolizidine alkaloid monocrotaline (MCT) to rats results in hypertensive pulmonary vascular disease characterized by a structurally based increase in pulmonary vascular resistance and right ventricular hypertrophy. Alterations in lung angiotensin converting enzyme activity in MCT-treated rats have suggested a role for angiotensin II (AII) in the pathogenesis of this model of hypertensive pulmonary vascular disease. To determine if increases in AII contribute to the development of pulmonary hypertension in MCT-treated rats, we examined the effect of chronic administration of the nonpeptide AII receptor antagonist Losartan on indices of pulmonary hypertension, Losartan (DuP 753; 10 mg/kg s.c.) administration for 21 days did not prevent the development of hypertensive pulmonary vascular disease in MCT-treated rats. However, 18 hr after the last dose of Losartan, AII (0.1 micrograms/kg i.v.)-induced pressor responses were inhibited by 63% in Losartan-treated rats. Losartan administration in MCT-treated rats did not prevent increases in pulmonary artery pressure or development of right ventricular hypertrophy. Additionally, increases in medial arterial thickness in pulmonary artery vessels (less than 50 microns and 50-100 microns external diameter) from MCT-treated rats were still evident in Losartan-treated rats. However, Losartan administration decreased medial pulmonary artery thickness of 50 to 100 microns external diameter vessels in control rats. These results demonstrate that AII. acting at the AT1 receptor subtype, does not contribute to pulmonary hypertension in this animal model.

Polyamines and epidermal growth factor in monocrotaline-induced pulmonary hypertension.

Multiple lines of evidence suggest that the polyamines, a family of low-molecular-weight organic cations with documented regulatory note in cell growth and differentiation, are involved with hyperplastic and hypertrophic responses of lung cells underlying hypertensive pulmonary vascular disease. Little is known, however, of the factor(s) initiating polyamine synthesis in pulmonary hypertension. This study tested the key aspects of the hypothesis that augmented polyamine synthesis, and attendent vascular structural alterations in monocrotaline (MCT)-treated rats can be ascribed to elaboration of an epidermal growth factor (EGF)-like mitogen. In lungs of rats treated 4 days previously with 60 mg/kg, EGF-like immunoreactivity was detected diffusely throughout perivascular regions. Intravenous administration of human recombinant EGF (125 pg/h) to rats for 1 wk was associated with medial thickening in pulmonary arteries between 100 and 200 microns in diameter, significant increases in lung polyamine contents, and a moderate elevation in mean pulmonary arterial pressure. These observations indicate that EGF can be detected in the lungs of MCT-treated rats and that exogenous EGF mimics some of the action of MCT on the rat lung. It is thus reasonable to speculate that an EGF-like mitogen may participate in the response to MCT in part through a polyamine-dependent mechanism.

Epidermal growth factor augments reactivity to angiotensin II in the rat pulmonary circulation.

To determine if epidermal growth factor (EGF), a vascular smooth muscle mitogen exhibiting systemic vasoactivity, causes constriction or dilation of the pulmonary vascular bed, this study evaluated the actions of EGF in isolated, buffer-perfused rat lungs and in isolated rat pulmonary arteries. In perfused rat lungs with baseline vasomotor tone, EGF administered at bolus doses of 10(-9) to 3 x 10(-7) M failed to exert either constrictor or dilator actions or to promote edema formation as evidenced by a constant lung wet-to-dry-weight ratio. Elevation of baseline tone with either prostaglandin (PG)F2 alpha or angiotensin II also failed to unmask an effect of EGF on pulmonary vascular resistance. In contrast to these negative observations, pretreatment with 5 x 10(-8) M EGF consistently augmented pressor responses evoked by angiotensin II. Constrictor responses to potassium chloride and to PGF2 alpha were unaffected by EGF pretreatment. In isolated rat extrapulmonary arteries, EGF provoked contraction in 40% of the preparations studied. Responsive vessels exhibited maximal EGF-induced contractions that were approximately 25% of that associated with angiotensin II and were characterized by an ED50 of 7 x 10(-8) M. Relaxant activity of EGF could not be demonstrated in isolated arterial preparations with normal resting tone or with tone elevated by addition of norepinephrine to the tissue bath. Endothelial denudation also failed to unmask contractile or relaxant effects of EGF. Similar to its actions in isolated, perfused rat lungs, EGF potentiated contractions of isolated pulmonary arteries induced by angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)