Endothelin-1 is elevated in monocrotaline pulmonary hypertension

Abstract

These studies document striking pulmonary vasoconstrictor response to nitric oxide synthase (NOS) inhibition in monocrotaline (MCT) pulmonary hypertension in rats. This constriction is caused by elevated endothelin (ET)-1 production acting on ETA receptors. Isolated, red blood cell plus buffer-perfused lungs from rats were studied 3 wk after MCT (60 mg/kg) or saline injection. MCT-injected rats developed pulmonary hypertension, right ventricular hypertrophy, and heightened pulmonary vasoconstriction to ANG II and the NOS inhibitor N G-monomethyl-l-arginine (l-NMMA). In MCT-injected lungs, the magnitude of the pulmonary pressor response to NOS inhibition correlated strongly with the extent of pulmonary hypertension. Pretreatment of isolated MCT-injected lungs with combined ETA (BQ-123) plus ETB (BQ-788) antagonists or ETA antagonist alone prevented thel-NMMA-induced constriction. Addition of ETA antagonist reversed establishedl-NMMA-induced constriction; ETB antagonist did not. ET-1 concentrations were elevated in MCT-injected lung perfusate compared with sham-injected lung perfusate, but ET-1 levels did not differ before and after NOS inhibition. NOS inhibition enhanced hypoxic pulmonary vasoconstriction in both sham- and MCT-injected lungs, but the enhancement was greater in MCT-injected lungs. Results suggest that in MCT pulmonary hypertension, elevated endogenous ET-1 production acting through ETA receptors causes pulmonary vasoconstriction that is normally masked by endogenous NO production.

Monocrotaline-induced pulmonary hypertension correlates with upregulation of connective tissue growth factor expression in the lung

“…ET-1 was shown to induce expression of matrix and matrix-associated genes including CTGF in various cell types (Chaqour et al, 2002;Shi-Wen et al, 2004). The importance of ET-1 is also suggested by the previous reports which showed that ET-1 is elevated in patients with PH (Giaid et al, 1993) as well as in animal models of PH (Mansoor et al, 1995;Frasch et al, 1999). Therefore, it is very likely that TGF-β1, together with ET-1, plays an active role in the upregulation of CTGF in MCT-induced PH.…”

Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension

“…On the other hand, the Ghr-GHSR signaling pathway can revert ET-1-induced vasoconstriction by mechanisms that act by GH/IGF-1 and endothelium-independent pathways (21,37). It should be emphasized that ET-1 is increased in PH and seems to be largely involved in MCT-induced PH (10). With regard to pulmonary vascular remodeling, the present study showed that the medial area in peripheral pulmonary arteries was significantly reduced by Ghr, indicating that attenuation of PH is, at least partially, mediated by this mechanism.…”

Concentrated Ambient Air Particles Induce Vasoconstriction of Small Pulmonary Arteries in Rats

“…Our study shows thickening of pulmonary arteries at the light microscopic level. In the animal model of monocrotaline-induced pulmonary hypertension (67,68), endothelial ET-1 production is elevated and NO activity is decreased. The fact that deaths occur in animals of this model when exposed to particles raises the possibility that the same mechanism involved in response to monocrotaline is operative in response to particle inhalation.…”