Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice.

BACKGROUND: The incidence of pulmonary arterial hypertension secondary to the use of indirect serotinergic agonists such as aminorex and dexfenfluramine led to the "serotonin hypothesis" of pulmonary arterial hypertension; however, the role of serotonin in dexfenfluramine-induced pulmonary arterial hypertension remains controversial. Here, we used novel transgenic mice lacking peripheral serotonin (deficient in tryptophan hydroxylase-1; Tph1(-/-) mice) or overexpressing the gene for the human serotonin transporter (SERT; SERT(+) mice) to investigate this further. METHODS AND RESULTS: Dexfenfluramine administration (5 mg x kg(-1) x d(-1) PO for 28 days) increased systolic right ventricular pressure and pulmonary vascular remodeling in wild-type mice but not in Tph1(-/-) mice, which suggests that dexfenfluramine-induced pulmonary arterial hypertension is dependent on serotonin synthesis. Dexfenfluramine was also administered to normoxic SERT(+) mice and SERT(+) mice exposed to chronic hypoxia. Dexfenfluramine and SERT overexpression had additive effects in increasing pulmonary vascular remodeling; however, in hypoxic SERT(+) mice, dexfenfluramine reduced both systolic right ventricular pressure and pulmonary vascular remodeling. Pulmonary arterial fibroblasts from SERT(+) mice, but not wild-type mice, proliferated in response to hypoxia. Dexfenfluramine inhibited hypoxia-induced proliferation of pulmonary arterial fibroblasts derived from SERT(+) mice in a manner dependent on SERT activity. Dexfenfluramine also inhibited the hypoxia-mediated increase in phosphorylation of p38 mitogen-activated protein kinase in SERT(+) pulmonary arterial fibroblasts. CONCLUSIONS: The results suggest that peripheral serotonin is critical for the development of dexfenfluramine-induced pulmonary arterial hypertension and that dexfenfluramine and SERT overexpression have additive effects on pulmonary vascular remodeling. We propose that dexfenfluramine can also inhibit hypoxia-induced pulmonary vascular remodeling via SERT activity and inhibition of hypoxia-induced p38 mitogen-activated protein kinase.

The in vivo effects of human urotensin II in the rabbit and rat pulmonary circulation: effects of experimental pulmonary hypertension.

In vivo haemodynamic responses to human urotensin-II were determined in two models of pulmonary hypertension: rabbits with left ventricular dysfunction following coronary artery ligation and the hypoxic rat. Effects were also examined in the presence of the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Human urotensin-II increased pulmonary arterial pressure to a greater extent in ligated rabbits than their controls and L-NAME increased pulmonary pressure without significantly affecting these responses to human urotensin-II. Human urotensin-II raised right ventricular pressure slightly in control rats but not in hypoxic rats. Human urotensin-II did not constrict control rat isolated small pulmonary arteries and only induced a small constriction of these vessels in hypoxic rats. In conclusion, exogenous human urotensin-II exerts pulmonary pressor responses in vivo in rabbits and also induced small pulmonary pressor responses in control rats. Pulmonary pressor responses to urotensin-II were increased by pulmonary hypertension in rabbits but not in rats.