Cardiotrophin-1 is a prophylactic against the development of chronic hypoxic pulmonary hypertension in rats.

Abstract

Cardiotrophin-1 (CT-1) reduces arterial blood pressure by activating nitric oxide synthesis. This study attempted to elucidate the effect of CT-1 on pulmonary arteries of pulmonary hypertensive rats. Pulmonary hypertension was induced in rats in a hypoxic chamber containing 10% to 11% oxygen. Rats kept in the hypoxic environment received either recombinant mouse CT-1 at a concentration of 50 micro g/kg (CT-1+hypoxia group, n = 21) or phosphate-buffered saline (hypoxia group, n = 30) once per day. Control rats housed in room air also received either the equivalent concentration of CT-1 (CT-1+normoxia group, n = 18) or phosphate-buffered saline (normoxia group, n = 39). Pulmonary arterial pressure, pulmonary vasorelaxation, and ventricular hypertrophy were measured. The mean pulmonary arterial pressures were as follows (from lowest to highest; p values are relative to the hypoxia group): normoxia group (20.3 +/- 4.0 mm Hg, p < 0.0001), CT-1+normoxia group (21.1 +/- 2.4 mm Hg, p < 0.0001), CT-1+hypoxia group (27.9 +/- 4.1 mm Hg, p = 0.0019), and hypoxia group (33.9 +/- 6.6 mm Hg). The endothelium-dependent vasorelaxation value was largest in the normoxia group (59.5% +/- 17.4%, p < 0.0001), with it decreasing in the other groups in the following order (p values are relative to the hypoxia group): CT-1+normoxia group (52.8% +/- 15.5%, p = 0.0005), CT-1+hypoxia group (42.3% +/- 14.8%, p = 0.0061), and hypoxia group (17.4% +/- 4.8%). Right ventricular hypertrophy was significant only in the hypoxia group. Our results demonstrate that treatment with CT-1 in a chronic hypoxic pulmonary hypertension model protects the endothelial function of the pulmonary artery; decreases pulmonary arterial pressure; and attenuates right ventricular hypertrophy.