Chronic activation of neurokinin-1 receptor induces pulmonary hypertension in rats

In this study we explored the hypothesis that chronic activation of neurokinin-1 (NK-1) receptor induces pulmonary hypertension in Wistar rats. First, the activation of NK-1 receptor on the pulmonary circulation was investigated by use of a chronic injection of NK-1 agonist [Ser9,Met(O2)11]-substance P (1 x 10(-9) mol/kg) for 2 wk at sea level (rats breathed room air) and during hypoxia (rats were placed in a hypobaric 380-Torr chamber). Second, we studied the effect of NK-1 antagonist (CP-96345) on developing and developed (after 4 wk of chronic hypoxia) pulmonary hypertension. Pulmonary arterial pressure, the weight ratio of right ventricle to left ventricle + septum, hematocrit, and substance P (SP) were measured. We found that NK-1 agonist significantly increased pulmonary arterial pressure in the sea-level but not in the hypoxic group. However, NK-1 agonist induced neither right heart hypertrophy nor polycythemia. CP-96345 significantly decreased pulmonary arterial pressure in the hypoxic group but had no effect in the sea-level group. Furthermore, CP-96345 significantly attenuated the acute SP-induced increase in pulmonary arterial pressure in the sea-level and hypoxic groups, with a larger increase in the hypoxic group. These results suggest that chronic activation of NK-1 receptor induces pulmonary hypertension and that there is an increase in the sensitivity of pulmonary vessels in response to SP in chronically hypoxic rats.