Effect of a serotonin receptor antagonist on interleukin-6-induced pulmonary hypertension in rats

Study objectives: To determine the significance of serotonin in the pathogenesis of interleukin (IL) 6-induced pulmonary hypertension (IL-6-PH) in rats, the plasma serotonin concentrations, and the effects of a specific antagonist of the serotonin (5-hydroxytryptamine [5-HT]) receptor, 1-[o-(m-methoxyphenyl)ethyl]phenoxy]-3-(dimethylamino)-2-propyl hydrogen succinate hydrochloride (MCI) on the degree of pulmonary hypertension (PH) were investigated in MCI-treated IL-6-PH (IL-6-MCI-PH) rats. Measurements: The thickness of the media of small pulmonary arteries and the ratio of the weight of the right ventricle free wall (RV) to that of the left ventricle with the septum (LV + S) were measured as indexes of the degree of PH. Serotonin concentrations in plasma and in supernatants of cultured vascular smooth muscle cells (VSMCs) stimulated by IL-6 were measured by high-performance liquid chromatography. The amplification of DNA encoding the 5-HT receptor in the lung specimen and VSMCs was performed by polymerase chain reaction. Results: The degree of PH, as determined by the medial thickness of small pulmonary arteries, was significantly increased in IL-6-PH rats as compared with normal control rats (p < 0.05), and that in IL-6-MCI-PH rats was not significantly different from that in normal control rats. The RV/LV + S weight ratio in the IL-6-PH rats was significantly higher than that in normal control rats (p < 0.01). The RV/LV + S weight ratio in IL-6-MCI-PH rats was significantly lower than that in IL-6-PH rats (p < 0.01) and was not significantly different from that in normal control rats. The serotonin concentration was significantly higher in IL-6-PH rats than in normal control rats (p < 0.02), and the serotonin concentration in IL-6-MCI-PH rats was not significantly different from that in the normal control rats. The expression levels of the 5-HT receptor messenger RNA in the lung tissue tended to increase in IL-6-PH rats but was suppressed in IL-6-MCI-PH rats. IL-6 significantly increased the amount of serotonin released from VSMCs (p < 0.02). The expression of the 5-HT receptor messenger RNA was observed with IL-6 stimulation as was observed with serotonin stimulation in VSMCs. Conclusions: Serotonin receptor antagonists could be considered as potentially useful agents for the treatment of chronic thromboembolic PH, as well as for that of primary PH and PH associated with collagen vascular diseases.