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

Study objectives: To determine the significance of serotonin in the pathoge nesis of interleukin (IL) 6-induced pulmonary hypertension (IL-6-PH) in rat s, the plasma serotonin concentrations, and the effects of a specific antag onist of the serotonin (5-hydroxytryptamine [5-HT]) receptor, 1-[o-(m-metho xyphenyl)ethyl]phenoxy]-3-(dimethylamino)-2-propyl hydrogen succinate hydro chloride (MCI) on the degree of pulmonary hypertension (PH) were investigat ed in MCI-treated IL-6-PH (IL-6-MCI-PH) rats. Measurements: The thickness of the media of small pulmonary arteries and th e 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 deg ree of PH. Serotonin concentrations in plasma and in supernatants of cultur ed 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 polymeras e chain reaction. Results: The degree of PH, as determined by the medial thickness of small p ulmonary 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 s ignificantly different from that in normal control rats. The RV/LV + S weig ht ratio in the IL-6-PH rats was significantly higher than that in normal c ontrol 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 signif icantly different from that in normal control rats. The serotonin concentra tion 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 sign ificantly different from that in the normal control rats. The expression le vels of the 5-HT receptor messenger RNA in the lung tissue tended to increa se in IL-6-PH rats but was suppressed in IL-6-MCI-PH rats. IL-6 significant ly increased the amount of serotonin released from VSMCs (p < 0.02). The ex pression of the 5-HT receptor messenger RNA was observed with IL-6 stimulat ion as was observed with serotonin stimulation in VSMCs. Conclusions: Serotonin receptor antagonists could be considered as potentia lly useful agents for the treatment of chronic thromboembolic PH, as well a s for that of primary PH and PH associated with collagen vascular diseases.