The effect of LU-49938 (nexopamil) on the activation by serotonin of mesangial cells.

Intraglomerular platelet activation may release vasoactive agents such as serotonin (5-hydroxytryptamine, 5-HT) that may affect local hemodynamics and promote mesangial proliferation, eventually leading to glomerular sclerosis. The main purpose of this study is to analyze whether nexopamil, a verapamil derivative, with the property of blocking simultaneously calcium channels and 5-HT2 receptors, could modify the contractile and mitogenic effects of serotonin on cultured rat mesangial cells. Serotonin caused a concentration-dependent increase in [3H]thymidine incorporation into DNA, and mesangial cell proliferation. The effects of 5-HT on thymidine uptake and cell proliferation were blocked by the selective 5-HT2 receptor blocker ketanserin 10(-5) M. Nexopamil abolished in a concentration-dependent way the serotonin-induced [3H]thymidine incorporation into DNA, and the serotonin-induced increase in number of cells. Using 5-HT 10(-4) or 10(-5) M, nexopamil had significant effects at concentration above 10(-7) M. Serotonin induced a concentration- and time-dependent reduction of planar cell surface area. This effect was also completely blocked by ketanserin. Nexopamil partially blocked the serotonin-induced mesangial cell contraction, in a dose-dependent manner. All these data suggest that nexopamil inhibits both 5-HT-induced mesangial cell contraction and proliferation by blocking 5-HT2 receptors and the voltage-operated Ca2+ channels.