Effects of hirsuteine, an indole alkaloid extracted from Uncaria genus, on nicotine- and high K-induced responses were investigated in rat pheochromocytoma PC12 cells. Hirsuteine (300 nM-10µM) inhibited dopamine release evoked by 100µM nicotine in a concentration-dependent manner. Hirsuteine did not produce a parallel shift of the concentration-response relationship curve for nicotine, but reduced maximal dopamine release. Dopamine release evoked by 60 and 155 mM KCl was also inhibited by hirsuteine, but the concentration necessary for significant inhibition was higher (more than 10µM), Under whole cell voltage-clamp, hirsuteine reversibly inhibited inward currents activated by 100 nicotine. The current inhibition was slightly accelerated by hyperpolarization. The results suggest that hirsuteine non-competitively antagonizes nicotine-evoked dopamine release by blocking ion permeation through nicotinic receptor channel complexes. The blockade of Ca channels, which are activated during nicotine-evoked depolarization, may not play a major role in the antagonism.
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