Inhibition by ethaverine of catecholamine secretion through blocking L-type Ca2+ channels in PC12 cells.
Ethaverine, a derivative of papaverine, is used as a vasodilator and antispasmodic drug. We have investigated the effects of ethaverine on the secretion of [3H]norepinephrine from PC12 cells, of neuroendocrine origin. Treatment with ethaverine reduced catecholamine secretion in a concentration-dependent manner. The maximal inhibitory effect (90%) was achieved with 10 microM ethaverine, and the IC50 for secretion was approximately 2 microM. Ethaverine pretreatment for 1 min prior to stimulation by 70 mM K+ also decreased the level of intracellular Ca2+ in a concentration-dependent manner, as measured by fura-2 fluorescence. The IC50 for the inhibition of the increase in intracellular Ca2+ was approximately 2 microM. Nifedipine, a dihydropyridine L-type Ca2+ channel blocker, did not enhance the inhibitory effect of ethaverine on the 70 mM K(+)-induced increase in [Ca2+]i or catecholamine secretion. In contrast, the addition of the N-type voltage-sensitive Ca2+ channel antagonist omega-conotoxin with ethaverine resulted in further reductions in the increase in [Ca2+]i and catecholamine release. Maximally effective concentrations of ethaverine and nifedipine showed the same inhibitory effect on the 70 mM K(+)-evoked responses. However, ethaverine pretreatment did not inhibit the bradykinin-induced secretion and [Ca2+]i rise, which are known to be produced through the receptor-operated Ca2+ channels. We conclude that ethaverine reduces catecholamine secretion by blocking the L-type voltage-sensitive Ca2+ channel.
Suh
B C
BC
Department of Life Science, Pohang University of Science and Technology, Korea.
Kim
K T
KT
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects*; D002395:Catecholamines / Q000378:metabolism*; D016764:Cell Polarity; D004305:Dose-Response Relationship, Drug; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D010208:Papaverine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011189:Potassium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology
D015220:Calcium Channels; D002395:Catecholamines; C007639:ethaverine; D011189:Potassium Chloride; D010208:Papaverine; D001920:Bradykinin; D002118:Calcium