Cotinine and nicotine inhibit each other's calcium responses in bovine chromaffin cells

Cotinine is the major metabolite of nicotine. It has some biological activi ty, but its pathophysiological effects are largely unclear. We studied whet her cotinine initiates calcium transients or affects those induced by nicot ine. In bovine adrenal chromaffm cells labeled with the fluorescent calcium indicator Fura 2, cotinine (0.32-3.2 mM) concentration-dependently increas ed the intracellular Ca2+ concentration ([Ca2+](i)). The effect was abolish ed by omitting extracellular Ca2+ during the stimulations. Also nicotinic r eceptor channel blockers hexamethonium (10 mu M-1 mM) and chlorisondamine ( 100 mu M), as well as a competitive nicotinic receptor antagonist dihydro-b eta-erythroidine (10-100 mu M), inhibited the response. Cotinine (0.32-3.2 mM) preincubation for 2 min inhibited both the nicotine-induced and the cot inine-induced increases in [Ca2+](i). Also nicotine (3.2-10 mu M) inhibited the cotinine-induced increase in [Ca2+](i). Tetrodotoxin (1 mu M) and thap sigargin (1 mu M) pretreatments did not affect the responses to cotinine, w hile 300 nM nimodipine partially inhibited the cotinine-induced increase in [Ca2+](i). The results indicate that cotinine has nicotine-like effects on chromaffin cells. It may also desensitize the nicotinic cholinergic recept ors, possibly by acting as a low-affinity agonist at these receptors, (C) 2 000 Academic Press.