CONCENTRATION-DEPENDENT MODES OF INHIBITION OF NICOTINIC RECEPTOR-MEDIATED [CA2+](C) INCREASE BY RANAKININ, A NOVEL TACHYKININ, IN ISOLATEDBOVINE ADRENAL CHROMAFFIN CELLS

It has been reported that substance P inhibits catecholamine secretion induced by nicotinic agonists in adrenal chromaffin cells, and that r anakinin (RK), a novel tachikinin, caused mobilization of Ca2+ from in tracellular stores in frog adrenochromaffin cells. In the present stud y, the mode of inhibitory effect of RK on the nicotine-induced [Ca2+]( c) was analyzed in isolated bovine adrenal chromaffin cells. A transie nt [Ca2+](c) rise was recorded during continuous stimulation with nico tine in fura2-loaded chromaffin cells. A quantitative relation was fou nd between the peak levels of the nicotine-induced [Ca2+](c) rise and the concentrations of nicotine over the range 1-10 mu M. The most sati sfactory explanation for the cellular mechanism of nicotine-induced [C a2+](c) rise requires the dominant binding of two molecules of nicotin e with two subunits of nicotinic receptor with a sequence of events re sulting in [Ca2+](c) increase. The addition of RK (10 and 30 mM) rever sibly inhibited the peak levels of nicotine-induced [Ca2+](c) rise. Th e inhibitory effect of 10 mM RK on nicotine-induced [Ca2+](c) rise cou ld quantitatively be explained by a kinetics scheme based on competiti ve inhibitory action of RK on the binding of nicotine with the nicotin ic receptor molecule. The inhibitory effect of 30 mM RK on nicotine-in duced [Ca2+](c) rise, however, could quantitively be explained by a ki netics scheme based on noncompetitive inhibitory action of RK on the b inding of nicotine with the nicotinic receptor molecule.