flunarizine and cobaltous-chloride

The effect of organic Ca2+ channel blockers and Co2+ on kainate-induced changes in 45Ca2+ efflux and amino acid release was studied in the rabbit hippocampus with the dialysis-perfusion technique. Administration of 1 mM kainate caused a transient, 50% drop of extracellular Ca2+. This effect was insensitive to 100 microM flunarizine or verapamil, 10 microM nimodipine, and 6 mM CoCl2. The organic Ca2+ entry blockers did not significantly influence kainate-induced changes in extracellular amino acids, whereas Co2+ affected both basal and kainic acid stimulated release of amino acids. These results indicate that kainate-regulated Ca2+ ionophores differ from Ca2+ channels in peripheral tissues in terms of sensitivity to Ca2+ entry inhibitors.

Topics: Amino Acids; Animals; Calcium; Calcium Channel Blockers; Cobalt; Flunarizine; Hippocampus; Kainic Acid; Nimodipine; Rabbits; Verapamil

A chemically heterogeneous group of compounds, the Ca++ channel antagonists, which includes verapamil, diltiazem and nifedipine inhibits excitation-contraction coupling in smooth and cardiac muscle by blocking Ca+ entry at a specific class of Ca++ channels. The binding of the nifedipine analog, [3H]nitrendipine, to a microsomal fraction from guinea-pig longitudinal smooth muscle has been characterized. Specific binding was saturable, linear with protein concentration and reversible. The apparent equilibrium dissociation constant was 1.63 +/- 0.06 X 10(-10)M and the maximum site density was 1.13 +/- 0.03 pmol/mg of protein determined from Scatchard analysis of equilibrium binding at 25 degrees C. Inhibition of binding was specific and stereoselective for Ca++ channel antagonist drugs and was unaffected by a variety of receptor active ligands. Correlations between binding and inhibition of mechanical response to methylfurmethide- and K+-stimulation in a series of nifedipine analogs were determined. A 1:1 correlation was found for the K+ tonic response, but for the phasic component of the K+ response and for both components of the methylfurmethide response the antagonists were more active as inhibitors of [3H]nitrendipine binding than as inhibitors of mechanical response. [3H]Nitrendipine binding was sensitive to other Ca++ channel antagonists including verapamil, D-600, diltiazem, flunarizine, lidoflazine and bepridil. Interaction with these agents suggests, consistent with previous reports, that more than one binding site for Ca++ antagonists exists. A variety of inorganic divalent and trivalent cations (Mn++, Co++, Ni++, Pb++, UO2++, Zn++, Cd++, Cu++, Tm+++ and La+++) inhibit specific [3H]nitrendipine binding. The data suggest that [3H]nitrendipine binding in smooth muscle is to a site which mediates the pharmacologic response.

Topics: Animals; Binding Sites; Binding, Competitive; Calcium Channel Blockers; Cinnarizine; Cobalt; Dose-Response Relationship, Drug; Drug Synergism; Flunarizine; Guinea Pigs; Ileum; Kinetics; Male; Muscle Contraction; Muscle, Smooth; Nicotinic Acids; Nifedipine; Nimodipine; Nitrendipine; Pyridines; Structure-Activity Relationship; Verapamil