Changing surface charge with salicylate differentiates between subgroups of calcium‐antagonists

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Abstract
Sosium salicylate (5-10 mM) was used to distinguish the effects of the 3 Ca-antagonist subgroups which were previously differentiated in functional studies. Sodium salicylate (10 mM) reduced the antagonistic effects of verapamil and diltiazem on Ca2+-induced contractions of K+ (40 mM)-depolarized tenia preparations from the guinea-pig cecum. Salicylate had no effect on the potency of nifedipine and increased the inhibitory effects of cinnarizine and flunarizine. Sodium salicylate (10 mM) had little effect on Ca2+-induced contractions per se. In preparations pretreated with Ca-antagonists and recontracted with high concentrations of Ca2+, salicylate (5 mM) caused an additional contraction when the preparations were pretreated with verapamil or diltiazem but had no effect in control or nifedipine-treated preparations. Salicylate relaxed Ca2+-induced contractions in tissues which were pretreated with cinnarizine, flunarizine, pimozide, bepridil, fendiline, perhexiline and with the calmodulin antagonist W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide]. The mechanism of action of salicylate was investigated. Inhibition of prostaglandin biosynthesis or of oxidative phosphorylation by salicylate was not responsible for these effects because indomethacin (28 .mu.M) and 2,4-dinitrophenol (20 .mu.M) did not differentiate between Ca antagonists. The effects of salicylate are ascribed to an increase in negative surface charge on the membrane because other agents changing surface charge (3,5-dichlorosalicylate, 0.3 mM; benzoate, 20 mM) have similar effects and their potency is dependent on their affinity for lipid membranes. Salicylate increased the effectiveness of the cationic local anesthetic, (+)-propranolol (100 .mu.M), but did not change the effects of the neutral local anesthetic, benzocaine (1 mM). Salicylate may increase the effectiveness of cinnarizine by increasing accumulation of this drug in the cell membrane or at intracellular sites whereas the reduced effectiveness of verapamil and diltiazem is secondary to a change in the state of the Ca2+ channel.