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

Sodium salicylate (5-10 mM) has been used to distinguish the effects of the three calcium-antagonist subgroups which had been 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 taenia preparations from the guinea-pig caecum. In contrast, 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 calcium-antagonists and recontracted with high concentrations of Ca2+, salicylate (5 mM) caused an additional contraction when the preparations had been pretreated with verapamil or diltiazem but had no effect in control or nifedipine-treated preparations. In contrast, salicylate relaxed Ca2+-induced contractions in tissues which had been pretreated with cinnarizine, flunarizine, pimozide, bepridil, fendiline, perhexiline and with the calmodulin antagonist W-7. 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 microM) and 2,4-dinitrophenol (20 microM) did not differentiate between calcium 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. Furthermore, salicylate increased the effectiveness of the cationic local anaesthetic, (+)-propranolol (100 microM), but did not change the effects of the neutral local anesthetic, benzocaine (1 mM). It is argued that salicylate increases 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.