Inhibition of some new cardiotonic agents by tetrodotoxin

The effects of sulmazole, milrinone and 1,5-dihydro-6-chloro-3-methylimidazo[2,1-b]quinazolone-2 on guinea pig left atria were studied, measuring the force of contraction in the absence and in the presence of 1 x 10(-5) mol/l octahydro-12-(hydroxymethyl)-2-imino-5,9: 7,10a-dimethano-10aH-[1,3]-dioxocino[6,5-d]pyrimidine- 4,7,10, 11,12-pentol (tetrodotoxin, TTX). The dihydropyridine derivative methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-tri-fluoromethylphenyl) pyridine-5-carboxylate, a Ca2+ agonist, was also tested. Protoveratrine B, which prolongs the Na+ current phase, was inhibited by TTX. Isoprenaline, whose activity is mediated by cyclic adenosine monophosphate and consequently by the increase in slow inward Ca2+ current, was not. TTX antagonized competitively sulmazole, milrinone and the quinazolone drug and reduced only the activity of the dihydropyridine derivative. These results suggest an interference of the new cardiotonic drugs with the fast Na+ channel.