Interaction of potassium channel openers and blockers in canine atrial muscle

The possibility that the interaction between potassium channel openers, e.g. cromakalim, pinacidil and nicorandil, and some potassium channel blockers involves a common site was investigated in canine atrial muscle. Cromakalim, pinacidil and nicorandil produced a negative inotropic effect, their pD₂ (-log EC₅₀) values being 6.11 ± 0.07, 5.37 ± 0.09 and 4.55 ± 0.07, respectively. The potassium channel blockers, tetraethylammonium (TEA), tetrabutylammonium (TBA), 3,4-diaminopyridine (DAP), CsCl and BaCl₂ all produced a positive inotropic effect. The concentration-effect curves for the negative inotropic actions of pinacidil were shifted in a parallel way to the right by low concentrations of TEA, TBA or BaCl₂. Maximum response to pinacidil were depressed by higher concentrations of the blockers. An analysis of the non-competitive antagonism by TEA yielded pK(A) (-log K(A)) values of 4.00-4.05 for pinacidil. The concentration-effect curves for cromakalim and nicorandil were shifted by TEA similarly to those for pinacidil, and a similar analysis yielded pK(A) values of 4.47-4.68 for cromakalim and 3.47-3.74 for nicorandil. The K(A) values of cromakalim, pinacidil and nicorandil were about 10-30 times greater than their EC₅₀ values, indicating that there are non-linear stimulus-effect relationships between the binding of the three potassium channel openers to their binding sites at potassium channels and their negative inotropic effects. The dissociation constants for TEA could also be estimated from pA₂ and pK(B) values for antagonizing competitively and non-competitively the negative inotropic effects to the three potassium channel openers; they were 3.47-3.89, and did not differ between the potassium channel openers. The concentration-effect curves for the three potassium channel openers were not affected by DAP or CsCl. These results suggest the following: (i) quaternary ammonium compounds like TEA and TBA antagonize the negative inotropic effect of cromakalim, pinacidil and nicorandil by binding to potassium channels, thus preventing binding of the channel openers to the same sites or closely related sites in canine right atrial muscles. (ii) The potassium channels responsible for the negative inotropic effects of the three potassium channel openers seem to be akin to apamin-insensitive and calcium-insensitive potassium channels in smooth muscle and are opened at the resting membrane potential.