Does cyclic GMP mediate the negative inotropic effect of acetylcholine in the heart?

Abstract

DURING vagal stimulation the pacemaker activity of the heart is diminished. The reduction in heart rate is due to a release of acetylcholine (ACh) from the parasympathetic nerve terminals that increases the permeability of the myocardial cell membrane for potassium ions (for review see ref. 1). This is accompanied by a shortening of the action potential duration in atrial muscle and a diminished calcium uptake², which in turn results in a negative inotropic effect. Voltage clamp experiments in mammalian atrial muscle have shown that with higher concentrations of ACh not only is the potassium current augmented but also the slow inward current of calcium is reduced³. It is not clear how the current changes brought about by ACh are mediated. I have described the negative inotropic action of 8-bromo-cyclic GMP in the mammalian heart⁴, and these findings were confirmed in ventricular fibre fragments from mouse hearts⁵. If cyclic GMP levels in the myocardial cell are linked to the effects of ACh, as George et al. proposed⁶, then 8-bromo-cyclic GMP in addition to its negative inotropy should produce changes in the ion movements similar to those described for ACh. I report here the effects of 8-bromo-cyclic GMP on the action potential and the presumed underlying ion movements in rat atrial muscle.