Acetylcholine and the mammalian 'slow inward' current: a computer investigation

Although it is accepted that acetylcholine has two possible actions on cardiac muscle, one being the opening of time-independent potassium channels and the other a block of time-dependent calcium current, there is considerable doubt about which mechanism, if either, is chiefly responsible for modulating vagal control in any given region of the heart. It seems of particular importance to resolve this problem in the case of the mammalian sino-atrial node because this tissue not only receives the densest vagal innervation, but it is also the primary pacemaker. Recent studies on intact rabbit node (Shibata et al. 1985) have produced results which can be largely reproduced by using a computer model based on experimental studies of the sinus node current mechanisms (Noble & Noble 1984). We studied perturbations of node activity by modifying a number of these mechanisms, including an acetylcholine-activated K+ channel, iK,ACh, introduced into the model for the first time. Our findings lead us to the conclusion that the most important factor in modulating moderate chronotropic changes is a block of calcium current permeability. Complete vagal inhibition may also depend as much upon this effect as upon activation of iK,ACh current. Because the experimental studies under consideration here used beta-blockers to abolish the action of noradrenaline released by vagal stimulation, we suggest how a muscarinic block of isi might occur in vivo in the absence of beta-agonists.