Novel oscillatory mechanisms in the cholinergic control of Guinea pig sino-atrial node discharge.

Oscillatory Mechanisms in Sinus Node Cholinergic Control. Introduction: The role of the oscillatory after-potential Vos and pre-potential ThVos in cholinergic control of discharge was studied in sino-atrial node (SAN). Methods and Results: A microelectrode technique was used in isolated guinea-pig SAN superfused in vitro in high [K+]o to visualize Vos and ThVos. The cholinergic agonist carbachol (CCh) decreased the amplitude and slope of Vos and ThVos at a time when there was no increase in maximum diastolic potential. The slowing in SAN rate was due to slower and smaller ThVos that missed intermittently the threshold and occurred gradually later in diastole, but not to a decrease in the intrinsic rate of ThVos. Eventually, quiescence followed. Larger CCh concentrations quickly induced a hyperpolarization that altogether prevented the occurrence of oscillatory potentials. During CCh washout, ThVos reappeared and consistently reinitiated discharge. Lower [Ca2+]o also decreased slopes and amplitude of Vos and ThVos, thereby slowing and stopping SAN discharge, as CCh did. Overdrive temporarily offset the negative chronotropic effects of CCh and of low [Ca2+]o. Cesium (a blocker of hyperpolarization-activated current If) did not abolish CCh inhibitory effects on oscillatory potentials. Conclusions: The cholinergic agonist CCh: (1) slows SAN discharge by decreasing the amplitude of Vos and ThVos, but not the rate of ThVos; (2) can cause hyperpolarization that altogether suppresses the oscillatory potentials; (3) is mimicked in its effects by low [Ca2+]o; (4) is antagonized by procedures that increase cellular calcium; and (5) modifies the oscillatory potentials independently of If. (J Cardiovasc Electrophysiol, Vol. 22, pp. 71-80, January 2011)