This article focuses on the regional heterogeneity of the mammalian sinoatrial (SA) node in terms of cell morphology, pacemaker activity, action potential configuration and conduction, densities of ionic currents (i(Na), i(Ca,L), i(to), i(K,r), i(K,s) and i(f)), expression of gap junction proteins (Cx40, Cx43 and Cx45), autonomic regulation, and ageing. Experimental studies on the single SA node cell to the whole animal are reviewed. The heterogeneity is considered in terms of the gradient model of the SA node, in which there is gradual change in the intrinsic properties of SA node cells from periphery to centre, and the alternative mosaic model, in which there is a variable mix of atrial and SA node cells from periphery to centre. The heterogeneity is important for the dependable functioning of the SA node as the pacemaker for the heart, because (i) via multiple mechanisms, it allows the SA node to drive the surrounding atrial muscle without being suppressed electrotonically; (ii) via an action potential duration gradient and a conduction block zone, it promotes antegrade propagation of excitation from the SA node to the right atrium and prevents reentry of excitation; and (iii) via pacemaker shift, it allows pacemaking to continue under diverse pathophysiological circumstances.

Mathematical models of the action potential in the periphery and center of the rabbit sinoatrial (SA) node have been developed on the basis of published experimental data. Simulated action potentials are consistent with those recorded experimentally: the model-generated peripheral action potential has a more negative takeoff potential, faster upstroke, more positive peak value, prominent phase 1 repolarization, greater amplitude, shorter duration, and more negative maximum diastolic potential than the model-generated central action potential. In addition, the model peripheral cell shows faster pacemaking. The models behave qualitatively the same as tissue from the periphery and center of the SA node in response to block of tetrodotoxin-sensitive Na(+) current, L- and T-type Ca(2+) currents, 4-aminopyridine-sensitive transient outward current, rapid and slow delayed rectifying K(+) currents, and hyperpolarization-activated current. A one-dimensional model of a string of SA node tissue, incorporating regional heterogeneity, coupled to a string of atrial tissue has been constructed to simulate the behavior of the intact SA node. In the one-dimensional model, the spontaneous action potential initiated in the center propagates to the periphery at approximately 0.06 m/s and then into the atrial muscle at 0.62 m/s.

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The complex profile of amiodarone actions on the electrophysiological properties of cardiac cells reviewed in this article may be summarized as follows. As acute effects, amiodarone inhibits both inward and outward currents. The inhibition of inward Na+ and Ca2+ currents is enhanced in a use- and voltage-dependent manner, resulting in suppression of excitability and conductivity in both iNa- and iCa-dependent cardiac tissues. The inhibition is greater in the tissues stimulated at higher frequencies, and in those with less negative resting (or diastolic) membrane potentials. As outward currents, iK (iKr and iKs), iK,ACh and iK,Na are inhibited by acute amiodarone, iKl could also be inhibited at high concentrations of amiodarone. Acute effects of amiodarone on i(to) remain unclear. Previous reports on the acute effects of amiodarone on APD are conflicting, presumably because different ionic currents are responsible for the repolarization of action potential in different animal species, cardiac tissues and experimental conditions. APD would be shortened if the inhibitory action of amiodarone on the inward current is greater than on the outward current, and vice versa in the opposite case. The major and consistent chronic effect of amiodarone is a moderate APD prolongation with minimal frequency-dependence. This prolongation is most likely due to a decrease in the current density of iK and i(to). Chronic effects of amiodarone are modulated by tissue accumulation of amiodarone and DEA. Variable suppression of excitability and conductivity of the heart by chronic amiodarone might reflect direct acute effects of the parent drug and/or its active metabolite (DEA) retained at the sites of action. Chronic amiodarone was shown to cause a down-regulation of Kv1.5 mRNA in rat hearts, suggesting a drug-induced modulation of potassium channel gene expression. Electrophysiological changes in the heart induced by chronic amiodarone resemble those induced by hypothyroidism. Three mechanisms have been proposed to explain this hypothyroid-like action of amiodarone. Amiodarone and/or DEA may inhibit peripheral conversion from T4 to T3, cellular uptake of T4 and T3, and T3 binding to nuclear receptors (TR). The second and third mechanisms are considered to be more important than the first. Amiodarone or DEA could antagonize T3 action on the heart at a cellular or subcellular level. Two distinct characteristics in the cellular electropharmacology or amiodarone are different from those of other antiarrhythmic drugs. First, it acts on many different types of molecular targets including Na+, Ca2+, and K+ channels as well as adrenoceptors. Second, it may cause antiarrhythmic remodeling of cardiac cells, probably through a modulation of gene expression of ion channels and other functional proteins. We hypothesize that this remodeling is mediated most likely by cellular or subcellular T3 antagonism. Nevertheless, much remains to be studied as ot the acute and especially chronic effects of amiodarone on ionic currents, transporters, receptors...