Ion Fluxes through K(Ca)2 (SK) and Ca(v)1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A(1) Receptor-Mediated Actions in Spontaneously Beating Rat Atria

Impulse generation in supraventricular tissue is inhibited by adenosine and acetylcholine via the activation of A(1) and M(2) receptors coupled to inwardly rectifying GIRK/K(IR)3.1/3.4 channels, respectively. Unlike M(2) receptors, bradycardia produced by A(1) receptors activation predominates over negative inotropy. Such difference suggests that other ion currents may contribute to adenosine chronoselectivity. In isolated spontaneously beating rat atria, blockade of K(Ca)2/SK channels with apamin and Ca(v)1 (L-type) channels with nifedipine or verapamil, sensitized atria to the negative inotropic action of the A(1) agonist, R-PIA, without affecting the nucleoside negative chronotropy. Patch-clamp experiments in the whole-cell configuration mode demonstrate that adenosine, via A(1) receptors, activates the inwardly-rectifying GIRK/K(IR)3.1/K(IR)3.4 current resulting in hyperpolarization of atrial cardiomyocytes, which may slow down heart rate. Conversely, the nucleoside inactivates a small conductance Ca(2+)-activated K(Ca)2/SK outward current, which eventually reduces the repolarizing force and thereby prolong action potentials duration and Ca(2+) influx into cardiomyocytes. Immunolocalization studies showed that differences in A(1) receptors distribution between the sinoatrial node and surrounding cardiomyocytes do not afford a rationale for adenosine chronoselectivity. Immunolabelling of K(IR)3.1, K(Ca)2.2, K(Ca)2.3, and Ca(v)1 was also observed throughout the right atrium. Functional data indicate that while both A(1) and M(2) receptors favor the opening of GIRK/K(IR)3.1/3.4 channels modulating atrial chronotropy, A(1) receptors may additionally restrain K(Ca)2/SK activation thereby compensating atrial inotropic depression by increasing the time available for Ca(2+) influx through Ca(v)1 (L-type) channels.