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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.

frontiers in pharmacology

Ion Fluxes through KCa2 (SK) and Cav1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A1 Receptor-Mediated Actions in Spontaneously Beating Rat Atria