Abstract
Impulse generation in supraventricular tissue is inhibited by adenosine and acetylcholine via the activation of A1 and M2 receptors coupled to inwardly rectifying GIRK/KIR3.1/3.4 channels, respectively. Unlike M2 receptors, bradycardia produced by A1 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 KCa2/SK channels with apamin and Cav1 (L-type) channels with nifedipine or verapamil, sensitized atria to the negative inotropic action of the A1 agonist, R-PIA, without affecting the nucleoside negative chronotropy. Patch-clamp experiments in the whole-cell configuration mode demonstrate that adenosine, via A1 receptors, activates the inwardly-rectifying GIRK/KIR3.1/KIR3.4 current resulting in hyperpolarization of atrial cardiomyocytes, which may slow down heart rate. Conversely, the nucleoside inactivates a small conductance Ca2+-activated KCa2/SK outward current, which eventually reduces the repolarizing force and thereby prolong action potentials duration and Ca2+ influx into cardiomyocytes. Immunolocalization studies showed that differences in A1 receptors distribution between the sinoatrial node and surrounding cardiomyocytes do not afford a rationale for adenosine chronoselectivity. Immunolabelling of KIR3.1, KCa2.2, KCa2.3, and Cav1 was also observed throughout the right atrium. Functional data indicate that while both A1 and M2 receptors favor the opening of GIRK/KIR3.1/3.4 channels modulating atrial chronotropy, A1 receptors may additionally restrain KCa2/SK activation thereby compensating atrial inotropic depression by increasing the time available for Ca2+ influx through Cav1 (L-type) channels.
Highlights
Intravenous bolus of adenosine is clinically useful for prompt conversion of paroxysmal supraventricular tachycardia to sinus rhythm and to control ventricular contraction rate in atrial fibrillation (Savelieva and Camm, 2008; Lim et al, 2009)
These findings suggest that the A2A receptor has limited importance in the response to adenosine in the isolated spontaneously beating rat atria, yet it may contribute to increase atrial contractile force when significant negative
Upon blocking GIRK/KIR3.1/3.4 channels with tertiapin Q, the A1 receptor agonist decreased, rather than increased, the outward component and this effect was fully prevented by co-application of the KCa2/SK channel blocker apamin. These findings clearly indicate that the net GIRK/KIR3.1/KIR3.4 outward current triggered by adenosine that is responsible for reducing the SA node automatism may be partially counteracted by the inactivation of an apaminsensitive Ca2+-activated KCa2/SK repolarizing current leading to prolongation of action potential duration and to Ca2+ influx into atrial cardiomyocytes via voltage-gated Cav1 (L-type) channels
Summary
Intravenous bolus of adenosine is clinically useful for prompt conversion of paroxysmal supraventricular tachycardia to sinus rhythm and to control ventricular contraction rate in atrial fibrillation (Savelieva and Camm, 2008; Lim et al, 2009). The A1 receptor promoter is highly active in the atrium as compared to the ventricle, resulting in high A1 receptor mRNA levels (Rivkees et al, 1999) This leads to a dominant localization of A1 receptors in atrial cardiomyocytes where they exert direct inhibitory effects on chronotropy and dromotropy (Shryock and Belardinelli, 1997; Auchampach and Bolli, 1999), as well as indirect anti-β-adrenergic inotropic responses by opposing the responses of sympathetic nerves activation and β1 receptors stimulation (Dobson, 1983; Romano et al, 1991). Activation of GIRK/KIR3.1/3.4 currents causes a reduction in the action potential duration, thereby decreasing the time available for Ca2+ influx through Cav (L-type) channels and, heart rate and the force of muscle contraction in atrial myocardium (Urquhart et al, 1993; Belardinelli et al, 1995; Neumann et al, 1999). Despite the extensive literature on this subject, several questions remain unanswered concerning the contribution of distinct K+ and Ca2+ channels to differential pharmacological responses of atrial cardiomyocytes to both adenosine and acetylcholine
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