Muscarinic stimulation and pinacidil produce similar facilitation of tachyarrhythmia induction in rat isolated atria.

Atrial tachyarrhythmias, the most common type of cardiac arrhythmias, are associated with greater stroke risk. Muscarinic cholinergic agonists have been shown to facilitate atrial tachyarrhythmia maintenance in the absence of cardiac disease. This has been attributed to action potential shortening, which enhances myocardial electrical anisotropy, and thus creates a substrate for reentrant excitation. In this study, we describe a similar effect of the ATP-sensitive K(+) channel (KATP) opener pinacidil on tachyarrhythmia induction in isolated rat atria. Pinacidil, which activates a weakly inwardly-rectifying current in isolated atrial myocytes, enhanced arrhythmia induction in the right and left atria. This effect was abolished by the KATP blocker glibenclamide, but not by atropine, which rules out a possible indirect effect due to stimulation of acetylcholine release. However, pinacidil attenuated carbachol-induced tachyarrhythmia facilitation, which may indicate that the action of these agonists converges to a common cellular mechanism. Both agonists caused marked action potential shortening in isolated atrial myocytes. Moreover, during arrhythmia in the presence of pinacidil and carbachol, the atrial vectorelectrographic patterns were similar and consistent with reentrant propagation of the electrical activity. From these results, we conclude that the KATP channel opening is pro-arrhythmic in atrial tissue, which may pose as an additional risk in the scenario of myocardial hypoxia. Moreover, the similarity of the electrophysiological effects of pinacidil and carbachol is suggestive that the sole increase in background K(+) conductance is sufficient for atrial tachyarrhythmia facilitation.

Determination of the vectorelectrogram in isolated rat atria: application to the study of arrhythmias.

Atrial tachyarrhythmias, the most frequent type of cardiac arrhythmia, are associated with increased stroke risk. Reentry and focal activity are considered as the main mechanisms underlying this dysfunction. In this study, we describe determination of the vectorelectrogram in isolated rat atria as a means to distinguish different patterns of electrical propagation. In all studied right atria beating at sinus rhythm, the mean electric vector (MEV) trajectory was clockwise, and each cycle was preceded by electric diastole (null MEV), either in the absence or presence of muscarinic cholinergic or beta-adrenergic receptor stimulation. During cholinergic tachyarrhythmia (induced by high-rate electric stimulation in both atria, plus exposure to carbachol in left atria), vector loops were ellipsoidal and stable, with variable direction, and did not cross the origin, which is consistent with reentrant activation and with findings obtained in vivo by other authors. In contrast, during spontaneous activity induced by rapid pacing in isoproterenol-exposed left atria, vector loops were similar to those in right atria at sinus rhythm, thus suggestive of focal activity. It is concluded that the vectorelectrogram approach allows discrimination of different patterns of propagation during arrhythmia in isolated atria and may be useful for high-output tests of pro- and anti-arrhythmic compounds.

Cholinergic-adrenergic antagonism in the induction of tachyarrhythmia by electrical stimulation in isolated rat atria.

Atrial tachyarrhythmias (AT) are the most common cardiac rhythm disturbance. In the present study, we analyzed the cholinergic-adrenergic interaction in the in vitro induction of cholinergic-dependent tachyarrhythmia by high-frequency electric stimulation. Tachyarrhythmia was evoked in isolated rat right atria by trains of electric stimuli. Atrial response was expressed as the tachyarrhythmia induction index (ATI, i.e. the fraction of applied trains that resulted in arrhythmia induction). ATI was reversibly increased by 0.6 microM carbachol (CCh), which also decreased atrial spontaneous rate (ASR). In contrast, 10 nM isoproterenol (ISO), 100 microM tyramine and the phosphodiesterase inhibitor isobutyl-methylxanthine (IBMX, 100 microM) increased ASR and decreased ATI. Amiodarone (AMI, 10 microM) reduced ATI in the presence and absence of CCh. Further CCh addition restored ATI in atria treated with either IBMX or AMI, but not when both compounds were present. Increase in ATI by CCh in atria pretreated with IBMX plus ISO was significantly attenuated by 3 mM NaF. The antagonism between cholinergic muscarinic and beta-adrenergic receptor stimulation (the former facilitating and the latter inhibiting tachyarrhythmia installation) possibly involves regulation of the phosphorylation status of adenosine cyclic 3'-5'-monophosphate (cAMP)-dependent protein kinase substrates. Additionally, cAMP-independent, AMI-sensitive mechanism stimulated by CCh (possibly muscarinic-dependent K(+) current activation) seems to contribute to AT facilitation.