Changes in I K, ACh single-channel activity with atrial tachycardia remodelling in canine atrial cardiomyocytes.
ABSTRACT Although atrial tachycardia (AT) remodelling promotes agonist-independent, constitutively active, acetylcholine-regulated K+-current (I K,ACh) that increases susceptibility to atrial fibrillation (AF), the underlying changes in I K,Ach channel function are unknown. This study aimed to establish how AT remodelling affects I K,ACh single-channel function.
I K,ACh single-channel activity was studied via cell-attached patch-clamp in isolated left atrial cardiomyocytes of control and AT (7 days, 400 min(-1)) dogs. Atrial tachycardia prolonged the mean duration of induced AF from 44 +/- 22 to 413 +/- 167 s, and reduced atrial effective refractory period at a 360 ms cycle length from 126 +/- 3 to 74 +/- 5 ms (n = 9/group, P < 0.001). In the absence of cholinergic stimulation, single-channel openings with typical I K,ACh conductance and rectification properties were sparse under control conditions. Atrial tachycardia induced prominent agonist-independent I K,ACh activity because of increased opening frequency (fo) and open probability (Po: approximately seven- and 10-fold, respectively, vs. control), but did not alter open time-constant, single-channel conductance, and membrane density. With maximum I K,ACh activation (10 micromol/L carbachol), channel Po was enhanced much more in control cells ( approximately 42-fold) than in AT-remodelled myocytes (approximately five-fold). The selective Kir3 current blocker tertiapin-Q (100 nmol/L) reduced fo and Po at -100 mV by 48 and 51%, respectively (P < 0.05 for each), without altering other channel properties, confirming the identity of I K,ACh. Atrial tachycardia had no significant effect on mRNA or protein expression of either of the subunits (Kir3.1, Kir3.4) underlying I K,ACh.
Atrial tachycardia increases agonist-independent constitutive I K,ACh single-channel activity by enhancing spontaneous channel opening, providing a molecular basis for AT effects on macroscopic I K,ACh observed in previous studies, as well as associated refractoriness abbreviation and tertiapin-suppressible AF promotion. These results suggest an important role for constitutive I K,Ach channel opening in AT remodelling and support its interest as a potential target for AF therapy.
Article: Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches.[show abstract] [hide abstract]
ABSTRACT: By 2050, atrial fibrillation (AF) will be present in 2% of the general population and in a far higher proportion of elderly patients. Currently, we are content with rate control and anticoagulation in elderly asymptomatic patients, whereas in younger patients with symptomatic recurrent AF, pulmonary vein isolation is the treatment of choice. However, in a large number of patients, there remains a genuine choice between anti-arrhythmic therapy to suppress the arrhythmia and rate control to control the ventricular rate. This review provides a contemporary evidence-based insight into the buoyant development of new anti-arrhythmic agents, exploring new mechanisms of action or novel combinations of established anti-arrhythmic activity. An attractive prospect for AF therapy is the introduction of agents with selective affinity to ion channels specifically involved in atrial repolarization, so-called atrial repolarization-delaying agents. Presently, there are several potential anti-arrhythmic drugs with this mode of action, which are currently in pre-clinical and clinical development. Vernakalant is in the most advanced phase of investigation and its intravenous formulation has recently been recommended for approval for pharmacological cardioversion of AF. However, although this agent has some electrophysiological effects which are specific to the atria, it has others which affect both the atria and the ventricles. Other drugs, such as XEND0101, block a single atrial-specific membrane current. The success of such agents depends critically on their atrial electrophysiological selectivity, freedom from cardiac adverse effects, and general safety. Other possibilities include modified analogues of traditional anti-arrhythmic drugs with additional novel mechanisms of action and less complex metabolic profiles. Dronedarone is an investigational agent with multiple electrophysiological effects, which is devoid of iodine substituents and is believed to have a better side effect profile than its predecessor amiodarone. The development portfolio of dronedarone is practically complete and approval for several indications in AF may soon be assessed. Innovative anti-arrhythmic agents with unconventional anti-arrhythmic mechanisms, such as stretch receptor antagonism, sodium-calcium exchanger blockade, late sodium channel inhibition, and gap junction modulation, have not yet reached clinical studies in AF. Gene- and cell-based therapies, which can selectively target individual currents, could provide ideal one-time only curative therapy for arrhythmias, and the first proof-of-concept studies have been reported. There is accumulating evidence in support of the anti-arrhythmic effects of non-anti-arrhythmic drugs. Treatments with angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, statins, and omega-3 fatty acids all seem promising, over and above any effect related to the treatment of underlying heart disease. However, despite exciting results from animal experiments and promising outcomes from retrospective analyses, there is no robust evidence of specific effects of these drugs to transform current clinical practice.Europace 07/2008; 10(6):647-65. · 1.98 Impact Factor
Revista Espa de Cardiologia 08/2009; 62(7):729-32. · 2.53 Impact Factor
Article: HL-1 cells express an inwardly rectifying K+ current activated via muscarinic receptors comparable to that in mouse atrial myocytes.[show abstract] [hide abstract]
ABSTRACT: An inwardly rectifying K(+) current is present in atrial cardiac myocytes that is activated by acetylcholine (I(KACh)). Physiologically, activation of the current in the SA node is important in slowing the heart rate with increased parasympathetic tone. It is a paradigm for the direct regulation of signaling effectors by the Gbetagamma G-protein subunit. Many questions have been addressed in heterologous expression systems with less focus on the behaviour in native myocytes partly because of the technical difficulties in undertaking comparable studies in native cells. In this study, we characterise a potassium current in the atrial-derived cell line HL-1. Using an electrophysiological approach, we compare the characteristics of the potassium current with those in native atrial cells and in a HEK cell line expressing the cloned Kir3.1/3.4 channel. The potassium current recorded in HL-1 is inwardly rectifying and activated by the muscarinic agonist carbachol. Carbachol-activated currents were inhibited by pertussis toxin and tertiapin-Q. The basal current was time-dependently increased when GTP was substituted in the patch-clamp pipette by the non-hydrolysable analogue GTPgammaS. We compared the kinetics of current modulation in HL-1 with those of freshly isolated atrial mouse cardiomyocytes. The current activation and deactivation kinetics in HL-1 cells are comparable to those measured in atrial cardiomyocytes. Using immunofluorescence, we found GIRK4 at the membrane in HL-1 cells. Real-time RT-PCR confirms the presence of mRNA for the main G-protein subunits, as well as for M2 muscarinic and A1 adenosine receptors. The data suggest HL-1 cells are a good model to study IKAch.Pflügers Archiv - European Journal of Physiology 02/2010; 460(1):99-108. · 4.46 Impact Factor