IK,ACh Does Not Mediate Negative Inotropy and Antiarrhythmic Action of Muscarinic Receptor Activation in Human Atrium

Objectives: Vagal nerve activity is an important regulator of cardiac function which is mediated by acetylcholine via muscarinic receptors (M-R). While in human heart M-R is expressed at similar levels in ventricular and atrial tissue, the acetylcholine-activated potassium currents (IK,ACh) is expressed only in the atrium. M-R regulates force development as well as electrical stability in human heart but it remains unclear to what extent IK,ACh contributes to this mechanism. Therefore, we employed a new selective blocker of IK,ACh to elaborate the contribution of IK,ACh to M-R activation-mediated effects in human atrium.

Methods: Right atrial appendages were obtained from 62 patients with stable sinus rhythm undergoing cardiac surgery. After excision, force was measured in vitro at 37°C (1 Hz pacing rate). Cumulative concentration–effect curve were measured for noradrenaline in time-matched control group (TMC), in the presence of carbachol [CCh; 1 μM] and in the concomitant presence of CCh and the IK,ACh-blocker XAF-1407 [1 μM]. To increase arrhythmias drastically we performed all experiments in the concomitant presence of cilostamide [0.3 μM] and rolipram [1 μM] to inhibit PDE3 and PDE4. Any additional contraction besides the 1-Hz rhythm was considered arrhythmic.

Result: Force in the absence of noradrenaline (NA) as well as in the presence of high concentrations of NA was not different between TMC and CCh-treated human atrial trabeculae. However, concentration–response curve for NA inotropy was significantly shifted to the right, indicating some antagonism. Rightward shift of the concentration–response curve for NA by CCh was not blunted by the presence of XAF-1407. In TMC ~40% of trabeculae developed arrhythmias when exposed to noradrenaline in the presence of cilostamide (0.3 μM) and rolipram (1 µM). CCh (0.01–1 μM) prevented concentration dependently the incidence of arrhythmias. CCh did not only prevent arrhythmias but was also able to stop them when given on top of noradrenaline. Interestingly maximum force increase by noradrenaline was not depressed by CCh. XAF-1407 (1 μM) did not blunt the reduction of arrhythmias by CCh (1 μM).

Conclusion: The well-known accentuated antagonisms of CCH on NA inotropy in human atrium is independent of IK,ACh. CCh blunts noradrenaline-induced arrhythmias but not maximum force in human atrium independent of IK,ACh.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
19 February 2021