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.
