The activity of the atrioventricular node (AVN) is established to be modulated by the autonomic nervous system. By contrast, whilst receptors for the peptide hormone endothelin-1 (ET-1) are known to be present in the AVN (e.g. Molenaar et al, 1993), until recently there has been little information on ET-1 modulation of AVN electrophysiology. Accordingly, we have studied effects of ET-1 on rabbit AVN cellular electrophysiology (Choisy et al, 2012a). For this investigation, adult male New Zealand White rabbits were killed in accordance with UK Home Office legislation and AVN cells were isolated by enzymatic and mechanical dispersion. Whole-cell voltage-clamp was performed at 37oC using a standard Tyrode’s solution and K+-based pipette solution (Choisy et al, 2012a). Application of 10 nM ET-1 to spontaneously active AVN cells led to a rapid cessation of spontaneous action potentials (APs), accompanied by a marked membrane potential hyperpolarization that partially ‘relaxed’ in the presence of ET-1 (Choisy et al, 2012a). Under voltage-clamp, ET-1 reduced L-type calcium current and rapid delayed rectifier K+ current, whilst during hyperpolarising voltage steps it activated a tertiapin-Q (TQ; 300 nM) sensitive inwardly rectifying current with properties similar to the muscarinic (GIRK) K+ current, IK,ACh (Choisy et al, 2012a). This response showed some time-dependent decline. When spontaneous APs were recorded in the presence of TQ, AP magnitude progressively declined and the maximum diastolic potential depolarised. Thus, in the absence of TQ, ET-1 activation of IK,ACh was the dominant response (Choisy et al, 2012a). Since our results with ET-1 were suggestive of some time-dependent decline of ET-1 activated IK,ACh, this phenomenon was studied further in experiments using either ET-1 (10 nM) or acetyl-choline (ACh; 1 μM or 100 nM), together with repetitive application of brief voltage-ramps (Choisy et al, 2012b). In these experiments, ACh application activated a large TQ-sensitive IK,ACh via M2 muscarinic receptors. This response showed rapid bi-exponential ‘fade’ (Choisy et al, 2012b). Comparative experiments with ET-1 using the same protocol demonstrated ‘fade’ of ET-1-activated IK,ACh, though with a different (mono-exponential) time-course. ‘Fade’ rate did not correlate with initial response (i.e. K+ flux) magnitude. Sequential application of ACh (1 μM) and ET-1 (10 nM) showed heterologous desensitization of the ET-1 response by ACh. These results suggest that ET-1 and ACh act on a common pool of GIRK channels and that IK,ACh ‘fade’ involves desensitization that may occur down-stream of receptor activation. Internal application of GDPβS (3 mM) to rabbit AVN cells via diffusion from the patch-pipette led to a reduction in the extent of desensitization of IK,ACh, consistent with an involvement of the G-protein cycle in rapid ‘fade’ of IK,ACh (cf Leaney et al, 2004). ‘Fade’ of IK,ACh was also observed in AVN myocytes isolated from a difference species (C57BL6J mice). Collectively, the results of these studies indicate that both ET-1 and ACh activate IK,ACh in AVN myocytes and that the response exhibits rapid desensitization. Some previous studies on anaesthetized dogs (Martin, 1983) and rabbit isolated atrial preparations (Salata and Jalife, 1985) have provided evidence for ‘fade’ of the response to vagal stimulation. Our findings raise the possibility that this may be attributable to desensitization-induced ‘fade’ of AVN IK,ACh.