Pharmacological Research 117 (2017) 140–147 Contents lists available at ScienceDirect Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs Invited Perspective Multiple nickel-sensitive targets elicit cardiac arrhythmia in isolated mouse hearts after pituitary adenylate cyclase-activating polypeptide-mediated chronotropy Etienne E. Tevoufouet ∗ , Erastus N. Nembo, Fabian Distler, Felix Neumaier, Jürgen Hescheler, Filomain Nguemo, Toni Schneider ∗ Institute of Neurophysiology, University of Köln, Robert-Koch-Str. 39, D-50931 Köln, Germany a r t i c l e i n f o Article history: Received 2 August 2016 Received in revised form 24 October 2016 Accepted 16 December 2016 Available online 19 December 2016 Keywords: Cardiac arrhythmia Cav2.3 Cav3.2 Knockout PACAP-27 Nickel a b s t r a c t The pituitary adenylate cyclase-activating polypeptide (PACAP)-27 modulates various biological pro- cesses, from the cellular level to function specification. However, the cardiac actions of this neuropeptide are still under intense studies. Using control (+|+) and mice lacking (−|−) either R-type (Ca v 2.3) or T-type (Ca v 3.2) Ca 2+ channels, we investigated the effects of PACAP-27 on cardiac activity of sponta- neously beating isolated perfused hearts. Superfusion of PACAP-27 (20 nM) caused a significant increase of baseline heart frequency in Ca v 2.3(+|+) (156.9 ± 10.8 to 239.4 ± 23.4 bpm; p < 0.01) and Ca v 2.3(−|−) (190.3 ± 26.4 to 270.5 ± 25.8 bpm; p < 0.05) hearts. For Ca v 3.2, the heart rate was significantly increased in Ca v 3.2(−|−) (133.1 ± 8.5 bpm to 204.6 ± 27.9 bpm; p < 0.05) compared to Ca v 3.2(+|+) hearts (185.7 ± 11.2 bpm to 209.3 ± 22.7 bpm). While the P wave duration and QTc interval were significantly increased in Ca v 2.3(+|+) and Ca v 2.3(−|−) hearts following PACAP-27 superfusion, there was no effect in Ca v 3.2(+|+) and Ca v 3.2(−|−) hearts. The positive chronotropic effects observed in the four study groups, as well as the effect on P wave duration and QTc interval were abolished in the presence of Ni 2+ (50 M) and PACAP-27 (20 nM) in hearts from Ca v 2.3(+|+) and Ca v 2.3(−|−) mice. In addition to suppressing PACAP’s response, Ni 2+ also induced conduction disturbances in investigated hearts. In conclusion, the most Ni 2+ -sensitive Ca 2+ channels (R- and T-type) may modulate the PACAP signaling cascade during cardiac excitation in isolated mouse hearts, albeit to a lesser extent than other Ni 2+ -sensitive targets. © 2016 Published by Elsevier Ltd. 1. Introduction The pituitary adenylate cyclase-activating polypeptide (PACAP) belongs to a large family of biologically active peptides and reg- ulates a wide range of physiological processes [1,2]. PACAP is highly conserved and is present in two bioactive forms: PACAP- 38 and PACAP-27 with 38 and 27 amino acid residues respectively. PACAP(1–27) (amino acid residues 1–28 on N-terminal amidated PACAP) exhibits high homology to vasoactive intestinal peptide [3]. This peptide is widely distributed in the brain and peripheral tis- sues and organs [4]. In recent years, the cardiac modulatory role of PACAP has received considerable attention [5]. ∗ Corresponding authors at: University of Cologne, Centre for Physiology and Pathophysiology, Robert-Koch-Str. 39, D-50931 Cologne, Germany. E-mail addresses: tevoufoe@uni-koeln.de (E.E. Tevoufouet), toni.schneider@uni-koeln.de (T. Schneider). Previous studies have reported an important role of PACAP in cardiac functions, both in vivo [6] and in vitro [1,7–9]. These studies revealed controversial and opposite results such as posi- tive inotropy, positive and negative chronotropy, and dromotropic effects of PACAP. The positive inotropic and chronotropic effects were attributed to direct stimulation of cardiomyocytes (CMs) [4,10], whereas bradycardia was suggested to be due to presynaptic regulation of acetylcholine release from intracardiac parasympa- thetic nerves [4]. In studies involving isolated guinea pig hearts, the PACAP-induced negative chronotropy was also mainly attributed to an increase in acetylcholine release from parasympathetic neurons, while tachycardia was suggested to originate from direct stimula- tion of sympathetic nerve terminals [6]. In addition, PACAP-27 was shown to induce chronotropy when reperfused in isolated mouse atria [1]. Taken together, the above mentioned results suggest that PACAP contributes to the regulation of cardiac function, but the mechanistic path is far from being understood. Given the function of voltage-dependent Ca 2+ channels (VDCCs) in regulating cardiac functions, it is hypothesized that highly Ni 2+ -sensitive VDCCs, espe- http://dx.doi.org/10.1016/j.phrs.2016.12.025 1043-6618/© 2016 Published by Elsevier Ltd.