title: Multiple nickel-sensitive targets elicit cardiac arrhythmia in isolated mouse hearts after pituitary adenylate cyclase-activating polypeptide-mediated chronotropy.
abstract: The pituitary adenylate cyclase-activating polypeptide (PACAP)-27 modulates various biological processes, 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 (Cav2.3) or T-type (Cav3.2) Ca2+channels, we investigated the effects of PACAP-27 on cardiac activity of spontaneously beating isolated perfused hearts. Superfusion of PACAP-27 (20nM) caused a significant increase of baseline heart frequency in Cav2.3(+|+) (156.9±10.8 to 239.4±23.4 bpm; p<0.01) and Cav2.3(-|-) (190.3±26.4 to 270.5±25.8 bpm; p<0.05) hearts. For Cav3.2, the heart rate was significantly increased in Cav3.2(-|-) (133.1±8.5 bpm to 204.6±27.9 bpm; p<0.05) compared to Cav3.2(+|+) hearts (185.7±11.2 bpm to 209.3±22.7 bpm). While the P wave duration and QTc interval were significantly increased in Cav2.3(+|+) and Cav2.3(-|-) hearts following PACAP-27 superfusion, there was no effect in Cav3.2(+|+) and Cav3.2(-|-) 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 Ni2+(50μM) and PACAP-27 (20nM) in hearts from Cav2.3(+|+) and Cav2.3(-|-) mice. In addition to suppressing PACAP's response, Ni2+also induced conduction disturbances in investigated hearts. In conclusion, the most Ni2+-sensitive Ca2+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 Ni2+-sensitive targets.
authors.affiliation: Institute of Neurophysiology, University of Köln, Robert-Koch-Str. 39, D-50931 Köln, Germany. Electronic address: tevoufoe@uni-koeln.de.
authors.forename: Etienne E
authors.initials: EE
authors.lastname: Tevoufouet
authors.affiliation: Institute of Neurophysiology, University of Köln, Robert-Koch-Str. 39, D-50931 Köln, Germany.
authors.forename: Erastus N
authors.initials: EN
authors.lastname: Nembo
authors.affiliation: Institute of Neurophysiology, University of Köln, Robert-Koch-Str. 39, D-50931 Köln, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Distler
authors.affiliation: Institute of Neurophysiology, University of Köln, Robert-Koch-Str. 39, D-50931 Köln, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Neumaier
authors.affiliation: Institute of Neurophysiology, University of Köln, Robert-Koch-Str. 39, D-50931 Köln, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
authors.affiliation: Institute of Neurophysiology, University of Köln, Robert-Koch-Str. 39, D-50931 Köln, Germany.
authors.forename: Filomain
authors.initials: F
authors.lastname: Nguemo
authors.affiliation: Institute of Neurophysiology, University of Köln, Robert-Koch-Str. 39, D-50931 Köln, Germany. Electronic address: toni.schneider@uni-koeln.de.
authors.forename: Toni
authors.initials: T
authors.lastname: Schneider
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000494:pharmacology; D009532:Nickel / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*
chemical_list: D020747:Calcium Channels, T-Type; D009479:Neuropeptides; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C106317:pituitary adenylate-cyclase-activating peptide (6-27); D009532:Nickel
keywords: Ca(v)2.3; Ca(v)3.2; Cardiac arrhythmia; Knockout; Nickel; PACAP-27