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 (Ca_v2.3) or T-type (Ca_v3.2) 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 Ca_v2.3(+|+) (156.9±10.8 to 239.4±23.4 bpm; p<0.01) and Ca_v2.3(-|-) (190.3±26.4 to 270.5±25.8 bpm; p<0.05) hearts. For Ca_v3.2, the heart rate was significantly increased in Ca_v3.2(-|-) (133.1±8.5 bpm to 204.6±27.9 bpm; p<0.05) compared to Ca_v3.2(+|+) 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_v2.3(+|+) and Ca_v2.3(-|-) hearts following PACAP-27 superfusion, there was no effect in Ca_v3.2(+|+) and Ca_v3.2(-|-) 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 Ca_v2.3(+|+) and Ca_v2.3(-|-) 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.

Keywords: Ca(v)2.3; Ca(v)3.2; Cardiac arrhythmia; Knockout; Nickel; PACAP-27.