Modulation of cardiac vagal tone by bradykinin acting on nucleus ambiguus

Neuroscience. 2017 Dec 4;365:23-32. doi: 10.1016/j.neuroscience.2017.09.034. Epub 2017 Sep 23.


Bradykinin (BK), a component of the kallikrein-kininogen-kinin system exerts multiple effects via B1 and B2 receptor activation. In the cardiovascular system, bradykinin has cardioprotective and vasodilator properties. We investigated the effect of BK on cardiac-projecting neurons of nucleus ambiguus, a key site for the parasympathetic cardiac regulation. BK produced a dose-dependent increase in cytosolic Ca2+ concentration. Pretreatment with HOE140, a B2 receptor antagonist, but not with R715, a B1 receptor antagonist, abolished the response to BK. A selective B2 receptor agonist, but not a B1 receptor agonist, elicited an increase in cytosolic Ca2+ similarly to BK. Inhibition of N-type voltage-gated Ca2+ channels with ω-conotoxin GVIA had no effect on the Ca2+ signal produced by BK, while pretreatment with ω-conotoxin MVIIC, a blocker of P/Q-type of Ca2+ channels, significantly diminished the effect of BK. Pretreatment with xestospongin C and 2-aminoethoxydiphenyl borate, antagonists of inositol 1,4,5-trisphosphate receptors, abolished the response to BK. Inhibition of ryanodine receptors reduced the BK-induced Ca2+ increase, while disruption of lysosomal Ca2+ stores with bafilomycin A1 did not affect the response. BK produced a dose-dependent depolarization of nucleus ambiguus neurons, which was prevented by the B2 receptor antagonist. In vivo studies indicate that microinjection of BK into nucleus ambiguus elicited bradycardia in conscious rats via B2 receptors. In summary, in cardiac vagal neurons of nucleus ambiguus, BK activates B2 receptors promoting Ca2+ influx and Ca2+ release from endoplasmic reticulum, and membrane depolarization; these effects are translated in vivo by bradycardia.

Keywords: calcium signaling; cardiovascular regulation; microinjection; vagal tone.

MeSH terms

  • Animals
  • Animals, Newborn
  • Barbiturates / metabolism
  • Bradykinin / analogs & derivatives
  • Bradykinin / pharmacology*
  • Bradykinin Receptor Antagonists / pharmacology
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology
  • Cells, Cultured
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Heart Rate / drug effects*
  • Isoxazoles / metabolism
  • Male
  • Medulla Oblongata / cytology*
  • Medulla Oblongata / drug effects
  • Membrane Potentials / drug effects
  • Neurons / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Vagus Nerve / drug effects
  • Vagus Nerve / physiology*
  • Vasodilator Agents / pharmacology*


  • Barbiturates
  • Bradykinin Receptor Antagonists
  • Calcium Channel Blockers
  • Isoxazoles
  • R 715
  • Vasodilator Agents
  • bis(1,3-dibutylbarbiturate)trimethine oxonol
  • icatibant
  • Bradykinin
  • Calcium