Aldosterone increases cardiac vagal tone via G protein-coupled oestrogen receptor activation

J Physiol. 2013 Sep 1;591(17):4223-35. doi: 10.1113/jphysiol.2013.257204. Epub 2013 Jul 22.


In addition to acting on mineralocorticoid receptors, aldosterone has been recently shown to activate the G protein-coupled oestrogen receptor (GPER) in vascular cells. In light of the newly identified role for GPER in vagal cardiac control, we examined whether or not aldosterone activates GPER in rat nucleus ambiguus. Aldosterone produced a dose-dependent increase in cytosolic Ca(2+) concentration in retrogradely labelled cardiac vagal neurons of nucleus ambiguus; the response was abolished by pretreatment with the GPER antagonist G-36, but was not affected by the mineralocorticoid receptor antagonists, spironolactone and eplerenone. In Ca(2+)-free saline, the response to aldosterone was insensitive to blockade of the Ca(2+) release from lysosomes, while it was reduced by blocking the Ca(2+) release via ryanodine receptors and abolished by blocking the IP3 receptors. Aldosterone induced Ca(2+) influx via P/Q-type Ca(2+) channels, but not via L-type and N-type Ca(2+) channels. Aldosterone induced depolarization of cardiac vagal neurons of nucleus ambiguus that was sensitive to antagonism of GPER but not of mineralocorticoid receptor. in vivo studies, using telemetric measurement of heart rate, indicate that microinjection of aldosterone into the nucleus ambiguus produced a dose-dependent bradycardia in conscious, freely moving rats. Aldosterone-induced bradycardia was blocked by the GPER antagonist, but not by the mineralocorticoid receptor antagonists. In summary, we report for the first time that aldosterone decreases heart rate by activating GPER in cardiac vagal neurons of nucleus ambiguus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials
  • Aldosterone / pharmacology*
  • Animals
  • Calcium / metabolism
  • Calcium Signaling
  • Cells, Cultured
  • Heart / drug effects
  • Heart / innervation
  • Heart / physiology*
  • Heart Rate
  • Male
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen / antagonists & inhibitors
  • Receptors, Estrogen / metabolism*
  • Receptors, Mineralocorticoid / metabolism
  • Selective Estrogen Receptor Modulators / pharmacology
  • Vagus Nerve / drug effects
  • Vagus Nerve / metabolism
  • Vagus Nerve / physiology*


  • Receptors, Estrogen
  • Receptors, Mineralocorticoid
  • Selective Estrogen Receptor Modulators
  • Aldosterone
  • Calcium