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

• Published in: The Journal of physiology Vol. 591; no. 17; pp. 4223 - 4235
• Main Authors: Brailoiu, G. Cristina, Benamar, Khalid, Arterburn, Jeffrey B., Gao, Erhe, Rabinowitz, Joseph E., Koch, Walter J., Brailoiu, Eugen
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2013; Wiley Subscription Services, Inc; Blackwell Science Inc
• Subjects: Action Potentials; Aldosterone - pharmacology; Animals; Calcium - metabolism; Calcium Signaling; Cardiac arrhythmia; Cells, Cultured; Heart - drug effects; Heart - innervation; Heart - physiology; Heart Rate; Male; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Estrogen - antagonists & inhibitors; Receptors, Estrogen - metabolism; Receptors, Mineralocorticoid - metabolism; Research Papers; Rodents; Selective Estrogen Receptor Modulators - pharmacology; Vagus Nerve - drug effects; Vagus Nerve - metabolism; Vagus Nerve - physiology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2013.257204

Key points •  Faster cellular effects of aldosterone incompatible with the genomic effects mediated by mineralocorticoid receptors have been proposed for 40 years but the receptors remained elusive. •  Recently, aldosterone has been shown to activate the G protein‐coupled oestrogen receptor (GPER) in the vasculature. •  Our results indicate that aldosterone activates the GPER in cardiac vagal neurons of nucleus ambiguus leading to an increase in cytosolic Ca2+ concentration and depolarization; in addition, in vivo studies indicate that microinjection of aldosterone in nucleus ambiguus produces bradycardia in conscious rats. •  In summary, our results identified a new role for aldosterone in the modulation of cardiac vagal tone via GPER activation in nucleus ambiguus.   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 Ca2+ 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 Ca2+‐free saline, the response to aldosterone was insensitive to blockade of the Ca2+ release from lysosomes, while it was reduced by blocking the Ca2+ release via ryanodine receptors and abolished by blocking the IP3 receptors. Aldosterone induced Ca2+ influx via P/Q‐type Ca2+ channels, but not via L‐type and N‐type Ca2+ 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.