1. Department of Pharmaceutical Sciences, Thomas Jefferson University, Jefferson School of Pharmacy, , Philadelphia, Pennsylvania, USA;2. Department of Pharmacology, Temple University School of Medicine, , Philadelphia, Pennsylvania, USA;3. Center for Translational Medicine, Temple University School of Medicine, , Philadelphia, Pennsylvania, USA;4. Center for Substance Abuse Research, Temple University School of Medicine, , Philadelphia, Pennsylvania, USA
Abstract:
Nesfatin‐1, a peptide whose receptor is yet to be identified, has been involved in the modulation of feeding, stress, and metabolic responses. More recently, increasing evidence supports a modulatory role for nesfatin‐1 in autonomic and cardiovascular activity. This study was undertaken to test if the expression of nesfatin‐1 in the nucleus ambiguus, a key site for parasympathetic cardiac control, may be correlated with a functional role. As we have previously demonstrated that nesfatin‐1 elicits Ca2+ signaling in hypothalamic neurons, we first assessed the effect of this peptide on cytosolic Ca2+ in cardiac pre‐ganglionic neurons of nucleus ambiguus. We provide evidence that nesfatin‐1 increases cytosolic Ca2+ concentration via a Gi/o‐coupled mechanism. The nesfatin‐1‐induced Ca2+ rise is critically dependent on Ca2+ influx via P/Q‐type voltage‐activated Ca2+ channels. Repeated administration of nesfatin‐1 leads to tachyphylaxis. Furthermore, nesfatin‐1 produces a dose‐dependent depolarization of cardiac vagal neurons via a Gi/o‐coupled mechanism. In vivo studies, using telemetric and tail‐cuff monitoring of heart rate and blood pressure, indicate that microinjection of nesfatin‐1 into the nucleus ambiguus produces bradycardia not accompanied by a change in blood pressure in conscious rats. Taken together, our results identify for the first time that nesfatin‐1 decreases heart rate by activating cardiac vagal neurons of nucleus ambiguus.