title: Urotensin II promotes vagal-mediated bradycardia by activating cardiac-projecting parasympathetic neurons of nucleus ambiguus.
abstract: Urotensin II (U-II) is a cyclic undecapeptide that regulates cardiovascular function at central and peripheral sites. The functional role of U-II nucleus ambiguus, a key site controlling cardiac tone, has not been established, despite the identification of U-II and its receptor at this level. We report here that U-II produces an increase in cytosolic Ca(2+) concentration in retrogradely labeled cardiac vagal neurons of nucleus ambiguus via two pathways: (i) Ca(2+) release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptor; and (ii) Ca(2+) influx through P/Q-type Ca(2+) channels. In addition, U-II depolarizes cultured cardiac parasympathetic neurons. Microinjection of increasing concentrations of U-II into nucleus ambiguus elicits dose-dependent bradycardia in conscious rats, indicating the in vivo activation of the cholinergic pathway controlling the heart rate. Both the in vitro and in vivo effects were abolished by the urotensin receptor antagonist, urantide. Our findings suggest that, in addition, to the previously reported increase in sympathetic outflow, U-II activates cardiac vagal neurons of nucleus ambiguus, which may contribute to cardioprotection.
authors: Department of Pharmaceutical Sciences, Thomas Jefferson University, Jefferson School of Pharmacy, Philadelphia, Pennsylvania, USA.
authors: Gabriela Cristina
authors: GC
authors: Brailoiu
authors: Elena
authors: E
authors: Deliu
authors: Joseph E
authors: JE
authors: Rabinowitz
authors: Douglas G
authors: DG
authors: Tilley
authors: Walter J
authors: WJ
authors: Koch
authors: Eugen
authors: E
authors: Brailoiu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001339:Autonomic Fibers, Preganglionic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001919:Bradycardia / Q000139:chemically induced / Q000503:physiopathology*; D001933:Brain Stem / Q000187:drug effects / Q000503:physiopathology*; D020865:Calcium Channels, P-Type / Q000187:drug effects / Q000502:physiology; D020907:Calcium Channels, Q-Type / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008845:Microinjections; D008955:Models, Cardiovascular; D009474:Neurons / Q000378:metabolism*; D010275:Parasympathetic Nervous System / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000502:physiology; D013610:Tachycardia / Q000139:chemically induced; D013618:Tachyphylaxis; D014579:Urotensins / Q000494:pharmacology / Q000502:physiology* / Q000633:toxicity; D014630:Vagus Nerve / Q000503:physiopathology*
chemical_list: D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D053496:Inositol 1,4,5-Trisphosphate Receptors; D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; C473142:Uts2r protein, rat; C029677:urotensin II
keywords: autonomic cardiovascular regulation; cytosolic Ca2+; endoplasmic reticulum; nucleus ambiguus