title: Central nicotinic acetylcholine receptor involved in Ca(2+) -calmodulin-endothelial nitric oxide synthase pathway modulated hypotensive effects.
abstract: OBJECTIVE
  Recent evidence has suggested that nicotine decreases blood pressure (BP) and heart rate (HR) in the nucleus tractus solitarii (NTS), indicating that nicotinic acetylcholine receptors (nAChRs) play an important role in BP control in the NTS. However, the signalling mechanisms involved in nAChR-mediated depressor effects in the NTS are unclear. Hence, the aim of this study was to investigate these signalling mechanisms.
  
  
  METHODS
  Depressor responses to nicotine microinjected into the NTS of Wistar-Kyoto rats were elicited in the absence and presence of an antagonist of α7 nAChR, the calcium chelator ethylene glycol tetraacetic acid, a calmodulin-specific inhibitor, nitric oxide (NO) synthase (NOS) inhibitor, endothelial NOS (eNOS)-selective inhibitor or neuronal NOS (nNOS)-specific inhibitor.
  
  
  RESULTS
  Microinjection of nicotine into the NTS produced a dose-dependent decrease in BP and HR, and increased nitrate levels. This depressor effect of nicotine was attenuated after pretreatment with a nAChR antagonist or blockers of the calmodulin-eNOS pathway. In contrast, N5-(1-Imino-3-butenyl)-L-ornithine (vinyl-L-NIO), nNOS-specific inhibitor, did not diminish these nicotine-mediated effects. Calmodulin was found to bind eNOS after nicotine injection into NTS. However, nicotine did not affect the eNOS phosphorylation level or eNOS upstream extracellular signal-regulated kinases (ERK)1/2 and Akt phosphorylation levels. Furthermore, pretreatment with an ERK1/2 or Akt inhibitor did not attenuate nicotine-induced depressor effects in the NTS.
  
  
  CONCLUSIONS
  These results suggest that the nAChR-Ca(2+) -calmodulin-eNOS-NO signalling pathway, but not nNOS, plays a significant role in central BP regulation, and neither the ERK1/2 nor Akt signalling pathway are significantly involved in the activation of eNOS by nAChRs in the NTS.
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Cheng
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.forename: Siang-Ru
authors.initials: SR
authors.lastname: Chen
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Ho
authors.forename: Wen-Han
authors.initials: WH
authors.lastname: Cheng
authors.forename: Ling-Zong
authors.initials: LZ
authors.lastname: Hong
authors.forename: Tung-Chen
authors.initials: TC
authors.lastname: Yeh
authors.forename: Gwo-Ching
authors.initials: GC
authors.lastname: Sun
authors.forename: Ling-Lin
authors.initials: LL
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Ching-Jiunn
authors.initials: CJ
authors.lastname: Tseng
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007022:Hypotension / Q000139:chemically induced*; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D011978:Receptors, Nicotinic / Q000378:metabolism*; D017552:Solitary Nucleus / Q000187:drug effects / Q000502:physiology
chemical_list: D002147:Calmodulin; D011978:Receptors, Nicotinic; D009569:Nitric Oxide; D009538:Nicotine; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D002118:Calcium