title: Inhibition of vascular adenosine triphosphate-sensitive potassium channels by sympathetic tone during sepsis.
abstract: OBJECTIVE
  Excessive opening of the adenosine triphosphate-sensitive potassium channel in vascular smooth muscle is implicated in the vasodilation and vascular hyporeactivity underlying septic shock. Therapeutic channel inhibition using sulfonylurea agents has proved disappointing, although agents acting on its pore appear more promising. We thus investigated the hemodynamic effects of adenosine triphosphate-sensitive potassium channel pore inhibition in awake, fluid-resuscitated septic rats, and the extent to which these responses are modulated by the high sympathetic tone present in sepsis. Temporal changes in ex-vivo channel activity and subunit gene expression were also investigated.
  
  
  METHODS
  In vivo and ex vivo animal study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Male adult Wistar rats.
  
  
  METHODS
  Fecal peritonitis was induced in conscious, fluid-resuscitated rats. Pressor responses to norepinephrine and PNU-37883A (a vascular adenosine triphosphate-sensitive potassium channel inhibitor acting on the Kir6.1 pore-forming subunit) were measured at 6 or 24 hrs, in the absence or presence of the autonomic ganglion blocker, pentolinium. The aorta and mesenteric artery were examined ex vivo for rubidium efflux as a marker of adenosine triphosphate-sensitive potassium channel activity, and for adenosine triphosphate-sensitive potassium channel subunit gene expression using quantitative reverse transcription-polymerase chain reaction.
  
  
  RESULTS
  A total of 120 rats (50 sham-operated controls, 70 septic) were included. Septic rats became hypotensive after 12 hrs, with a 24-hr mortality of 51.7% (0% in controls). At 6 hrs, there was an attenuated pressor response to norepinephrine (p < .01) despite blood pressure being elevated (p < .01). PNU-37883A had no pressor effect, except in the presence of pentolinium (p < .01). Kir6.1 subunit mRNA increased significantly in the mesenteric artery while rubidium efflux was increased in both the aorta and mesenteric artery at 24 hrs.
  
  
  CONCLUSIONS
  Despite evidence of increased adenosine triphosphate-sensitive potassium channel activity in sepsis, it appears to be inhibited in vivo by high sympathetic tone. This may explain, at least in part, the reduced efficacy of adenosine triphosphate-sensitive potassium channel blockers in human septic shock.
authors.affiliation: Bloomsbury Institute of Intensive Care Medicine, Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, UK.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Chan
authors.forename: Nelson N
authors.initials: NN
authors.lastname: Orie
authors.forename: Alex
authors.initials: A
authors.lastname: Dyson
authors.forename: Valerie
authors.initials: V
authors.lastname: Taylor
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Stidwill
authors.forename: Lucie H
authors.initials: LH
authors.lastname: Clapp
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D005730:Ganglionic Blockers / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D009025:Morpholines / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010425:Pentolinium Tartrate / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000378:metabolism / Q000503:physiopathology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D005730:Ganglionic Blockers; D009025:Morpholines; C082658:U 37883A; D010425:Pentolinium Tartrate; D000254:Sodium-Potassium-Exchanging ATPase; D000218:Adamantane; D009638:Norepinephrine