title: In vivo evidence for nitric oxide-mediated calcium-activated potassium-channel activation during human endotoxemia.
abstract: BACKGROUND
  During septic shock, the vasoconstrictor response to norepinephrine is seriously blunted. Animal experiments suggest that hyperpolarization of smooth muscle cells by opening of potassium (K) channels underlies this phenomenon. In the present study, we examined whether K-channel blockers and/or nitric oxide (NO) synthase inhibition could restore norepinephrine sensitivity during experimental human endotoxemia.
  
  
  RESULTS
  Volunteers received 2 ng/kg Escherichia coli endotoxin intravenously. Forearm blood flow (FBF) was measured with venous occlusion plethysmography. Infusion of 4 dose steps of norepinephrine into the brachial artery decreased the FBF ratio (ratio of FBF in the experimental arm to FBF in the control arm) to 84 +/- 4%, 70 +/- 4%, 55 +/- 4%, and 38 +/- 4% (mean +/- SEM) of its baseline value. After endotoxin administration, norepinephrine-induced vasoconstriction was attenuated (FBF ratio, 101 +/- 4%, 92 +/- 4%, 83 +/- 6%, and 56 +/- 7%; n = 30; P = 0.0018; pooled data). Intrabrachial infusion of the K-channel blocker tetraethylammonium (TEA) completely restored the vasoconstrictor response to norepinephrine from 104 +/- 5%, 93 +/- 7%, 93 +/- 12%, and 69 +/- 12% to 89 +/- 9%, 73 +/- 4%, 59 +/- 5%, and 46 +/- 8% (n = 6; P = 0.045). Other K-channel blockers did not affect the response to norepinephrine. The NO synthase inhibitor N(G)-monomethyl-l-arginine (L-NMMA; 0.2 mg x min(-1) x dL(-1) intra-arterially) also restored the norepinephrine sensitivity. In the presence of L-NMMA, TEA did not have an additional effect on the norepinephrine-induced vasoconstriction (n = 6; P = 0.9).
  
  
  CONCLUSIONS
  The K-channel blocker TEA restores the attenuated vasoconstrictor response to norepinephrine during experimental human endotoxemia. Coadministration of L-NMMA abolishes this potentiating effect of TEA, suggesting that NO mediates the endotoxin-induced effect on vascular K channels. In the absence of an effect of the selective adenosine triphosphate-dependent K-channel blocker tolbutamide, we conclude that the blunting effect of endotoxin on norepinephrine-induced vasoconstriction is caused by NO-mediated activation of calcium-activated K channels in the vascular wall.
authors.affiliation: Department of Intensive Care Medicine (551), Radboud University Nijmegen Medical Centre, GeertGrooteplein 10, PO Box 9101, 6500HB, Nijmegen, Netherlands. p.pickkers@ic.umcn.nl
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.forename: Mirrin J
authors.initials: MJ
authors.lastname: Dorresteijn
authors.forename: Martijn P W J M
authors.initials: MP
authors.lastname: Bouw
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
authors.forename: Paul
authors.initials: P
authors.lastname: Smits
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000503:physiopathology*; D004731:Endotoxins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli / Q000502:physiology; D004927:Escherichia coli Infections / Q000503:physiopathology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology; D019789:Tetraethylammonium / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004731:Endotoxins; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019789:Tetraethylammonium; C044101:endotoxin, Escherichia coli; D014044:Tolbutamide; D019001:Nitric Oxide Synthase; D009638:Norepinephrine