title: Activation of the ATP-dependent potassium channel attenuates norepinephrine-induced vasoconstriction in the human forearm.
abstract: Sepsis-induced vasodilation is characterized by an attenuated sensitivity to vasoconstrictor substances such as norepinephrine, possibly mediated by activation of vascular potassium channels. We determined whether vasodilation associated with potassium channel activation resulted in an attenuated vasoconstrictive response to norepinephrine in humans and whether the vasodilation associated with potassium channel activation could be inhibited by pharmacological potassium channel blockers. In 30 volunteers, the brachial artery was cannulated for infusion of drugs. Forearm blood flow (FBF) was measured in both arms using strain-gauge venous occlusion plethysmography. Forearm vascular resistance (FVR, mean arterial pressure/FBF) was calculated. The effects of vasodilation induced by sodium nitroprusside (SNP, nitric oxide donor) or diazoxide (activator of the ATP-dependent potassium channel) on norepinephrine-mediated vasoconstriction were examined. Also, the effects of potassium channel blockers on vasodilation associated with potassium channel activation were determined. Intraarterial SNP infusion (2 microg/min/dL) increased forearm blood flow by 235%, from (mean +/- SEM) 2.8 +/- 0.7 to 9.4 +/- 1.5 mL/min/dL (P < 0.0001). Subsequent norepinephrine infusion (10, 30, 100, 300, 1000 ng/min/dL) increased FVR dose-dependently from 13 +/- 4 AU to 249 +/- 45 AU at the highest norepinephrine infusion. Intraarterial diazoxide infusion (1 mg/min/dL) increased FBF by 209% from 2.2 +/- 0.3 to 6.8 +/- 1.0 mL/min/dL (P < 0.001). Subsequent norepinephrine infusion increased FVR from 18 +/- 5 to 51 +/- 6 AU at the highest norepinephrine infusion rate (n = 10), significantly different from the norepinephrine-induced effects during SNP coinfusion (P < 0.001). Diazoxide-induced fall in FVR in the infused forearm was inhibited by potassium channel blockers tetraethyl ammonium (1 mg/min/dL, n = 10, P = 0.004) and quinine (50 microg/min/dL, n = 10, P = 0.016). Vasodilation induced by vascular potassium channel activation is associated with an impressive reduction in the vasoconstrictor response to norepinephrine in humans. In accordance with animal experiments, this indicates that potassium channel activation could account for the diminished norepinephrine sensitivity in septic patients. Vasodilation associated with potassium channel activation can be inhibited by pharmacological potassium channel blockade. The possible role of potassium channel blockers during sepsis-induced potassium channel activation and vasodilation in humans needs further elucidation.
authors.affiliation: Department of Intensive Care Medicine,University Medical Centre St. Radboud, Nijmegen, The Netherlands. p.pickkers@ic.umcn.nl
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.forename: Aarnout J
authors.initials: AJ
authors.lastname: Jansen Van Rosendaal
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; D001794:Blood Pressure / Q000187:drug effects; D003981:Diazoxide / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology*; D010991:Plethysmography; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D012039:Regional Blood Flow / Q000187:drug effects; D016037:Single-Blind Method; D019789:Tetraethylammonium / Q000494:pharmacology; D014655:Vascular Resistance / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D019789:Tetraethylammonium; D003981:Diazoxide; D009638:Norepinephrine