Official Title: “Blockade of Vascular Potassium Channels During Human Endotoxemia”

Background: Activation of NO-synthase and vascular potassium (K) channels may play a role in the sepsis-induced attenuated sensitivity to norepinephrine. We examined whether various K channel blockers and NO-synthase inhibition could restore norepinephrine sensitivity during experimental human endotoxemia.

Methods and Results: Volunteers received 2ng/kg E. coli endotoxin. The brachial artery was cannulated for infusion of drugs. Forearm blood flow (FBF) was measured using venous occlusion plethysmography. Intrabrachial norepinephrine infusion (1-3-10-30ng/min/dl) decreased FBF to 84±4, 70±4, 55±4, and 38±4% of baseline ratio, mean±SEM). Following endotoxin administration, norepinephrine-induced vasoconstriction was attenuated: 101±4, 92±4, 83±6, and 56±7% (P=0.0018, pooled data, n=30). Intrabrachial infusion of the K channel blocker tetra-ethyl ammonium (TEA) completely restored the vasoconstrictive effect of 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), whereas other K channel blockers had no effect. NO-synthase inhibitor L-NMMA (0.2mg/min/dl) also restored the norepinephrine sensitivity (from 92±5, 85±4, 68±11, and 43±13% after endotoxin to 71±3, 66±7, 48±11, and 21±3% in the presence of L-NMMA, n=6, P=0.009). Furthermore, 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 completely restores the attenuated vasoconstrictive effects of norepinephrine during experimental human endotoxemia. Co-administration of L-NMMA abolishes this potentiating effect of TEA, suggesting that NO mediates the endotoxin-induced effect on K channels. In the absence of an effect of the selective KATP channel blocker tolbutamide we conclude that endotoxin-induced vasorelaxation is the result of NO-mediated activation of KCa channels.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Pharmacokinetics/Dynamics Study

Study Primary Completion Date: June 2005

Intervention(s) in this Clinical Trial

• Drug: endotoxin
• Drug: Potassium channel blockers: TEA, Quinin, Tolbutamide
• Drug: L-NMMA

Primary Measures

• Hemodynamics
  • Time Frame: 24 hrs after LPS administration
    
• Markers of Inflammation
  • Time Frame: 24 hrs after LPS administration
    
• Cytokines
  • Time Frame: 24 hrs after LPS administration
    
• Markers of Renal Injury
  • Time Frame: 24 hrs after LPS administration
    
• Inducible NO synthase expression
  • Time Frame: 24 hrs after LPS administration
    
• NO-metabolites
  • Time Frame: 24 hrs after LPS administration
    
• Mediators of Vascular reactivity
  • Time Frame: 24 hrs after LPS administration
    
• Sensitivity to norepinephrine
  • Time Frame: 24 hrs after LPS administration
    

Inclusion Criteria:

• healthy volunteers

Exclusion Criteria:

• drug, alcohol, nicotine abuse

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 35 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: Radboud University

Overall Clinical Trial Officials and Contacts

Peter Pickkers, MD, PhD Principal Investigator Radboud University  

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00185003

Study ID Number: PP02

ClinicalTrials.gov Identifier: NCT00185003

Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)