ClinicalTrials.gov
 Home    Search    Study Topics    Glossary  
 

  Full Text View  
  Tabular View  
  Contacts and Locations  
  Related Studies  
Blockade of Vascular Potassium Channels During Human Endotoxemia

This study has been completed.

Sponsors and Collaborators: Radboud University
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by: Radboud University
ClinicalTrials.gov Identifier: NCT00185003
  Purpose

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.


Condition Intervention Phase
Endotoxemia
Drug: endotoxin
Drug: Potassium channel blockers: TEA, Quinin, Tolbutamide
Drug: L-NMMA
Phase I

ChemIDplus related topics:   Nitric oxide    Potassium chloride    Tolbutamide    Norepinephrine    Norepinephrine bitartrate    omega-N-Methylarginine   

U.S. FDA Resources

Study Type:   Interventional
Study Design:   Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Pharmacokinetics/Dynamics Study
Official Title:   Blockade of Vascular Potassium Channels During Human Endotoxemia

Further study details as provided by Radboud University:

Primary Outcome 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 ]

Enrollment:   36
Study Start Date:   January 2003
Study Completion Date:   June 2005
Primary Completion Date:   June 2005 (Final data collection date for primary outcome measure)

  Eligibility
Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes

Criteria

Inclusion Criteria:

  • healthy volunteers

Exclusion Criteria:

  • drug, alcohol, nicotine abuse
  Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00185003

Sponsors and Collaborators
Radboud University
ZonMw: The Netherlands Organisation for Health Research and Development

Investigators
Principal Investigator:     Peter Pickkers, MD, PhD     Radboud University    
  More Information

Publications of Results:

Study ID Numbers:   PP02, ZONMW grant 907-00-056
First Received:   September 13, 2005
Last Updated:   April 10, 2008
ClinicalTrials.gov Identifier:   NCT00185003
Health Authority:   Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Radboud University:
Endotoxemia  
vascular potassium channels  
cytokine  
norepinephrine  
regional blood flow,  
inflammation,
ion channels,
nitric oxide synthase,
pharmacology.

Study placed in the following topic categories:
Nitric Oxide
Systemic Inflammatory Response Syndrome
Sepsis
Omega-N-Methylarginine
Norepinephrine
Bacteremia
Endotoxemia
Tolbutamide
Toxemia
Inflammation

Additional relevant MeSH terms:
Hypoglycemic Agents
Pathologic Processes
Physiological Effects of Drugs
Infection
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 04, 2008




Links to all studies - primarily for crawlers