Endothelial Hyperpolarization in Humans

This study has been terminated.
(Limited clinical staff)
Sponsor:
Information provided by (Responsible Party):
Arshed A. Quyyumi, Emory University
ClinicalTrials.gov Identifier:
NCT00166166
First received: September 13, 2005
Last updated: May 12, 2015
Last verified: May 2015
  Purpose

The purpose of this study is to elucidate the role Endothelium-Derived Hyperpolarizing Factor (EDHF) plays in dilating blood vessels and whether it differs between healthy people and those with high cholesterol. A second purpose of the study is to determine the identity of EDHF.


Condition Intervention Phase
Hyperlipidemia
Drug: Tetraethylammonium (TEA)
Drug: L-NG-monomethyl Arginine (L-NMMA)
Drug: Bradykinin
Drug: Sodium nitroprusside
Drug: Acetylcholine
Drug: Saline
Drug: Fluconazole
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Physiology and Pathologic Role of Endothelium-Derived Hyperpolarizing Factor in Humans

Resource links provided by NLM:


Further study details as provided by Emory University:

Primary Outcome Measures:
  • Percent Change in Forearm Blood Flow (FBF) After Tetraethylammonium (TEA) Administration [ Time Frame: Baseline, 5 minutes ] [ Designated as safety issue: No ]
    Simultaneous forearm blood flow (FBF) measurements were obtained in both arms using a dual-channel venous occlusion strain gauge plethysmograph at rest and after administration of tetraethylammonium (TEA). Flow measurements were recorded for approximately 7 seconds, every 15 seconds up to eight times and a mean FBF value was computed. Percent change is the difference from baseline FBF and after TEA administration.

  • Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA) [ Time Frame: Baseline, 5 minutes ] [ Designated as safety issue: No ]
    Simultaneous forearm blood flow (FBF) measurements were obtained in both arms using a dual-channel venous occlusion strain gauge plethysmograph after administration of L-NG-monomethyl Arginine (L-NMMA). Flow measurements were recorded for approximately 7 seconds, every 15 seconds up to eight times and a mean FBF value was computed. Percent change is the difference in FBF from baseline and after L-NMMA administration.


Secondary Outcome Measures:
  • Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA) and Tetraethylammonium (TEA) [ Time Frame: 5 minutes, 10 minutes ] [ Designated as safety issue: No ]
    Simultaneous forearm blood flow (FBF) measurements were obtained in both arms using a dual-channel venous occlusion strain gauge plethysmograph after administration of L-NG-monomethyl Arginine (L-NMMA) and Tetraethylammonium (TEA). Flow measurements were recorded for approximately 7 seconds, every 15 seconds up to eight times and a mean FBF value was computed. Percent change is the difference in FBF from after L-NMMA administration and after TEA administration.

  • Percent Change in Forearm Blood Flow (FBF) After Fluconazole Administration [ Time Frame: Baseline, 5 minutes ] [ Designated as safety issue: No ]
    Simultaneous forearm blood flow (FBF) measurements were obtained in both arms using a dual-channel venous occlusion strain gauge plethysmograph at rest and after administration of fluconazole. Flow measurements were recorded for approximately 7 seconds, every 15 seconds up to eight times and a mean FBF value was computed. Percent change is the difference from baseline FBF and after fluconazole administration.

  • Percent Change in Forearm Blood Flow (FBF) After L-NG-monomethyl Arginine (L-NMMA) and Fluconazole Administration [ Time Frame: 5 minutes, 10 minutes ] [ Designated as safety issue: No ]
    Simultaneous forearm blood flow (FBF) measurements were obtained in both arms using a dual-channel venous occlusion strain gauge plethysmograph after L-NMMA administration and administration of fluconazole. Flow measurements were recorded for approximately 7 seconds, every 15 seconds up to eight times and a mean FBF value was computed. Percent change is the difference in FBF after L-NMMA administration and then fluconazole administration.

  • Percent Change in Forearm Blood Flow (FBF) After Fluconazole and Tetraethylammonium (TEA) Administration [ Time Frame: 5 minutes, 10 minutes ] [ Designated as safety issue: No ]
    Simultaneous forearm blood flow (FBF) measurements were obtained in both arms using a dual-channel venous occlusion strain gauge plethysmograph after administration of fluconazole and Tetraethylammonium (TEA) administration. Flow measurements were recorded for approximately 7 seconds, every 15 seconds up to eight times and a mean FBF value was computed. Percent change is the difference from FBF after fluconazole administration and after Tetraethylammonium (TEA) administration.

  • Forearm Blood Flow (FBF) After Sodium Nitroprusside Administration [ Time Frame: 5 minutes ] [ Designated as safety issue: No ]
    Simultaneous forearm blood flow (FBF) measurements were obtained in both arms using a dual-channel venous occlusion strain gauge plethysmograph after administration of sodium nitroprusside. Flow measurements were recorded for approximately 7 seconds, every 15 seconds up to eight times and a mean FBF value was computed.

  • Change in Tissue Plasminogen Activator (t-PA) Release [ Time Frame: Baseline, 30 minutes ] [ Designated as safety issue: No ]
    Individual net t-PA release at each time point were calculated by the following formula: net release = (Cv-CA) x {FBF x [101-hematocrit/100]}, where Cv and CA represent the concentration of t-PA in the brachial vein and artery, respectively. Change is the difference of t-PA at baseline and t-PA after bradykinin 400 ng/min

  • Change in Tissue Plasminogen Activator (t-PA) Release After Tetraethylammonium (TEA) and Bradykinin Administration [ Time Frame: 30 minutes, 60 minutes ] [ Designated as safety issue: No ]
    Individual net t-PA release at each time point were calculated by the following formula: net release = (Cv-CA) x {FBF x [101-hematocrit/100]}, where Cv and CA represent the concentration of t-PA in the brachial vein and artery, respectively. Change is the difference of t-PA after Tetraethylammonium (TEA) and t-PA after bradykinin 400 ng/min

  • Change in Tissue Plasminogen Activator (t-PA) Release After Fluconazole and Bradykinin Administration [ Time Frame: 30 minutes, 60 minutes ] [ Designated as safety issue: No ]
    Individual net t-PA release at each time point were calculated by the following formula: net release = (Cv-CA) x {FBF x [101-hematocrit/100]}, where Cv and CA represent the concentration of t-PA in the brachial vein and artery, respectively. Change is the difference of t-PA after fluconazole and t-PA after bradykinin 400 ng/min

  • Change in Tissue Plasminogen Activator (t-PA) Release After Fluconazole, Tetraethylammonium (TEA), and Bradykinin Administration [ Time Frame: 60 minutes, 90 minutes ] [ Designated as safety issue: No ]
    Individual net t-PA release at each time point were calculated by the following formula: net release = (Cv-CA) x {FBF x [101-hematocrit/100]}, where Cv and CA represent the concentration of t-PA in the brachial vein and artery, respectively. Change is the difference of t-PA after fluconazole and tetraethylammonium (TEA) and t-PA after bradykinin 400 ng/min


Enrollment: 174
Study Start Date: July 2002
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Healthy Controls
Healthy subjects had venous occlusion plethysmography after intra-arterial infusions of saline, L-NG-monomethyl Arginine (L-NMMA), Tetraethylammonium (TEA), fluconazole, bradykinin, sodium nitroprusside and acetylcholine
Drug: Tetraethylammonium (TEA)
5 minute intra-arterial infusion of Tetraethylammonium at 1 mg/min
Drug: L-NG-monomethyl Arginine (L-NMMA)
5 minute intra-arterial infusion of L-NMMA 8 μmol/min
Other Name: Methylarginine
Drug: Bradykinin
Intra-arterial infusion of bradykinin at 100, 200, and 400 ng/min. Each dose will be given for 5 minutes.
Drug: Sodium nitroprusside
Intra-arterial infusion of sodium nitroprusside at 1.6 and 3.2 mg/min. Each dose will be given for 5 minutes.
Other Name: Nitropress
Drug: Acetylcholine
Intra-arterial infusion of acetylcholine at 7.5, 15 and 30 μg/min. Each dose will be given for 5 minutes.
Drug: Saline
5 minute intra-arterial infusion of 0.9% saline at 2.5ml/min
Drug: Fluconazole
5 minute intra-arterial infusion of fluconazole at 0.4 mg/L/min
Other Name: Diflucan
Experimental: Risk Factors
Non-hypertensive subjects with cardiovascular risk factors had venous occlusion plethysmography after intra-arterial infusions of saline, L-NG-monomethyl Arginine (L-NMMA), Tetraethylammonium (TEA), fluconazole, bradykinin, sodium nitroprusside and acetylcholine
Drug: Tetraethylammonium (TEA)
5 minute intra-arterial infusion of Tetraethylammonium at 1 mg/min
Drug: L-NG-monomethyl Arginine (L-NMMA)
5 minute intra-arterial infusion of L-NMMA 8 μmol/min
Other Name: Methylarginine
Drug: Bradykinin
Intra-arterial infusion of bradykinin at 100, 200, and 400 ng/min. Each dose will be given for 5 minutes.
Drug: Sodium nitroprusside
Intra-arterial infusion of sodium nitroprusside at 1.6 and 3.2 mg/min. Each dose will be given for 5 minutes.
Other Name: Nitropress
Drug: Acetylcholine
Intra-arterial infusion of acetylcholine at 7.5, 15 and 30 μg/min. Each dose will be given for 5 minutes.
Drug: Saline
5 minute intra-arterial infusion of 0.9% saline at 2.5ml/min
Drug: Fluconazole
5 minute intra-arterial infusion of fluconazole at 0.4 mg/L/min
Other Name: Diflucan

Detailed Description:

The vascular endothelium synthesizes at least four potent vasodilator substances: nitric oxide (NO), prostacyclin, carbon monoxide and endothelium-derived hyperpolarizing factor (EDHF) that contribute to vasodilator tone, and to inhibition of platelet activation and inflammation. EDHF release is stimulated by receptor-dependent agonists such as acetylcholine and bradykinin (BK), and leads to hyperpolarization of the underlying smooth muscle cells presumably by opening Ca2+-activated K+ channels. Indirect pharmacological evidence suggests that EDHF is a cytochrome P450-derived arachidonic acid metabolite, presumably an epoxide. Although the pivotal role of NO to conduit vessel dilation in response to acute increases in shear stress is well known, its' contribution to dilation with sustained increases in flow are minimal, and may be due to EDHF release.

  Eligibility

Ages Eligible for Study:   21 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Hyperlipidemic (LDL > 140)
  • Healthy Volunteer

Exclusion Criteria:

  • Pregnancy
  • Diabetes mellitus
  • Cardiovascular Disease
  • Hypertension
  • Use of any regular medications
  • Renal insufficiency
  • Smoking (current or within the past 5 years)
  • Bleeding disorder
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00166166

Locations
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
Emory University
Investigators
Principal Investigator: Arshed A Quyyumi, MD Emory University School of Medicine, Division of Cardiology
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Arshed A. Quyyumi, Professor, Emory University
ClinicalTrials.gov Identifier: NCT00166166     History of Changes
Other Study ID Numbers: IRB00021886, 1 RO1 HL079115-01, 0605-2002
Study First Received: September 13, 2005
Results First Received: May 8, 2015
Last Updated: May 12, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Emory University:
hyperlipidaemia
EDHF
FMD

Additional relevant MeSH terms:
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Acetylcholine
Bradykinin
Fluconazole
Kininogens
Nitroprusside
Omega-N-Methylarginine
Tetraethylammonium
14-alpha Demethylase Inhibitors
Anti-Infective Agents
Antifungal Agents
Antihypertensive Agents
Cardiovascular Agents
Cholinergic Agents
Cholinergic Agonists
Cysteine Proteinase Inhibitors
Enzyme Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Nitric Oxide Donors
Pharmacologic Actions
Physiological Effects of Drugs
Potassium Channel Blockers
Protease Inhibitors
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on August 27, 2015