We updated the design of this site on December 18, 2017. Learn more.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Endothelial Hyperpolarization in Humans

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00166166
Recruitment Status : Terminated (Limited clinical staff)
First Posted : September 14, 2005
Results First Posted : May 13, 2015
Last Update Posted : May 13, 2015
Sponsor:
Information provided by (Responsible Party):
Arshed A. Quyyumi, Emory University

Brief Summary:
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 or disease Intervention/treatment 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

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 174 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Physiology and Pathologic Role of Endothelium-Derived Hyperpolarizing Factor in Humans
Study Start Date : July 2002
Primary Completion Date : January 2013
Study Completion Date : January 2013

Arm Intervention/treatment
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



Primary Outcome Measures :
  1. Percent Change in Forearm Blood Flow (FBF) After Tetraethylammonium (TEA) Administration [ Time Frame: Baseline, 5 minutes ]
    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.

  2. Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA) [ Time Frame: Baseline, 5 minutes ]
    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 :
  1. 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 ]
    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.

  2. Percent Change in Forearm Blood Flow (FBF) After Fluconazole Administration [ Time Frame: Baseline, 5 minutes ]
    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.

  3. Percent Change in Forearm Blood Flow (FBF) After L-NG-monomethyl Arginine (L-NMMA) and Fluconazole Administration [ Time Frame: 5 minutes, 10 minutes ]
    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.

  4. Percent Change in Forearm Blood Flow (FBF) After Fluconazole and Tetraethylammonium (TEA) Administration [ Time Frame: 5 minutes, 10 minutes ]
    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.

  5. Forearm Blood Flow (FBF) After Sodium Nitroprusside Administration [ Time Frame: 5 minutes ]
    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.

  6. Change in Tissue Plasminogen Activator (t-PA) Release [ Time Frame: Baseline, 30 minutes ]
    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

  7. Change in Tissue Plasminogen Activator (t-PA) Release After Tetraethylammonium (TEA) and Bradykinin Administration [ Time Frame: 30 minutes, 60 minutes ]
    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

  8. Change in Tissue Plasminogen Activator (t-PA) Release After Fluconazole and Bradykinin Administration [ Time Frame: 30 minutes, 60 minutes ]
    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

  9. Change in Tissue Plasminogen Activator (t-PA) Release After Fluconazole, Tetraethylammonium (TEA), and Bradykinin Administration [ Time Frame: 60 minutes, 90 minutes ]
    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



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   21 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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

Publications:
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
1R01HL079115-01 ( U.S. NIH Grant/Contract )
0605-2002 ( Other Identifier: Other )
First Posted: September 14, 2005    Key Record Dates
Results First Posted: May 13, 2015
Last Update Posted: May 13, 2015
Last Verified: May 2015

Keywords provided by Arshed A. Quyyumi, Emory University:
hyperlipidaemia
EDHF
FMD

Additional relevant MeSH terms:
Hyperlipidemias
Hyperlipoproteinemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Fluconazole
omega-N-Methylarginine
Kininogens
Nitroprusside
Acetylcholine
Bradykinin
Tetraethylammonium
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Antihypertensive Agents
Vasodilator Agents
Nitric Oxide Donors
Cholinergic Agonists
Cholinergic Agents
Neurotransmitter Agents