Endothelial Hyperpolarization in Humans

• ClinicalTrials.gov Identifier: NCT00166166
• Recruitment Status: Terminated
• First Posted: September 14, 2005
• Results First Posted: May 13, 2015
• Last Update Posted: August 15, 2018
• Sponsor: Emory University
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Arshed A. Quyyumi, Emory University

Tracking Information

• First Submitted Date: September 13, 2005
• First Posted Date: September 14, 2005
• Results First Submitted Date: May 8, 2015
• Results First Posted Date: May 13, 2015
• Last Update Posted Date: August 15, 2018
• Study Start Date: July 2002
• Actual Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 12, 2015)

• 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.
• 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.

• Original Primary Outcome Measures (submitted: September 13, 2005): Bradykinin mediated forearm blood flow.

Current Secondary Outcome Measures (submitted: May 12, 2015)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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
• 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
• 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
• 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

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Endothelial Hyperpolarization in Humans
• Official Title: Physiology and Pathologic Role of Endothelium-Derived Hyperpolarizing Factor in Humans
• 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.
• 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
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Diagnostic
• Condition: Hyperlipidemia

Intervention

• 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

Study Arms

• 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
  Interventions:

  • Drug: Tetraethylammonium (TEA)
  • Drug: L-NG-monomethyl Arginine (L-NMMA)
  • Drug: Bradykinin
  • Drug: Sodium nitroprusside
  • Drug: Acetylcholine
  • Drug: Saline
  • Drug: Fluconazole
• 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
  Interventions:

  • Drug: Tetraethylammonium (TEA)
  • Drug: L-NG-monomethyl Arginine (L-NMMA)
  • Drug: Bradykinin
  • Drug: Sodium nitroprusside
  • Drug: Acetylcholine
  • Drug: Saline
  • Drug: Fluconazole

Publications *

• Ozkor MA, Murrow JR, Rahman AM, Kavtaradze N, Lin J, Manatunga A, Quyyumi AA. Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease. Circulation. 2011 May 24;123(20):2244-53. doi: 10.1161/CIRCULATIONAHA.110.990317. Epub 2011 May 9.
• Ozkor MA, Hayek SS, Rahman AM, Murrow JR, Kavtaradze N, Lin J, Manatunga A, Quyyumi AA. Contribution of endothelium-derived hyperpolarizing factor to exercise-induced vasodilation in health and hypercholesterolemia. Vasc Med. 2015 Feb;20(1):14-22. doi: 10.1177/1358863X14565374. Epub 2015 Feb 3.
• Rahman AM, Murrow JR, Ozkor MA, Kavtaradze N, Lin J, De Staercke C, Hooper WC, Manatunga A, Hayek S, Quyyumi AA. Endothelium-derived hyperpolarizing factor mediates bradykinin-stimulated tissue plasminogen activator release in humans. J Vasc Res. 2014;51(3):200-8. doi: 10.1159/000362666. Epub 2014 Jun 4.
• Ozkor MA, Rahman AM, Murrow JR, Kavtaradze N, Lin J, Manatunga A, Hayek S, Quyyumi AA. Differences in vascular nitric oxide and endothelium-derived hyperpolarizing factor bioavailability in blacks and whites. Arterioscler Thromb Vasc Biol. 2014 Jun;34(6):1320-7. doi: 10.1161/ATVBAHA.113.303136. Epub 2014 Mar 27.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 12, 2015): 174
• Original Enrollment (submitted: September 13, 2005): 60
• Actual Study Completion Date: January 2013
• Actual Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00166166
• Other Study ID Numbers: IRB00021886; 1R01HL079115-01 ( U.S. NIH Grant/Contract ); 0605-2002 ( Other Identifier: Other )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Arshed A. Quyyumi, Emory University
• Original Responsible Party: Not Provided
• Current Study Sponsor: Emory University
• Original Study Sponsor: Same as current
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Arshed A Quyyumi, MD; Emory University School of Medicine, Division of Cardiology

• PRS Account: Emory University
• Verification Date: July 2018