Endothelial Hyperpolarization in Humans - Full Text View

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:

Drug Information available for: Acetylcholine chloride Arginine Sodium nitroprusside Nitroprusside Fluconazole

U.S. FDA Resources

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

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 (Adult)
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:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.


Responsible Party:	Arshed A. Quyyumi, Professor, Emory University
ClinicalTrials.gov Identifier:	NCT00166166 History of Changes
Other Study ID Numbers:	IRB00021886 1R01HL079115-01 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 Fluconazole Omega-N-Methylarginine Kininogens Acetylcholine Nitroprusside 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 Vasodilator Agents Cholinergic Agonists Cholinergic Agents Neurotransmitter Agents Antihypertensive Agents Nitric Oxide Donors Cysteine Proteinase Inhibitors

Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Fluconazole
Omega-N-Methylarginine
Kininogens
Acetylcholine
Nitroprusside
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
Vasodilator Agents
Cholinergic Agonists
Cholinergic Agents
Neurotransmitter Agents
Antihypertensive Agents
Nitric Oxide Donors
Cysteine Proteinase Inhibitors

ClinicalTrials.gov processed this record on September 23, 2016