Clinical trial NCT00166166: Endothelial Hyperpolarization in Humans
Official title: Physiology and Pathologic Role of Endothelium-Derived Hyperpolarizing Factor in Humans
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hyperlipidemia
Keywords: hyperlipidaemia
EDHF
FMD
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2005-09-14
Enrollment: 174
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

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.

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

Primary outcomes:
measure: Percent Change in Forearm Blood Flow (FBF) After Tetraethylammonium (TEA) Administration
timeFrame: Baseline, 5 minutes
measure: Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA)
timeFrame: Baseline, 5 minutes
Secondary outcomes:
measure: Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA) and Tetraethylammonium (TEA)
timeFrame: 5 minutes, 10 minutes
measure: Percent Change in Forearm Blood Flow (FBF) After Fluconazole Administration
timeFrame: Baseline, 5 minutes
measure: Percent Change in Forearm Blood Flow (FBF) After L-NG-monomethyl Arginine (L-NMMA) and Fluconazole Administration
timeFrame: 5 minutes, 10 minutes
measure: Percent Change in Forearm Blood Flow (FBF) After Fluconazole and Tetraethylammonium (TEA) Administration
timeFrame: 5 minutes, 10 minutes
measure: Forearm Blood Flow (FBF) After Sodium Nitroprusside Administration
timeFrame: 5 minutes
measure: Change in Tissue Plasminogen Activator (t-PA) Release
timeFrame: Baseline, 30 minutes
measure: Change in Tissue Plasminogen Activator (t-PA) Release After Tetraethylammonium (TEA) and Bradykinin Administration
timeFrame: 30 minutes, 60 minutes
measure: Change in Tissue Plasminogen Activator (t-PA) Release After Fluconazole and Bradykinin Administration
timeFrame: 30 minutes, 60 minutes
measure: Change in Tissue Plasminogen Activator (t-PA) Release After Fluconazole, Tetraethylammonium (TEA), and Bradykinin Administration
timeFrame: 60 minutes, 90 minutes
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
Study officials:
affiliation: Emory University School of Medicine, Division of Cardiology
name: Arshed A Quyyumi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.