Endothelial Hyperpolarization in Humans

Hyperlipidemia Clinical Trial

Official title:

Physiology and Pathologic Role of Endothelium-Derived Hyperpolarizing Factor in Humans

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00166166
• Other study ID #: IRB00021886
• Secondary ID: 1R01HL079115-010
• Status: Terminated
• Phase: Phase 2
• Start date: July 2002
• Est. completion date: January 2013

Study information

• Verified date: July 2018
• Source: Emory University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 174
• Est. completion date: January 2013
• Est. primary completion date: January 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Hyperlipidemia
• Hyperlipidemias
• Hyperlipoproteinemias

Intervention

Drug:
• Tetraethylammonium (TEA)
5 minute intra-arterial infusion of Tetraethylammonium at 1 mg/min
• L-NG-monomethyl Arginine (L-NMMA)
5 minute intra-arterial infusion of L-NMMA 8 µmol/min
• Bradykinin
Intra-arterial infusion of bradykinin at 100, 200, and 400 ng/min. Each dose will be given for 5 minutes.
• Sodium nitroprusside
Intra-arterial infusion of sodium nitroprusside at 1.6 and 3.2 mg/min. Each dose will be given for 5 minutes.
• Acetylcholine
Intra-arterial infusion of acetylcholine at 7.5, 15 and 30 µg/min. Each dose will be given for 5 minutes.
• Saline
5 minute intra-arterial infusion of 0.9% saline at 2.5ml/min
• Fluconazole
5 minute intra-arterial infusion of fluconazole at 0.4 mg/L/min

Locations

Country	Name	City	State
United States	Emory University School of Medicine	Atlanta	Georgia

Sponsors (2)

Lead Sponsor	Collaborator
Emory University	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change in Forearm Blood Flow (FBF) After Tetraethylammonium (TEA) Administration	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.	Baseline, 5 minutes
Primary	Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA)	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.	Baseline, 5 minutes
Secondary	Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA) and Tetraethylammonium (TEA)	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.	5 minutes, 10 minutes
Secondary	Percent Change in Forearm Blood Flow (FBF) After Fluconazole Administration	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.	Baseline, 5 minutes
Secondary	Percent Change in Forearm Blood Flow (FBF) After L-NG-monomethyl Arginine (L-NMMA) and Fluconazole Administration	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.	5 minutes, 10 minutes
Secondary	Percent Change in Forearm Blood Flow (FBF) After Fluconazole and Tetraethylammonium (TEA) Administration	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 minutes, 10 minutes
Secondary	Forearm Blood Flow (FBF) After Sodium Nitroprusside Administration	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.	5 minutes
Secondary	Change in Tissue Plasminogen Activator (t-PA) Release	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	Baseline, 30 minutes
Secondary	Change in Tissue Plasminogen Activator (t-PA) Release After Tetraethylammonium (TEA) and Bradykinin Administration	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	30 minutes, 60 minutes
Secondary	Change in Tissue Plasminogen Activator (t-PA) Release After Fluconazole and Bradykinin Administration	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	30 minutes, 60 minutes
Secondary	Change in Tissue Plasminogen Activator (t-PA) Release After Fluconazole, Tetraethylammonium (TEA), and Bradykinin Administration	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	60 minutes, 90 minutes