Endothelial Hyperpolarization in Humans

• Sponsor: Emory University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00166166
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 174
• Location: 1
• Arms: 2
• Duration (Months): 126.1
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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 Design

• Study Type: Interventional
• 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: Jul 1, 2002
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: Diflucan

Outcome Measures

Primary Outcome Measures

1. Percent Change in Forearm Blood Flow (FBF) After Tetraethylammonium (TEA) Administration [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) [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) [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 [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 [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 [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 [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 [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 [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 [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 [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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Locations

	Site	City	State	Country	Postal Code
1	Emory University School of Medicine	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• Emory University
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Arshed A. Quyyumi, Professor, Emory University
• ClinicalTrials.gov Identifier: NCT00166166
• Other Study ID Numbers: IRB00021886; 1R01HL079115-01; 0605-2002
• First Posted: Sep 14, 2005
• Last Update Posted: Aug 15, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Arshed A. Quyyumi, Professor, Emory University: hyperlipidaemia; EDHF; FMD
• Additional relevant MeSH terms: Hyperlipidemias; Hyperlipoproteinemias; Fluconazole; Nitroprusside; Tetraethylammonium; Acetylcholine; Bradykinin; omega-N-Methylarginine; Kininogens

Study Results

Participant Flow

Arm/Group Title	Healthy Controls	Risk Factors
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	103	71
COMPLETED	103	71
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Healthy Controls	Risk Factors	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	103	71	174
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34 (11)	46 (12)	40 (12)
Sex: Female, Male (Count of Participants)
Female	49 47.6%	32 45.1%	81 46.6%
Male	54 52.4%	39 54.9%	93 53.4%

Outcome Measures

1. Primary Outcome

Title	Percent Change in Forearm Blood Flow (FBF) After Tetraethylammonium (TEA) Administration
Description	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.
Time Frame	Baseline, 5 minutes

Outcome Measure Data

Analysis Population Description

Only 62 of the original 174 subjects were treated for this portion of the study.

Arm/Group Title	Healthy Controls	Risk Factors
Arm/Group Description	Healthy subjects had venous occlusion plethysmography after intra-arterial infusions of saline (baseline) and Tetraethylammonium (TEA).	Non-hypertensive subjects with cardiovascular risk factors had venous occlusion plethysmography after intra-arterial infusions of saline (baseline) and Tetraethylammonium (TEA)
Measure Participants	37	25
Mean (Standard Error) [percent change]	-18 (16)	-24 (13)

2. Primary Outcome

Title	Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA)
Description	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.
Time Frame	Baseline, 5 minutes

Outcome Measure Data

Analysis Population Description

Only 62 of the original 174 subjects were treated for this portion of the study.

Arm/Group Title	Healthy Controls	Risk Factors
Arm/Group Description	Healthy subjects had venous occlusion plethysmography after intra-arterial infusions of saline (baseline) and L-NG-monomethyl Arginine (L-NMMA)	Non-hypertensive subjects with cardiovascular risk factors had venous occlusion plethysmography after intra-arterial infusions of saline (baseline) and L-NG-monomethyl Arginine (L-NMMA)
Measure Participants	37	25
Mean (Standard Error) [percent change]	-29 (17)	-23 (15)

3. Secondary Outcome

Title	Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA) and Tetraethylammonium (TEA)
Description	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.
Time Frame	5 minutes, 10 minutes

Outcome Measure Data

Analysis Population Description

Only 62 of the original 174 subjects were treated for this portion of the study.

Arm/Group Title	Healthy Controls	Risk Factors
Arm/Group Description	Healthy subjects had venous occlusion plethysmography after intra-arterial infusions of saline (baseline) and L-NG-monomethyl Arginine (L-NMMA)	Non-hypertensive subjects with cardiovascular risk factors had venous occlusion plethysmography after intra-arterial infusions of saline (baseline) and L-NG-monomethyl Arginine (L-NMMA)
Measure Participants	37	25
Mean (Standard Error) [percent change]	-38 (17)	-39 (17)

4. Secondary Outcome

Title	Percent Change in Forearm Blood Flow (FBF) After Fluconazole Administration
Description	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.
Time Frame	Baseline, 5 minutes

Outcome Measure Data

Analysis Population Description

Only 33 of the original 174 subjects were treated for this portion of the study.

Arm/Group Title	Healthy Controls	Risk Factors
Arm/Group Description	Healthy subjects had venous occlusion plethysmography after intra-arterial infusions of saline (baseline) and fluconazole.	Non-hypertensive subjects with cardiovascular risk factors had venous occlusion plethysmography after intra-arterial infusions of saline (baseline) and fluconazole
Measure Participants	26	7
Mean (Standard Error) [percent change]	-13 (16)	-17 (13)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Only 15 of the original 174 subjects were treated for this portion of the study.

Arm/Group Title	Healthy Controls	Risk Factors
Arm/Group Description	Healthy subjects had venous occlusion plethysmography after intra-arterial infusions of L-NG-monomethyl Arginine (L-NMMA), and fluconazole	Non-hypertensive subjects with cardiovascular risk factors had venous occlusion plethysmography after intra-arterial infusions of L-NG-monomethyl Arginine (L-NMMA) and fluconazole
Measure Participants	8	7
Mean (Standard Error) [percent change]	-26 (22)	-26 (22)

6. Secondary Outcome

Title	Percent Change in Forearm Blood Flow (FBF) After Fluconazole and Tetraethylammonium (TEA) Administration
Description	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.
Time Frame	5 minutes, 10 minutes

Outcome Measure Data

Analysis Population Description

Only 19 of the original 174 subjects were treated for this portion of the study.

Arm/Group Title	Healthy Controls
Arm/Group Description	Healthy subjects had venous occlusion plethysmography after intra-arterial infusions of fluconazole and Tetraethylammonium (TEA)
Measure Participants	19
Mean (Standard Error) [percent change]	-22 (23)

7. Secondary Outcome

Title	Forearm Blood Flow (FBF) After Sodium Nitroprusside Administration
Description	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.
Time Frame	5 minutes

Outcome Measure Data

Analysis Population Description

Only 80 of the original 174 subjects were treated for this portion of the study.

Arm/Group Title	Healthy Controls	Risk Factors
Arm/Group Description	Healthy subjects had venous occlusion plethysmography after intra-arterial infusions of sodium nitroprusside	Non-hypertensive subjects with cardiovascular risk factors had venous occlusion plethysmography after intra-arterial infusions of sodium nitroprusside
Measure Participants	42	38
Mean (Standard Error) [mL min^-1 * 100 mL^-1]	10.4 (4)	10.9 (5)

8. Secondary Outcome

Title	Change in Tissue Plasminogen Activator (t-PA) Release
Description	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
Time Frame	Baseline, 30 minutes

Outcome Measure Data

Analysis Population Description

Only 33 of the original 174 subjects were treated for this portion of the study.

Arm/Group Title	Healthy Controls
Arm/Group Description	Healthy subjects had venous occlusion plethysmography after intra-arterial infusions of bradykinin
Measure Participants	33
Mean (Standard Error) [ng/mL]	5.6 (0.8)

9. Secondary Outcome

Title	Change in Tissue Plasminogen Activator (t-PA) Release After Tetraethylammonium (TEA) and Bradykinin Administration
Description	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
Time Frame	30 minutes, 60 minutes

Outcome Measure Data

Analysis Population Description

Only 18 of the original 174 subjects were treated for this portion of the study.

Arm/Group Title	Healthy Controls
Arm/Group Description	Healthy subjects had venous occlusion plethysmography after intra-arterial infusions of bradykinin and Tetraethylammonium (TEA)
Measure Participants	18
Mean (Standard Error) [ng/mL]	0.03 (0.7)

10. Secondary Outcome

Title	Change in Tissue Plasminogen Activator (t-PA) Release After Fluconazole and Bradykinin Administration
Description	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
Time Frame	30 minutes, 60 minutes

Outcome Measure Data

Analysis Population Description

Only 11 of the original 174 subjects were treated for this portion of the study.

Arm/Group Title	Healthy Controls
Arm/Group Description	Healthy subjects had venous occlusion plethysmography after intra-arterial infusions of bradykinin and fluconazole
Measure Participants	11
Mean (Standard Error) [ng/mL]	4.4 (1.4)

11. Secondary Outcome

Title	Change in Tissue Plasminogen Activator (t-PA) Release After Fluconazole, Tetraethylammonium (TEA), and Bradykinin Administration
Description	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
Time Frame	60 minutes, 90 minutes

Outcome Measure Data

Analysis Population Description

Only 10 of the original 174 subjects were treated for this portion of the study.

Arm/Group Title	Healthy Controls
Arm/Group Description	Healthy subjects had venous occlusion plethysmography after intra-arterial infusions of bradykinin, fluconazole and tetraethylammonium (TEA)
Measure Participants	10
Mean (Standard Error) [ng/mL]	1.6 (0.4)

Adverse Events

Arm/Group Title	Healthy Controls		Risk Factors
Arm/Group Description	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		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
All Cause Mortality
	Healthy Controls		Risk Factors
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Healthy Controls		Risk Factors
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/103 (0%)		0/71 (0%)
Other (Not Including Serious) Adverse Events
	Healthy Controls		Risk Factors
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/103 (0%)		0/71 (0%)

Limitations/Caveats

Findings are limited to the forearm microcirculations, thus other vascular beds including conductance arteries warrant further investigation. Nevertheless, it is known that the contribution of EDHF is less in conductance vessels than in microvessels.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.