Hyperlipidemia
Conditions
Keywords
hyperlipidaemia, EDHF, FMD
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.
Interventions
DRUGTetraethylammonium (TEA)
5 minute intra-arterial infusion of Tetraethylammonium at 1 mg/min
5 minute intra-arterial infusion of L-NMMA 8 μmol/min
DRUGBradykinin
Intra-arterial infusion of bradykinin at 100, 200, and 400 ng/min. Each dose will be given for 5 minutes.
DRUGSodium nitroprusside
Intra-arterial infusion of sodium nitroprusside at 1.6 and 3.2 mg/min. Each dose will be given for 5 minutes.
DRUGAcetylcholine
Intra-arterial infusion of acetylcholine at 7.5, 15 and 30 μg/min. Each dose will be given for 5 minutes.
DRUGSaline
5 minute intra-arterial infusion of 0.9% saline at 2.5ml/min
DRUGFluconazole
5 minute intra-arterial infusion of fluconazole at 0.4 mg/L/min
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Emory University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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 |
| 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 |
| 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 |
| 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 |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 103 |
| 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 | 71 |
| Total | 174 |
Baseline characteristics
| Characteristic | Healthy Controls | Risk Factors | Total |
|---|---|---|---|
| Age, Continuous | 34 years STANDARD_DEVIATION 11 | 46 years STANDARD_DEVIATION 12 | 40 years STANDARD_DEVIATION 12 |
| Sex: Female, Male Female | 49 Participants | 32 Participants | 81 Participants |
| Sex: Female, Male Male | 54 Participants | 39 Participants | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 103 | 0 / 71 |
| serious Total, serious adverse events | 0 / 103 | 0 / 71 |
Outcome results
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.
Time frame: Baseline, 5 minutes
Population: Only 62 of the original 174 subjects were treated for this portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA) | -29 percent change | Standard Error 17 |
| Risk Factors | Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA) | -23 percent change | Standard Error 15 |
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.
Time frame: Baseline, 5 minutes
Population: Only 62 of the original 174 subjects were treated for this portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Percent Change in Forearm Blood Flow (FBF) After Tetraethylammonium (TEA) Administration | -18 percent change | Standard Error 16 |
| Risk Factors | Percent Change in Forearm Blood Flow (FBF) After Tetraethylammonium (TEA) Administration | -24 percent change | Standard Error 13 |
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
Time frame: Baseline, 30 minutes
Population: Only 33 of the original 174 subjects were treated for this portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in Tissue Plasminogen Activator (t-PA) Release | 5.6 ng/mL | Standard Error 0.8 |
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
Time frame: 30 minutes, 60 minutes
Population: Only 11 of the original 174 subjects were treated for this portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in Tissue Plasminogen Activator (t-PA) Release After Fluconazole and Bradykinin Administration | 4.4 ng/mL | Standard Error 1.4 |
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
Time frame: 60 minutes, 90 minutes
Population: Only 10 of the original 174 subjects were treated for this portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in Tissue Plasminogen Activator (t-PA) Release After Fluconazole, Tetraethylammonium (TEA), and Bradykinin Administration | 1.6 ng/mL | Standard Error 0.4 |
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
Time frame: 30 minutes, 60 minutes
Population: Only 18 of the original 174 subjects were treated for this portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in Tissue Plasminogen Activator (t-PA) Release After Tetraethylammonium (TEA) and Bradykinin Administration | 0.03 ng/mL | Standard Error 0.7 |
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.
Time frame: 5 minutes
Population: Only 80 of the original 174 subjects were treated for this portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Forearm Blood Flow (FBF) After Sodium Nitroprusside Administration | 10.4 mL min^-1 * 100 mL^-1 | Standard Error 4 |
| Risk Factors | Forearm Blood Flow (FBF) After Sodium Nitroprusside Administration | 10.9 mL min^-1 * 100 mL^-1 | Standard Error 5 |
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.
Time frame: 5 minutes, 10 minutes
Population: Only 62 of the original 174 subjects were treated for this portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA) and Tetraethylammonium (TEA) | -38 percent change | Standard Error 17 |
| Risk Factors | Percent Change in Forearm Blood Flow (FBF) After Administration of L-NG-monomethyl Arginine (L-NMMA) and Tetraethylammonium (TEA) | -39 percent change | Standard Error 17 |
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.
Time frame: Baseline, 5 minutes
Population: Only 33 of the original 174 subjects were treated for this portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Percent Change in Forearm Blood Flow (FBF) After Fluconazole Administration | -13 percent change | Standard Error 16 |
| Risk Factors | Percent Change in Forearm Blood Flow (FBF) After Fluconazole Administration | -17 percent change | Standard Error 13 |
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.
Time frame: 5 minutes, 10 minutes
Population: Only 19 of the original 174 subjects were treated for this portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Percent Change in Forearm Blood Flow (FBF) After Fluconazole and Tetraethylammonium (TEA) Administration | -22 percent change | Standard Error 23 |
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.
Time frame: 5 minutes, 10 minutes
Population: Only 15 of the original 174 subjects were treated for this portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Percent Change in Forearm Blood Flow (FBF) After L-NG-monomethyl Arginine (L-NMMA) and Fluconazole Administration | -26 percent change | Standard Error 22 |
| Risk Factors | Percent Change in Forearm Blood Flow (FBF) After L-NG-monomethyl Arginine (L-NMMA) and Fluconazole Administration | -26 percent change | Standard Error 22 |