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.
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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
DIAGNOSTIC
Masking
NONE
Enrollment
174
5 minute intra-arterial infusion of Tetraethylammonium at 1 mg/min
5 minute intra-arterial infusion of L-NMMA 8 μmol/min
Intra-arterial infusion of bradykinin at 100, 200, and 400 ng/min. Each dose will be given for 5 minutes.
Emory University School of Medicine
Atlanta, Georgia, United States
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
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
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
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.
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Intra-arterial infusion of sodium nitroprusside at 1.6 and 3.2 mg/min. Each dose will be given for 5 minutes.
Intra-arterial infusion of acetylcholine at 7.5, 15 and 30 μg/min. Each dose will be given for 5 minutes.
5 minute intra-arterial infusion of 0.9% saline at 2.5ml/min
5 minute intra-arterial infusion of fluconazole at 0.4 mg/L/min
Time frame: Baseline, 5 minutes
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
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
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
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
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
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
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