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Renin-Angiotensin Aldosterone System and Fibrinolysis Interaction in Humans-Specific Aim 3

Primary Purpose

Obesity

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Control (bradykinin)
L-NMMA + bradykinin
Isosorbide + L-NMMA + bradykinin
Sildenafil + L-NMMA + bradykinin
Sponsored by
Vanderbilt University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional health services research trial for Obesity focused on measuring Bradykinin, Obesity, Nitric Oxide Donor, tissue type plasminogen activator, isosorbide dinitrate, phosphodiesterase inhibitor, Renin-Angiotensin Aldosterone System, Fibrinolysis, Angiotensin converting enzyme

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • 18-70 years of age
  • Male and female subjects
  • Surgical sterilization
  • Childbearing potential: beta HCG on study day
  • Subjects with a body mass index of 25 or greater

Exclusion Criteria:

  • Diabetes type 1 to type 2 as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication
  • Use of hormone replacement therapy
  • Statin therapy
  • In hypertensive subjects, a seated systolic blood pressure greater than 179 mmHg or a seated diastolic blood pressure greater than 110 mmHg or taking hypertensives
  • Pregnancy/Breast Feeding
  • Cardiovascular disease such as myocardial infarction with 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable) deep vein thrombosis, pulmonary embolism, second or three degree heart block, mitral valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy
  • Treatment with anticoagulants
  • History of serious neurologic disease such as cerebral hemorrhage, stroke or transient ischemic attack
  • Diagnosis of asthma
  • Clinically significant gastrointestinal impairment that could interfere with drug absorption
  • Hematocrit <35%
  • Hyperlipidemic fasting Total Cholesterol >220mg/dl
  • Impaired renal function (Serum creatinine >1.5 mg/dl)
  • History or presence of immunological or hematological disorders
  • Any underlying or acute disease requiring regular medication which could possible pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult
  • Impaired hepatic function (Serum glutamic oxaloacetic transaminase, serum glutamate pyruvate transaminase > 60)
  • Treatment with chronic systemic glucocorticoid therapy (more than 7 days in 1 month)
  • Treatment with lithium salts
  • History of Alcohol or drug abuse
  • Treatment with any investigational drug 1 month preceding study
  • Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
  • Inability to comply with the protocol

Sites / Locations

  • Vanderbilt University Medical Center-GCRC

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Control (bradykinin infusion)

L-NMMA + bradykinin

Isosorbide + L-NMMA + bradykinin

Sildenafil + L-NMMA + bradykinin

Arm Description

Bradykinin (Clinalfa AG, Läufelfingen, Switzerland)

N-monomethyl-L-arginine (L-NMMA, NO synthase inhibitor; Bachem, Torrance, CA)

Isosorbide (NO donor)

Sildenafil (phosphodiesterase type 5 (PDE5) inhibitor

Outcomes

Primary Outcome Measures

Net Tissue-type 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.

Secondary Outcome Measures

Forearm Blood Flow (FBF)
Forearm blood flow was measured by strain gauge plethysmography

Full Information

First Posted
May 27, 2008
Last Updated
January 21, 2013
Sponsor
Vanderbilt University
Collaborators
National Institutes of Health (NIH), National Center for Research Resources (NCRR), National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT00685945
Brief Title
Renin-Angiotensin Aldosterone System and Fibrinolysis Interaction in Humans-Specific Aim 3
Official Title
Renin-Angiotensin Aldosterone System and Fibrinolysis(RAAS) Interaction in Humans- Specific Aim 3
Study Type
Interventional

2. Study Status

Record Verification Date
January 2013
Overall Recruitment Status
Completed
Study Start Date
December 2007 (undefined)
Primary Completion Date
January 2009 (Actual)
Study Completion Date
January 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University
Collaborators
National Institutes of Health (NIH), National Center for Research Resources (NCRR), National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of the study is to determine if giving isosorbide,a drug that is used to treat chest pain, affects blood vessel release of an anti-clotting factor.
Detailed Description
To test the hypothesis that the administration of the NO donor isosorbide dinitrate,but not the phosphodiesterase inhibitor sildenafil, will attenuate stimulated vascular t-PA release whereas both agents will improve glucose uptake.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obesity
Keywords
Bradykinin, Obesity, Nitric Oxide Donor, tissue type plasminogen activator, isosorbide dinitrate, phosphodiesterase inhibitor, Renin-Angiotensin Aldosterone System, Fibrinolysis, Angiotensin converting enzyme

7. Study Design

Primary Purpose
Health Services Research
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
Participant
Allocation
Randomized
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Control (bradykinin infusion)
Arm Type
Experimental
Arm Description
Bradykinin (Clinalfa AG, Läufelfingen, Switzerland)
Arm Title
L-NMMA + bradykinin
Arm Type
Experimental
Arm Description
N-monomethyl-L-arginine (L-NMMA, NO synthase inhibitor; Bachem, Torrance, CA)
Arm Title
Isosorbide + L-NMMA + bradykinin
Arm Type
Experimental
Arm Description
Isosorbide (NO donor)
Arm Title
Sildenafil + L-NMMA + bradykinin
Arm Type
Experimental
Arm Description
Sildenafil (phosphodiesterase type 5 (PDE5) inhibitor
Intervention Type
Drug
Intervention Name(s)
Control (bradykinin)
Intervention Description
Graded doses of bradykinin (Clinalfa AG, Läufelfingen, Switzerland) will be infused at 50, 100, and 200ng/min. Each dose will be infused for 5 minutes and FBF will measured during the last 2 minutes of infusion. Arterial and venous blood samples will be obtained for measurement of net t-PA release after each dose.
Intervention Type
Drug
Intervention Name(s)
L-NMMA + bradykinin
Other Intervention Name(s)
N-monomethyl-L-arginine
Intervention Description
Thirty minutes after administration of bradykinin a continuous intra-arterial infusion of L-NMMA at 12 micromol/min will be started started. While continuing the infusion of L-NMMA, baseline measurements and infusion of bradykinin will be repeated.
Intervention Type
Drug
Intervention Name(s)
Isosorbide + L-NMMA + bradykinin
Intervention Description
Following the second bradykinin infusion, 12 subjects will receive 5mg isosorbide dinitrate (an exogenous NO donor; Major Pharmaceuticals Inc, Livonia MI). Sixty minutes after the administration of isosorbide the continuous intra-arterial infusion of L-NMMA at 12 micromol/min will be restarted and baseline measurements and bradykinin infusion will be repeated.
Intervention Type
Drug
Intervention Name(s)
Sildenafil + L-NMMA + bradykinin
Intervention Description
Following the second bradykinin infusion, 12 subjects will receive 50mg sildenafil (phosphodiesterase type 5 (PDE5) inhibitor to increase cGMP without increasing NO; Pfizer, NY). Sixty minutes after the administration of sildenafil the continuous intra-arterial infusion of L-NMMA at 12 micromol/min will be restarted and baseline measurements and bradykinin infusion will be repeated.
Primary Outcome Measure Information:
Title
Net Tissue-type 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.
Time Frame
During and after each study drug administration
Secondary Outcome Measure Information:
Title
Forearm Blood Flow (FBF)
Description
Forearm blood flow was measured by strain gauge plethysmography
Time Frame
During and after each study drug administration
Other Pre-specified Outcome Measures:
Title
Net Glucose Uptake
Description
Individual net reuptake rates at each time point were calculated by the following formula: net uptake = (Cv-CA) x {FBF x [101-hematocrit/100]}, where Cv and CA represent the concentration of glucose in the brachial vein and artery, respectively.
Time Frame
At baseline and after maximum dose of bradykinin

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: 18-70 years of age Male and female subjects Surgical sterilization Childbearing potential: beta HCG on study day Subjects with a body mass index of 25 or greater Exclusion Criteria: Diabetes type 1 to type 2 as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication Use of hormone replacement therapy Statin therapy In hypertensive subjects, a seated systolic blood pressure greater than 179 mmHg or a seated diastolic blood pressure greater than 110 mmHg or taking hypertensives Pregnancy/Breast Feeding Cardiovascular disease such as myocardial infarction with 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable) deep vein thrombosis, pulmonary embolism, second or three degree heart block, mitral valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy Treatment with anticoagulants History of serious neurologic disease such as cerebral hemorrhage, stroke or transient ischemic attack Diagnosis of asthma Clinically significant gastrointestinal impairment that could interfere with drug absorption Hematocrit <35% Hyperlipidemic fasting Total Cholesterol >220mg/dl Impaired renal function (Serum creatinine >1.5 mg/dl) History or presence of immunological or hematological disorders Any underlying or acute disease requiring regular medication which could possible pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult Impaired hepatic function (Serum glutamic oxaloacetic transaminase, serum glutamate pyruvate transaminase > 60) Treatment with chronic systemic glucocorticoid therapy (more than 7 days in 1 month) Treatment with lithium salts History of Alcohol or drug abuse Treatment with any investigational drug 1 month preceding study Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study Inability to comply with the protocol
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nancy J Brown, MD
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University Medical Center-GCRC
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
19841473
Citation
Pretorius M, Brown NJ. Endogenous nitric oxide contributes to bradykinin-stimulated glucose uptake but attenuates vascular tissue-type plasminogen activator release. J Pharmacol Exp Ther. 2010 Jan;332(1):291-7. doi: 10.1124/jpet.109.160168. Epub 2009 Oct 19.
Results Reference
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Renin-Angiotensin Aldosterone System and Fibrinolysis Interaction in Humans-Specific Aim 3

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