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

This study has been completed.
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Nancy J. Brown, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT00685945
First received: May 27, 2008
Last updated: January 21, 2013
Last verified: January 2013
  Purpose

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.


Condition Intervention
Obesity
Drug: Control (bradykinin)
Drug: L-NMMA + bradykinin
Drug: Isosorbide + L-NMMA + bradykinin
Drug: Sildenafil + L-NMMA + bradykinin

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Primary Purpose: Health Services Research
Official Title: Renin-Angiotensin Aldosterone System and Fibrinolysis(RAAS) Interaction in Humans- Specific Aim 3

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • Net Tissue-type Plasminogen Activator (t-PA) Release [ Time Frame: During and after each study drug administration ] [ Designated as safety issue: No ]
    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) [ Time Frame: During and after each study drug administration ] [ Designated as safety issue: No ]
    Forearm blood flow was measured by strain gauge plethysmography


Other Outcome Measures:
  • Net Glucose Uptake [ Time Frame: At baseline and after maximum dose of bradykinin ] [ Designated as safety issue: No ]
    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.


Enrollment: 24
Study Start Date: December 2007
Study Completion Date: January 2009
Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Control (bradykinin infusion)
Bradykinin (Clinalfa AG, Läufelfingen, Switzerland)
Drug: Control (bradykinin)
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.
Experimental: L-NMMA + bradykinin
N-monomethyl-L-arginine (L-NMMA, NO synthase inhibitor; Bachem, Torrance, CA)
Drug: L-NMMA + bradykinin
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.
Other Name: N-monomethyl-L-arginine
Experimental: Isosorbide + L-NMMA + bradykinin
Isosorbide (NO donor)
Drug: Isosorbide + L-NMMA + bradykinin
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.
Experimental: Sildenafil + L-NMMA + bradykinin
Sildenafil (phosphodiesterase type 5 (PDE5) inhibitor
Drug: Sildenafil + L-NMMA + bradykinin
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.

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00685945

Locations
United States, Tennessee
Vanderbilt University Medical Center-GCRC
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
Investigators
Principal Investigator: Nancy J Brown, MD Vanderbilt University
  More Information

Publications:
Responsible Party: Nancy J. Brown, Professor of Medicine and Clinical Pharmacology, Vanderbilt University
ClinicalTrials.gov Identifier: NCT00685945     History of Changes
Other Study ID Numbers: RAAS & Fibrinolysis, 2R01HL060906, HL065193, UL1RR024975, 5R01HL085740-05
Study First Received: May 27, 2008
Results First Received: August 25, 2011
Last Updated: January 21, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Vanderbilt University:
Bradykinin
Obesity
Nitric Oxide Donor
tissue type plasminogen activator
isosorbide dinitrate
phosphodiesterase inhibitor
Renin-Angiotensin Aldosterone System
Fibrinolysis
Angiotensin converting enzyme

Additional relevant MeSH terms:
Obesity
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Isosorbide-5-mononitrate
Sildenafil
Bradykinin
Isosorbide Dinitrate
Tissue Plasminogen Activator
Kininogens
Omega-N-Methylarginine
Isosorbide
Nitric Oxide Donors
Phosphodiesterase Inhibitors
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Cysteine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Fibrinolytic Agents
Fibrin Modulating Agents

ClinicalTrials.gov processed this record on April 21, 2014