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Completed

NCT Number: NCT00685945

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

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.

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Key information

Conditions

Obesity Body Weight Nutrition Disorders Nutritional and Metabolic Diseases Overnutrition Overweight Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Vanderbilt University Medical Center-GCRC

Nashville, Tennessee, 37232, United States

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Control (bradykinin)

Drug

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.

L-NMMA + bradykinin

Drug

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 names: N-monomethyl-L-arginine

Isosorbide + L-NMMA + bradykinin

Drug

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.

Sildenafil + L-NMMA + bradykinin

Drug

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 outcomes

  1. Net Tissue-type Plasminogen Activator (t-PA) Release

    Time frame: During and after each study drug 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.

Secondary outcomes

  1. Forearm Blood Flow (FBF)

    Time frame: During and after each study drug administration

    Forearm blood flow was measured by strain gauge plethysmography

Other outcomes

  1. Net Glucose Uptake

    Time frame: At baseline and after maximum dose of bradykinin

    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.

Sponsors and collaborators

Lead sponsor

Vanderbilt University

Other

Collaborators

  • National Center for Research Resources (NCRR)
  • National Heart, Lung, and Blood Institute (NHLBI)
  • National Institutes of Health (NIH)

Registry information

Official study title

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

Important dates

Study start
2007
Primary completion
2009
Study completion
2009
First posted
May 29, 2008
Registry last updated
Feb 25, 2013

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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