Official Title: “Renin-Angiotensin Aldosterone System and Fibrinolysis(RAAS) 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.

Study Type: Interventional

Study Design: Health Services Research, Non-Randomized, Open Label, Uncontrolled, Parallel Assignment

Study Primary Completion Date: April 2010

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 during ACE inhibition whereas both agents will improve glucose uptake.

Intervention(s) in this Clinical Trial

• Drug: Isosorbide
  • After arterial line and intravenous line placement; subject is given Aspirin 325 mg. After 30 minute rest period, a measurement of basal forearm bloodflow is obtained. After measurement, Bradykinin will be infused at 50, 100 and 200 ng/min. Each dose will be infused for 5 minutes and blood samples will be obtained. After a 30 minute rest period, LNMMA (12 umol/min) will be infused for 10 minutes and Bradykinin will be repeated. Blood samples will be obtained after each dose. Subjects will then be given IDSN 5 mg. One hour later, the LNMMA and Bradykinin infusion will be repeated and blood samples obtained.
• Drug: Sildenafil
  • After arterial line and intravenous line placement; subject is given Aspirin 325 mg. After 30 minute rest period, a measurement of basal forearm bloodflow is obtained. After measurement, Bradykinin will be infused at 50, 100 and 200 ng/min. Each dose will be infused for 5 minutes and blood samples will be obtained. After a 30 minute rest period, LNMMA (12 umol/min) will be infused for 10 minutes and Bradykinin will be repeated. Blood samples will be obtained after each dose. Subjects will then be given Sildenafil 50 mg. One hour later, the LNMMA and Bradykinin infusion will be repeated and blood samples obtained.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: Isosorbide- A
  • Subjects received Isosorbide Dinitrate 5 mg po after receiving Bradykinin and LNMMA. The Bradykinin and LNMMA is then repeated
• Active Comparator: Sildenafil - B
  • Subjects received Sildenafil after receiving Bradykinin and LNMMA. After 1 hour, Bradykinin and LNMMA is repeated.

Primary Measures

• Measure tPA release
  • Time Frame: end of each study
    Safety Issue?: No

Secondary Measures

• Measurement of forearm flow
  • Time Frame: end of each study
    Safety Issue?: No

Inclusion Criteria:

• 18-70 years of age
• Male and female subjects
• Surgical sterilization
• Childbearing potential: beta HCg on study day
• Subjects with a BMI 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 mm Hg 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 >220
• 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 (SGOT, SGPT > 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: Vanderbilt University

Overall Clinical Trial Officials and Contacts

Nancy J Brown, MD Principal Investigator Vanderbilt University  

Overall Contact: Delia M Woods, BSN 615-322-3371 delia.woods@vanderbilt.edu

Information obtained from ClinicalTrials.gov on August 28, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00685945

Study ID Number: RAAS & Fibrinolysis

ClinicalTrials.gov Identifier: NCT00685945

Health Authority: United States: Institutional Review Board