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

Not Applicable

Completed

Conditions: Obesity

Interventions: Drug: Control (bradykinin)
Drug: L-NMMA + bradykinin
Drug: Isosorbide + L-NMMA + bradykinin
Drug: Sildenafil + L-NMMA + bradykinin

Registration Number: NCT00685945

Lead Sponsor: Vanderbilt University

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 24

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Control (bradykinin infusion)	Control (bradykinin)	Bradykinin (Clinalfa AG, Läufelfingen, Switzerland)
L-NMMA + bradykinin	L-NMMA + bradykinin	N-monomethyl-L-arginine (L-NMMA, NO synthase inhibitor; Bachem, Torrance, CA)
Isosorbide + L-NMMA + bradykinin	Isosorbide + L-NMMA + bradykinin	Isosorbide (NO donor)
Sildenafil + L-NMMA + bradykinin	Sildenafil + L-NMMA + bradykinin	Sildenafil (phosphodiesterase type 5 (PDE5) inhibitor

Primary Outcome Measures

Name	Time	Method
Net Tissue-type Plasminogen Activator (t-PA) Release	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 Outcome Measures