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

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.

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.

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