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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Obesity

Intervention / Treatment
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* Drug: Control (bradykinin)
* Drug: L-NMMA + bradykinin
* Drug: Isosorbide + L-NMMA + bradykinin
* Drug: Sildenafil + L-NMMA + bradykinin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Control (bradykinin infusion)<br>Bradykinin (Clinalfa AG, Läufelfingen, Switzerland) | Drug: Control (bradykinin)<br>* 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.<br>|
| Experimental: L-NMMA + bradykinin<br>N-monomethyl-L-arginine (L-NMMA, NO synthase inhibitor; Bachem, Torrance, CA) | Drug: L-NMMA + bradykinin<br>* 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.<br>* Other names: N-monomethyl-L-arginine;|
| Experimental: Isosorbide + L-NMMA + bradykinin<br>Isosorbide (NO donor) | Drug: Isosorbide + L-NMMA + bradykinin<br>* 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.<br>|
| Experimental: Sildenafil + L-NMMA + bradykinin<br>Sildenafil (phosphodiesterase type 5 (PDE5) inhibitor | Drug: Sildenafil + L-NMMA + bradykinin<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Net Tissue-type Plasminogen Activator (t-PA) Release | 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. | During and after each study drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forearm Blood Flow (FBF) | Forearm blood flow was measured by strain gauge plethysmography | During and after each study drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bradykinin, Obesity, Nitric Oxide Donor, tissue type plasminogen activator, isosorbide dinitrate, phosphodiesterase inhibitor, Renin-Angiotensin Aldosterone System, Fibrinolysis, Angiotensin converting enzyme