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.

Study Overview

• Status: Completed
• Conditions: Obesity
• Intervention / Treatment: Drug: Control (bradykinin); Drug: L-NMMA + bradykinin; Drug: Isosorbide + L-NMMA + bradykinin; Drug: Sildenafil + L-NMMA + bradykinin

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center-GCRC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: HEALTH_SERVICES_RESEARCH
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: SINGLE

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Net Glucose Uptake	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.	At baseline and after maximum dose of bradykinin

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH); National Center for Research Resources (NCRR)

Publications and helpful links

General Publications

• Pretorius M, Brown NJ. Endogenous nitric oxide contributes to bradykinin-stimulated glucose uptake but attenuates vascular tissue-type plasminogen activator release. J Pharmacol Exp Ther. 2010 Jan;332(1):291-7. doi: 10.1124/jpet.109.160168. Epub 2009 Oct 19.

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (ACTUAL): January 1, 2009
• Study Completion (ACTUAL): January 1, 2009

Study Registration Dates

• First Submitted: May 27, 2008
• First Submitted That Met QC Criteria: May 28, 2008
• First Posted (ESTIMATE): May 29, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): February 25, 2013
• Last Update Submitted That Met QC Criteria: January 21, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: Obesity; Bradykinin; phosphodiesterase inhibitor; Fibrinolysis; isosorbide dinitrate; Angiotensin converting enzyme; Nitric Oxide Donor; tissue type plasminogen activator; Renin-Angiotensin Aldosterone System
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Protease Inhibitors; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Nitric Oxide Donors; Cysteine Proteinase Inhibitors; Sildenafil Citrate; Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate; omega-N-Methylarginine; Bradykinin; Kininogens
• Other Study ID Numbers: RAAS & Fibrinolysis; 2R01HL060906 (NIH); HL065193 (OTHER_GRANT: NIH); UL1RR024975 (U.S. NIH Grant/Contract); 5R01HL085740-05 (NIH)