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

NCT00685945 | Completed Results DMC

• 5 other identifiers: RAAS & Fibrinolysis2R01HL060906HL065193UL1RR0249755R01HL085740-05
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Obesity

Keywords

Bradykinin; Obesity; Nitric Oxide Donor; tissue type plasminogen activator; isosorbide dinitrate; phosphodiesterase inhibitor; Renin-Angiotensin Aldosterone System; Fibrinolysis; Angiotensin converting enzyme

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Forearm Blood Flow (FBF)

  During and after each study drug administration

Other Outcomes (1)

• Net Glucose Uptake

  At baseline and after maximum dose of bradykinin

Study Arms (4)

Control (bradykinin infusion)

EXPERIMENTAL

Bradykinin (Clinalfa AG, Läufelfingen, Switzerland)

Drug: Control (bradykinin)

L-NMMA + bradykinin

EXPERIMENTAL

N-monomethyl-L-arginine (L-NMMA, NO synthase inhibitor; Bachem, Torrance, CA)

Drug: L-NMMA + bradykinin

Isosorbide + L-NMMA + bradykinin

EXPERIMENTAL

Isosorbide (NO donor)

Drug: Isosorbide + L-NMMA + bradykinin

Sildenafil + L-NMMA + bradykinin

EXPERIMENTAL

Sildenafil (phosphodiesterase type 5 (PDE5) inhibitor

Drug: Sildenafil + L-NMMA + bradykinin

Interventions

Control (bradykinin) DRUG

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.

Control (bradykinin infusion)

L-NMMA + bradykinin DRUG

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.

Also known as: N-monomethyl-L-arginine

L-NMMA + bradykinin

Isosorbide + L-NMMA + bradykinin DRUG

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.

Isosorbide + L-NMMA + bradykinin

Sildenafil + L-NMMA + bradykinin DRUG

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.

Sildenafil + L-NMMA + bradykinin

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (1)

Vanderbilt University Medical Center-GCRC

Nashville, Tennessee, 37232, United States

Location

Related Publications (1)

• 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.

  PMID: 19841473 RESULT

MeSH Terms

Conditions

Obesity

Interventions

Bradykinin; omega-N-Methylarginine; Isosorbide; Sildenafil Citrate

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Kinins; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Neuropeptides; Oligopeptides; Proteins; Nerve Tissue Proteins; Autacoids; Inflammation Mediators; Biological Factors; Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Diamino; Amino Acids, Essential; Sorbitol; Sugar Alcohols; Alcohols; Organic Chemicals; Carbohydrates; Sulfonamides; Amides; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Dr. Mias Pretorius
• Organization: Vanderbilt University

mias.pretorius@vanderbilt.edu

615-343-0665

Study Officials

• Nancy J Brown, MD

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine and Clinical Pharmacology

Study Record Dates

• First Submitted: May 27, 2008
• First Posted: May 29, 2008
• Study Start: December 1, 2007
• Primary Completion: January 1, 2009
• Study Completion: January 1, 2009
• Last Updated: February 25, 2013
• Results First Posted: February 25, 2013

Record last verified: 2013-01

Locations

US (1)