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

NCT ID: NCT00685945

Last Updated: 2013-02-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-12-31
• Study Completion Date: 2009-01-31

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.

Conditions

Obesity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: HEALTH_SERVICES_RESEARCH
• Blinding Strategy: SINGLE

Study Groups

Control (bradykinin infusion)

Bradykinin (Clinalfa AG, Läufelfingen, Switzerland)

Group Type: EXPERIMENTAL

Control (bradykinin)

Intervention Type: 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.

L-NMMA + bradykinin

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

Group Type: EXPERIMENTAL

L-NMMA + bradykinin

Intervention Type: 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.

Isosorbide + L-NMMA + bradykinin

Isosorbide (NO donor)

Group Type: EXPERIMENTAL

Isosorbide + L-NMMA + bradykinin

Intervention Type: 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.

Sildenafil + L-NMMA + bradykinin

Sildenafil (phosphodiesterase type 5 (PDE5) inhibitor

Group Type: EXPERIMENTAL

Sildenafil + L-NMMA + bradykinin

Intervention Type: 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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

N-monomethyl-L-arginine

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Center for Research Resources (NCRR)

NIH

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Nancy J. Brown

Professor of Medicine and Clinical Pharmacology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nancy J Brown, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt University Medical Center-GCRC

Nashville, Tennessee, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 19841473 (View on PubMed)

Other Identifiers

2R01HL060906

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HL065193

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

UL1RR024975

Identifier Type: NIH

Identifier Source: secondary_id

View Link

5R01HL085740-05

Identifier Type: NIH

Identifier Source: secondary_id

View Link

RAAS & Fibrinolysis

Identifier Type: -

Identifier Source: org_study_id