Pathophysiology of Cardiometabolic Risk Factors in African Americans

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Vanderbilt University
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Cyndya Shibao, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT01122407
First received: May 10, 2010
Last updated: April 25, 2014
Last verified: April 2014
  Purpose

The overall goal of this proposal is to determine the autonomic and nitric oxide contribution in the pathogenesis of hypertension and insulin resistance in obese African American women. For this purpose we will use two non-FDA approved drugs:

Trimethaphan IND# 63826 Approval date 12/20/2001 L-NMMA IND# 41735 Approval date 09/1993


Condition Intervention
Obesity
Hypertension
Drug: Trimethaphan, L-NMMA
Drug: Trimethaphan

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Official Title: Obesity, Hypertension in African American Women, Neuro-metabolic Mechanism

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • change in systolic blood pressure in response to trimethaphan, as a measurement of the tonic sympathetic contribution to blood pressure. [ Time Frame: 30 minutes after initiation of Trimethaphan infusion ] [ Designated as safety issue: No ]
    Will infuse trimethaphan for until complete autonomic blockade is achieved.


Secondary Outcome Measures:
  • increase in systolic blood pressure induced by NOS inhibition with 250 ug/kg/min L-NMMA during autonomic withdrawal with trimethaphan. [ Time Frame: within 30 minutes ] [ Designated as safety issue: No ]
    After achieving complete autonomic blockade will infuse L-NMMA.


Estimated Enrollment: 46
Study Start Date: January 2010
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
trimethaphan
Patient will serve as their own control. Two interventions will be assessed. Trimethaphan and Trimethaphan and L-NMMA.
Drug: Trimethaphan
Will infuse trimethaphan for until complete autonomic blockade is achieved.
Trimethaphan plus L-NMMA Drug: Trimethaphan, L-NMMA
Trimethaphan up to 5 mg/min L-NMMA 250 ug/Kg/min

Detailed Description:

The overall goal of this proposal is to determine the autonomic and nitric oxide contribution in the pathogenesis of hypertension and insulin resistance in obese African American women.

Each year cardiovascular disease causes the deaths of approximately 54,000 African American women in the United States.Obesity, hypertension and insulin resistance are more prevalent among African American women as compared to men and Caucasians. These conditions put them at increased risk for the development of diabetes mellitus and cardiovascular disease.

Obesity is associated with increased sympathetic nervous system activity. A positive linear association has been consistently reported between body fat and muscle sympathetic nerve activity (MSNA), a direct measurement of baroreflex modulated vasoconstrictive sympathetic outflow. We and others have reported that in Caucasians this increased sympathetic activation contributes to obesity-associated hypertension. Our preliminary data in African American women indicates that for the same body mass index (BMI), African American women have lower autonomic contribution to blood pressure than Caucasians. We also found important differences in body composition with African American women having less fat mass. When total fat mass is analyzed based on its different components, visceral fat has shown to be a more metabolic active tissue than subcutaneous fat mass, and correlates with sympathetic activity better than any other indices of obesity. Therefore, in specific aim 1a, we propose to test the hypothesis that visceral fat mass modulates the contribution of the autonomic nervous system to blood pressure in obese African American women.

If the autonomic nervous system does not contribute to obesity-associated hypertension in African American women, then what causes these racial differences?. Other pathways involved in blood pressure regulation, such as nitric oxide, might be altered in this group. Several studies have reported that, compared to Caucasians, African Americans have decreased nitric oxide function in isolated vascular beds. The significance of these findings on blood pressure regulation is unknown. We have implemented in our laboratory, new approaches to isolate the contribution of nitric oxide (NO) to blood pressure, by blocking autonomic ganglia neurotransmission with trimethaphan and the production of NO with a nitric oxide synthase inhibitor. This paradigm allows us to define nitric oxide function in the absence of baroreflex buffering or interactions with the autonomic nervous system. In specific aim 1b, we propose to test the hypothesis that obese African American women have impaired NO contribution to blood pressure as part of the pathogenesis of hypertension in this group.

  Eligibility

Ages Eligible for Study:   30 Years to 50 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Race will be self-defined, but only subjects who report both parents of the same race will be included.

All subjects will be pre-menopausal. Age 30-50 years old. We will recruit subjects with wide range of BMI 30-45 kg/m2. Both hypertensives and non-hypertensives will be recruited Hypertension will be defined as a seated blood pressure >130/85 determined in at least two occasions, and therefore, includes patients with "pre-hypertension".

Subjects will be required to have a negative serum/urine pregnancy test. In addition, they will be asked to use a reliable contraceptive method prior to enrollment as determined by the PI (Dr. Cyndya Shibao).

THE ACCEPTED METHOD OF CONTRACEPTION USED (PLEASE CIRCLE):

BARRIER METHODS, BIRTH CONTROL PILLS, HORMONAL METHODS (PILLS, INJECTIONS, VAGINAL RING, PATCH), INTRAUTERINE DEVICES, SURGICAL STERILIZATION (HISTERECTOMY, TOTAL, PARTIAL), TUBAL LIGATION, ESSURE, POSTMENOPAUSAL.

Exclusion Criteria:

Previous allergic reactions to any of the study medications (trimethaphan, L-NMMA, phenylephrine) or inability to take study medications as prescribed during the course of the study.

Use of pacemaker or any metal implant NOT COMPATIBLE WITH MRI (artificial heart valves, implanted drug infusion ports, artificial limb, implanted nerve stimulator, metal pins, screws, plates, surgical staples).

Type 1 or 2 diabetes mellitus as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication.

Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy.

History of smoking or current smokers. Significant weight change >5% from baseline in the past three months. Pregnancy or breast-feeding. History of serious neurological disease such as cerebral hemorrhage stroke, transient ischemic attack.

History or presence of immunological or hematological disorders. Clinical significant gastrointestinal impairment that could interfere with drug absorption.

Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >1.5X upper limit of normal range).

Impaired renal function (estimated glomerular filtration rate (eGFR) of <60mL/min).

Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult.

History of alcohol or drug abuse. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study.

Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01122407

Contacts
Contact: Ginnie Farley 6153220083 ginnie.farley@vanderbilt.edu
Contact: Cyndya Shibao, MD 6155120956 cyndya.shibao@vanderbilt.edu

Locations
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37232
Contact: Ginnie Farley, research assistant    6153220083    ginnie.farley@vanderbilt.edu   
Contact: Cyndya A Shibao, MD    6155120956    cyndya.shibao@vanderbilt.edu   
Principal Investigator: Cyndya Shibao, MD         
Sub-Investigator: Italo Biaggioni, MD         
Sub-Investigator: Luis Okamoto, MD         
Sub-Investigator: Amy Arnold, PhD         
Sub-Investigator: Alfredo Gamboa, MD         
Sub-Investigator: Andre Diedrich, MD         
Sponsors and Collaborators
Vanderbilt University
Investigators
Principal Investigator: Cyndya Shibao, MD Vanderbilt University
  More Information

No publications provided

Responsible Party: Cyndya Shibao, Assistant Professor of Medicine, Vanderbilt University
ClinicalTrials.gov Identifier: NCT01122407     History of Changes
Other Study ID Numbers: 091282
Study First Received: May 10, 2010
Last Updated: April 25, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Additional relevant MeSH terms:
Hypertension
Obesity
Body Weight
Cardiovascular Diseases
Nutrition Disorders
Overnutrition
Overweight
Signs and Symptoms
Vascular Diseases
Trimethaphan
Trimethaphan camsylate
Adjuvants, Anesthesia
Antihypertensive Agents
Autonomic Agents
Cardiovascular Agents
Central Nervous System Agents
Cholinergic Agents
Cholinergic Antagonists
Ganglionic Blockers
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Nicotinic Antagonists
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on October 30, 2014