Pathophysiology of Cardiometabolic Risk Factors in African Americans

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.

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.