Pathophysiology of Cardiometabolic Risk Factors in African Americans
Condition: Obesity; Hypertension
MeSH terms: Hypertension; Obesity
Study type: Interventional
Phase: Phase 1

Summary: 
      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
    

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.
    

Intervention name(s): L-NMMA; Trimethaphan
Intervention type(s): Drug; Drug
Intervention description(s): L-NMMA 250 ug/Kg/min; Will infuse trimethaphan for until complete autonomic blockade is achieved.
Intervention MeSH terms: Trimethaphan; Trimethaphan camsylate
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)