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. 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
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
|Official Title:||Obesity, Hypertension in African American Women, Neuro-metabolic Mechanism|
- 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.
- 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.
|Study Start Date:||January 2010|
|Study Completion Date:||November 2016|
|Primary Completion Date:||November 2016 (Final data collection date for primary outcome measure)|
Patient will serve as their own control. Two interventions will be assessed. Trimethaphan and Trimethaphan and L-NMMA.
Will infuse trimethaphan for until complete autonomic blockade is achieved.
Trimethaphan plus L-NMMA
Trimethaphan infusion 4 mg/min L-NMMA (L-NG-monomethyl Arginine citrate)
Drug: Trimethaphan, L-NMMA
Trimethaphan up to 5 mg/min L-NMMA 250 ug/Kg/min
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01122407
|United States, Tennessee|
|Vanderbilt University Medical Center|
|Nashville, Tennessee, United States, 37232|
|Principal Investigator:||Cyndya Shibao, MD||Vanderbilt University|