sympathetic mechanisms in the cardiovascular and metabolic alterations of obesity

Conditions: Obesity-Associated Insulin Resistance

Summary: the purpose of this study is to study the role of sympathetic mechanisms involved in chronic regulation of cardiovascular and metabolic abnormalities seen in obesity. the investigators will study the effects chronic sympathetic inhibition on insulin sensitivity, inflammation and endothelial function in obese hypertensive human subjects.

continuing review (cr, 2021/08/04) update: removal of the angiotensin receptor blockade arm of the study the presence of obesity increases the risk for hypertension and diabetes, in part due to the development of insulin resistance. obesity is also associated with sympathetic activation and the overarching hypothesis is that sympathetic activation contributes to insulin resistance with impairment of its vascular and metabolic actions. preliminary studies suggest that 1) blood pressure can be normalized by autonomic blockade in obese hypertensives, 2) sympathetic activation provides no metabolic benefit because the increase in resting energy expenditure associated with obesity is due to an increase in fat free mass rather than sympathetic activation. on the contrary, autonomic blockade: 3) improves insulin sensitivity in obese hypertensives, 4) reverses their impaired no-mediated dilation, and 5) reduces plasma isoprostanes, a measure of oxidative stress. furthermore, these abnormalities are interrelated in negative feedback loops, whereby inflammation/oxidative stress impairs nitric oxide mechanisms, which in turn reduces insulin-mediated vasodilation important for substrate delivery, thus contributing to insulin resistance; insulin resistance leads to compensatory increases in insulin levels, which contributes to further sympathetic activation. current treatment guidelines do not specifically address the treatment of obesity hypertension, and do not target sympathetic activation as a first line approach. it is important, therefore, to determine whether or not targeting sympathetic activation offers unique advantages in the treatment of obesity hypertension over current approaches. the investigators propose a proof-of-concept mechanistic study comparing the metabolic, vascular, and anti-inflammatory effects of sympathetic inhibition, calcium channel blockade and angiotensin receptor blockade in obesity hypertension. the investigators will test the hypotheses that sympathetic activation contributes to 1) metabolic insulin resistance, which impairs the suppression of endogenous glucose production and the stimulation of glucose uptake normally provided by insulin, 2) vascular insulin resistance, which impairs insulin-mediated vasodilation and microvascular recruitment that normally promote glucose uptake, and 3) inflammation and oxidative stress, which contribute to insulin resistance and hypertension. the proposed studies will gauge the contribution of sympathetic activation to the cardiovascular and metabolic complications of obesity and provide the mechanistic insight to determine whether or not it should foster the efforts currently under way to develop novel therapies targeting sympathetic activation for hypertension.

Eligibility criteria:
inclusion criteria: * males and females of all races between 18 and 60 years of age * hypertension defined by two or more properly measured seated blood pressure readings \>130/85 mmhg or currently on antihypertensive medication. * obesity will be defined as having a body mass index (bmi) ≥ 30 kg/m2. * able and willing to provide informed consent. exclusion criteria: * pregnancy or breast feeding * current smokers or history of heavy smoking (\>2 packs/day) * history of alcohol or drug abuse * previous allergic reaction to study medications * evidence of type i diabetes * cardiovascular disease other than hypertension * history of serious cerebrovascular disease * history or presence of immunological or hematological disorders * impaired renal function * treatment with any investigational drug in the 1 month preceding the study * inability to give, or withdraw, informed consent * other factors which in the investigator's opinion would prevent the subject from completing the protocol