Sympathetic neural patterns and transduction in obesity-associated hypertension

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PROJECT SUMMARY Cardiovascular mortality attributable to hypertension (HTN) has increased by more than 10 percent in the last decade, due in part to the escalating obesity epidemic. Effective therapeutic options for HTN are limited and despite a high prevalence of multi-pharmacological approaches, more than 50% of hypertensive individuals remain uncontrolled. As such, studies that advance understanding of basic mechanisms of blood pressure regulation in humans are needed to identify novel therapeutic targets. Exaggerated sympathetic nervous activity (SNA) and vasoconstriction are hallmark features of many cardiovascular diseases including obesity-associated HTN (Ob-HTN). Causes of exaggerated sympathetic vasoconstriction are unclear, however recent advances in quantification of sympathetic activity have uncovered unique action potential patterns that influence the peripheral vasoconstrictor response to stress. In animal models, sympathetic firing patterns during stress increase co-release of the potent vasoconstrictor neuropeptide Y (NPY) in conjunction with norepinephrine, causing a shift in the mechanisms of vasoconstriction towards NPY-mediated signaling. NPY causes vasoconstriction via activation of NPY 1 receptors (Y1R), and facilitates α-adrenergic mediated signaling causing exaggerated sympathetic vasoconstriction. We hypothesize that physiological stressors like obesity and hypoxia alter sympathetic action potential patterns that cause vasoconstriction to rely on NPY-mediated signaling. The overall aim of this proposal is to 1) identify how sympathetic action potential patterns change in response to chemoreflex and mental stress 2) to assess the impact of action potential patterns on mechanisms of vasoconstriction in healthy adults and in patients with Ob-HTN. To accomplish these goals, we will we will assess beat-by-beat vasoconstriction in response to endogenous bursts of SNA during pharmacological manipulation of α-adrenergic receptors and Y1Rs to determine the mechanisms of exaggerated sympathetic vasoconstriction during chemoreflex/mental stress in healthy adults and Ob-HTN patients. We anticipate that these investigations will 1) further understanding of the basic signaling mechanisms responsible for neurovascular transduction in humans including the interaction between action potential patterns, neurotransmission and vasoconstriction 2) identify new mechanisms underlying exaggerated neurovascular transduction in Ob-HTN and 3) provide avenues for research in other patient populations characterized by elevated SNA and exaggerated vasoconstriction including sleep apnea, metabolic disease, and heart failure.