The renin-angiotensin system (RAS) is present within the cardiovascular regulatory centers of the brainstem and is an important contributing factor to both hypertension and heart failure. RAS hyperactivity is thought to underlie much of the inappropriate sympathoexcitatory drive that is common to these diseases, though the mechanism is still unclear. The presympathetic neurons of the rostral ventrolateral medulla (RVLM), particularly the C1-adrenergic cell group, play an important role in the dynamic control of sympathetic vasomotor tone and are probable targets of this hyperactive RAS. Activity of the RVLM neurons is modulated by many factors including angidtensin-ll (Angll) which is generally stimulatory, though the molecular basis of this modulation is also not defined. Under pathological conditions, upregulation of the RAS, including AT1 receptors and angiotensin converting enzyme (ACE), produces a tonic activation of presympathetic neurons that can be abrogated by receptor antagonists or targeted gene disruption. Although studies have attempted to address the role of Angll receptors in regulating brainstem neurons and in promoting hypertension, the extent to which the Angll receptors expressed by the C1 neurons contribute to hypertension remains to be determined. Identifying the important ionic conductances that are modulated by Angll in C1 neurons (via in vitro recording) and determining the contribution of Angll receptors on these cells to promote the hypertensive state (via lentiviral-mediated, C1-selective overexpression of AT1) are the primary goals of this proposal. Results from these studies could serve as a foundation for the development of novel therapeutic strategies to treat these pathologies.
Hypertension (high blood pressure) is one of the most prevalent cardiovascular disorders, afflicting approximately 33.6% of the population. The research proposed herein will serve to advance our understanding of the specific mechanisms involved in the development and maintenance of this disease.
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