Aging is typified by progressive impairments in cardiovascular regulation that may include increased sympathetic outflow, reduced vagal activity and reduced vascular distensibility. These cardiovascular changes are also associated with decreased activity of the renin-angiotensin (Ang) system (RAS) and insulin resistance. The over-arching goal of Project 4 is to define how insulin and specific components of the RAS act together as major contributors to altered cardiovascular regulation that ultimately lead to elevated systolic pressure and exacerbation of hyperinsulinemia and hyperglycemia during the course of aging. We focus on the opposing actions of Ang II and Ang-(1-7) in the nucleus of the solitary tract (nTS) to modulate the baroreceptor reflex control of sympathetic and parasympathetic outflow. The investigations will define how insulin may act in concert with or opposition to these two peptides in neural regulation of autonomic outflow via actions at cardiovascular relevant regions of the medulla oblongata and hypothalamus. Our experimental strategy will draw upon the combined expertise of members of the Project to define the neural systems, peptide receptor pathways, and metabolic components that interact to account for modification of cardiovascular regulation during aging.
Specific Aim 1 investigates the hypothesis that the role of endogenous Ang-(1-7) to facilitate baroreceptor reflex function diminishes with aging, such that the effects of Ang II and insulin are unopposed, thereby contributing to reduced cardiac vagal outflow, enhanced sympathetic outflow, and hypertension. Experiments will focus on the nTS, paraventricular nucleus of the hypothalamus, and rostral ventrolateral medulla as key sites in the brain where actions of Ang peptides and insulin change during the aging process. As one mechanism contributing to the altered roles of Ang peptides and insulin during aging Specific Aim 2 will test the hypothesis that Ang-(1-7) in brain tissue diminishes with age, leading to a shift in the function or expression of Ang II and insulin. Since receptors constitute a key functional component in the aforementioned central regulation of cardiovascular function during aging, Specific Aim 3 will assess the hypothesis that Ang II and Ang-(1-7) receptors undergo a dynamic regulation, in part, determined by alterations in the tissue levels of these two peptides. In particular, the proposed experiments will establish the functional interactions that develop between the AT1b receptor and the mas orphan receptor as key elements responsive to Ang-(1-7). The proposed experiments utilize a transgenic rat model deficient in the production of brain angiotensinogen (ASrAogen), which we show does NOT exhibit cardiovascular impairments over the same time frame typically associated with aging in Sprague-Dawley rats.
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