Vagal afferent cell bodies as sensors of blood-borne factors

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DESCRIPTION (provided by applicant): Vagal afferent nerves play vital roles in the "moment to moment" and "long-term" regulation of hemodynamic status. This project focuses on the unique nature of the occipital artery microvasculature in nodose ganglia and its importance to the regulation of vagal afferent activity and cardiovascular function. Our first hypothesis is that the occipital artery microvasculature lacks an effective "blood-ganglion barrier" in order for circulating factors to gain access to, and regulate the activity of, vagal afferent cell bodies in nodose ganglia via interactions with cell-surface receptors. Such a system would allow for the "moment to moment" regulation of centrally-directed action potentials in vagal afferents and transmission of afferent information into the brain. At present, there is no consensus as to how disease processes such as humorally-induced hypertension, diabetes and inflammatory states affect the synthesis and disposition of receptors in vagal afferent neurons. Our second hypothesis is that the unique functional morphology of the occipital artery-nodose ganglion complex allows sustained increases in blood-borne factors to alter the synthesis of receptors in vagal afferent cell bodies and therefore the net availability of these receptors for insertion into the plasma membranes of the cell bodies and for axonal transport to the peripheral and central afferent terminals. This would represent a novel "long-term" homeostatic mechanism that allows vagal afferents to effectively adapt to increased levels of factors that are detrimental to afferent and cardiovascular function. The major focus of our project is to determine the importance of the occipital artery-nodose ganglion complex in integrative cardiovascular physiology in control rats and in 2-kidney-1 clip (2K-1C) hypertensive rats, a clinically-relevant model of humoral (renin)-dependent hypertension. We will employ functional in vivo, and in vitro techniques, and receptor binding/immunohistochemistry methods in a comprehensive approach to addressing our specific aims, which are to characterize (1) the accessibility of blood-borne factors to vagal afferent cell bodies, (2) the receptor sub-types involved in the actions of key circulating factors on afferent cell bodies, (3) the temporal changes in the expression and function of receptors in vagal afferents of control and 2K-1C hypertensive rats, and (4) the effects of and receptor-subtypes by which circulating factors regulate smooth muscle tone in the occipital artery microvasculature of control and 2K-1C rats. In lay terms, the aim of this project is to determine whether the cell bodies of nerves that regulate blood pressure by sending signals into the brain are able to respond directly to chemicals in the blood. This unique response mechanism may be vital in helping the body to defend the cardiovascular system against disease states that threaten human health such as high blood pressure, inflammation and diabetes.