Prolonged exposure to bedrest or microgravity in humans results in a number of adverse cardiovascular consequences, leading to cardiovascular deconditioning. Rat hindlimb unloading (HU) is an animal model of cardiovascular deconditioning and results in similar cardiovascular consequences including orthostatic intolerance. The mechanisms responsible for cardiovascular dysfunction in humans following bedrest or microgravity, and in rats after HU, are not clear, but alterations in regulation of the autonomic nervous system likely play an important role Blunted sympathetic vasoconstriction and enhanced cardiopulmonary receptor inhibition appear to contribute to autonomic dysfunction in deconditioned humans and HU rats. We have evidence that central nervous system mechanisms contribute to altered cardiovascular regulation in HU rats. Specifically, we have observed increased GABA-A and nitric oxide (NO) inhibition at the rostral ventrolateral medulla (RVLM) and increased neuronal nitric oxide synthase in the paraventricular nucleus (PVN) of the hypothalamus. These brain regions are critically important in normal autonomic regulation, and have been implicated in altered autonomic function in a variety of disease states. The proposed studies will test the general hypothesis that cardiovascular deconditioning alters neurohumoral regulatory mechanisms in the medulla and hypothalamus, specifically the RVLM and PVN, that contribute significantly to impaired cardiovascular function. We will address these questions using whole animal studies in conscious and anesthetized control and HU rats (Fos, microinjections, extracellular recording), immunohistochemistry, studies in single dissociated spinally projecting RVLM and PVN neurons, and molecular techniques.
SPECIFIC AIM 1 : Examine central mechanisms within the rostral ventrolateral medulla (RVLM) that contribute to impaired cardiovascular regulation due to deconditioning.
SPECIFIC AIM 2 : Examine central mechanisms within the paraventricular nucleus (PVN) of the hypothalamus that are altered by cardiovascular deconditioning.
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