There is considerable evidence for the role of both the central nervous system and the sympathetic nervous system in the development and/or maintenance of hypertention in the SHR. The SHR is excessively responsive behaviorally and physiologically to a variety of stressful stimuli. Neuropeptide-Y(NPY) is a 36 amino acid peptide that has been shown to be co-localized with norepinephrine in peripheral noradrenergic neurons as well as with norepinephrine or epinephrine in central catecholamine neurons. The Working Hypothesis of this proposal is that, """"""""NPY may be released together with norepinephrine upon nerve stimulation; that NPY may work together with norepinephrine in causing certain physiological responses such as contraction of vascular smooth muscle, presynaptic inhibition of norepinephrine release and centrally mediated decreases in blood pressure; and that alterations in the actions of NPY may contribute to the development and maintenance of hypertension."""""""" The purpose of the present investigation will be to carry out a systematic study of several aspects of NPY's actions at the vascular neuroeffector junction and central catecholamine neurons and to examine the interaction between NPY and catecholamine systems in normotensive and hypertensive animals in which stress is known to play an important role. Experiments will be carried out in Sprague-Dawley rats, Spontaneously Hypertensive rats and Wistar-Kyoto normotensive rats.
Six Specific Aims will be addressed: 1) to determine and characterize the effects of NPY on the isolated caudal artery and perfused mesentery arterial bed in vitro and in situ; 2) to determine the effect of NPY on noradrenergic neurotransmission at the vascular neuroeffector junction. Similar preparations as in Aim One will be used; 3) to assess the release of NPY from noradrenergic neurons innervating blood vessels, release of NPY will be measured from caudal arteries in response to field stimulation; the perfused mesenteric bed to periarterial nerve stimulation and into the plasma in pithed rats in which the sympathetic outflow is stimulated at the level of the spinal cord; 4) to characterize the effect of NPY on blood pressure following microinjection into specific regions of the hypothalamus or brainstem; 5) to determine the effect of NPY in the evoked release of catecholamines from slices of hypothalamus or brainstem or following push-pull perfusion; and 6) to assess the release of NPY from these same brain regions following stimulation. It is thought that this investigation will better define and characterize the physiological and pathophysiological role of NPY in circulatory control mechanisms, stress and hypertension.

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National Heart, Lung, and Blood Institute (NHLBI)
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Saint Louis University
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Saint Louis
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Westfall, T C; McCullough, L A; Vickery, L et al. (1998) Effects of neuropeptide Y at sympathetic neuroeffector junctions. Adv Pharmacol 42:106-10
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Westfall, T C; Curfman-Falvey, M (1995) Amylin-induced relaxation of the perfused mesenteric arterial bed: meditation by calcitonin gene-related peptide receptors. J Cardiovasc Pharmacol 26:932-6
Westfall, T C; Yang, C L; Curfman-Falvey, M (1995) Neuropeptide-Y-ATP interactions at the vascular sympathetic neuroeffector junction. J Cardiovasc Pharmacol 26:682-7
McCullough, L A; Westfall, T C (1995) Neuropeptide Y inhibits depolarization-stimulated catecholamine synthesis in rat pheochromocytoma cells. Eur J Pharmacol 287:271-7
Macarthur, H; Mattammal, M B; Westfall, T C (1995) A new perspective on the inhibitory role of nitric oxide in sympathetic neurotransmission. Biochem Biophys Res Commun 216:686-92

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