NPY is a 36 amino acid peptide originally discovered in 1982 romextracts of brain tissue. Since its identification, evidence has been accumulating to favor its role in the regulationof the cardiovascular system. Most of this activity has been ascribed to both direct vasoconstriction and its ability to post-synaptically potentiate other vasoconstrictors action. Other reported regulatory functions concern NPY modulationof brainstem areas controlling the autonomic outflow to cardiac and vacular components and its ability to moduate the release of norepinephrine and other transmitters from perivascular nerves and the sympathetic and intrinsic nerves at the heart level. Although limited, there is evidence to support a NPY modulation at the endothelial level. In large vessel endothelial models. NPY has been observed in one hand to potentiate leukocyte adhesion in a time and concentration dependent manner and in the other hand to modify prostacyclin production. Using an in vitro model of cultured capillary endothelial cells derived from bovine adrenal medulla we have reported the presence of high affinity specific binding sites for NPY and its analogs and have observed that the neuropeptide is capable of inducing signaling events associated with NPY receptor activation in other model systems. Moreover, we have preliminary data to support a comparable signaling responses in microvascular tissue from bovine retina but not with endothelium derived from bovine aorta. Our present goal with the following proposal is to contribute to define the nature of NPY interaction with the microvascular endothelium. Our general hypothesis is that NPY receptors are preferentially distributed in capillary endothelium and that their activation results inthe formation of endothelialderived vasodilators. In order to prove this hypothesis we are propsing to carry out the following specific aims: (1) Evaluate whether NPY receptors are preferentially expressed in other microvasculatures. This will be achieved by performing radioligand binding studies with cultured endothelial cells dervied from large vessels and the microvasculature of several tissues. (2) Test the hypothesis that NPY induces the release of NO and PGI2 from microvascular endothelium through the detection of the basal and stimulated release of these vasodilators in the presence and absence of the neuropeptide. (3) Evaluate the interaction of NPY induced calcium response with other signaling cascades implied in the modulation of endothelial function, specifically (a) the involvement of protein tyrosine kinase pathways through the assessment of the effect of proteinkinases inhibitors and the immunodetectionof phosphorylated proteins upon NPY receptor activation. (b) therole of Ca2+-activated K+ channels through the performance of patch-clamp experiments to detect the effect of NPY on the electrophysiologic parameters associated with the expression of these channels. (4) Test whether the NPY negative coupling to adenylate cyclase modulates the stimulated release of NO and PGI2 by measuring the relese of these agents after manipulations to alter cAMP levels. Altogether the studies should provide insight into the functional role of NPY at the level of the microvscular endothelium expanding our understanding of the regulation of the cardiovascular system provided by this neuropeptide.

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Universidad Central Del Caribe
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