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Lameu, C/ Gomes, CL. The central nervous system as target for anti-hypertensive actions of a proline-rich peptide from Bothrops jararaca venom. 2009. 158p. PhD Thesis – Graduate Program in Biochemistry. Instituto de Quimica, Universidade de Sao Paulo, Sao Paulo. Pyroglutamyl proline-rich oligopeptides, denominated bradykinin-potentiating peptides (BPPs), present in the venom of the viper Bothrops jararaca were the first described naturally occurring angiotensine-converting enzyme (ACE) inhibitors. The biochemical and pharmacological properties of theses peptides were essential for the development of captopril, the first active site-directed inhibitor of ACE, currently used to treat human hypertension. Recent data have suggested that the pharmacological activity of BPPs could not only be explained by their inhibitory action on the ACE activity and that BPPmediated effects may involve the central nervous system. In this work, we have characterized BPP-10c [<ENWPHPQIPP]-induced calcium signaling in neuronal cells obtained as primary culture from day 1 of postnatal rat brain. Elevations of [Ca]i induced by increasing concentrations of BPP-10c revealed an atypical dose-response curve. Maximal [Ca]i peak values were measured at 1 μM BPP-10c concentration, while further raising BPP-10c concentrations led to a decline of [Ca]i responses. This effect was independent from kinin-B2 receptor activity and was mediated by a yet unknown Gi/0 protein-coupled receptor. BPP-10c signaling promoted an increase of nitric oxide (NO) production in neuronal cells, as consequence of Ca-dependent NO synthase activation and upregulated gene expression of endothelial NO synthase (eNOS) and argininosuccicinato synthase (ASS), a limiting step enzyme in the NOcitrulline cycle. Furthermore, affinity chromatography assays revealed ASS and PDF created with pdfFactory trial version www.pdffactory.com

O sistema nervoso central como alvo das ações anti-hipertensivas de um peptídeo rico em resíduo de prolina do veneno da Bothrops jararaca