RESUMO
Bradykinin-potentiating peptides (BPPs) or proline-rich oligopeptides (PROs) isolated from the venom glands of Bothrops jararaca (Bj) were the first natural inhibitors of the angiotensin-converting enzyme (ACE) described. Bj-PRO-5a (Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia
, Bothrops
, Venenos de Crotalídeos/farmacologia
, Domínios Proteicos Ricos em Prolina/fisiologia
, Receptor B2 da Bradicinina/fisiologia
, Receptor Muscarínico M1/fisiologia
, Vasodilatação/efeitos dos fármacos
, Inibidores da Enzima Conversora de Angiotensina/química
, Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação
, Animais
, Células CHO
, Cricetinae
, Cricetulus
, Venenos de Crotalídeos/química
, Venenos de Crotalídeos/isolamento & purificação
, Relação Dose-Resposta a Droga
, Células HEK293
, Humanos
, Masculino
, Camundongos
, Camundongos Endogâmicos BALB C
, Vasodilatação/fisiologia
RESUMO
The biological activity of the proline-rich decapeptide Bj-PRO-10c, a processing product of the C-type natriuretic peptide precursor protein, expressed in the brain and the venom gland of the pit viper Bothrops jararaca, was originally attributed to the inhibition of the somatic angiotensin-converting enzyme activity with subsequent anti-hypertensive effect. However, recent results suggest broader biological activity may also be involved in the cardiovascular effects of this peptide. Here we show that Bj-PRO-10c enhances and sustains the generation of nitric oxide (NO) by regulating argininosuccinate synthase activity and thereby velocity of the citrulline-NO cycle. Bj-PRO-10c-mediated effects not restricted to the cardiovascular system, since NO production was also induced in cells of astroglial origin. Bj-PRO-10c was internalized by C6 astroglioma cells where it induces NO production and upregulation of the citrulline-NO cycle cells in a dose-dependent fashion. In view of that, astroglial cells function as L-arginine pool for NO production in neighboring neurons, we suggest a regulatory function for Bj-PRO-10c on the metabolism of this gaseous neurotransmitter in the CNS. Moreover, proliferation of astroglial cells was reduced in the presence of Bj-PRO-10c; however, cell death was not induced. Since NO donors have been studied for the treatment of solid cancers, Bj-PRO-10c may serve as structural model for developing drugs to improve the effects of cancer therapy based on the peptide's ability to augment NO production.