ABSTRACT
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 (Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology
, Bothrops
, Crotalid Venoms/pharmacology
, Proline-Rich Protein Domains/physiology
, Receptor, Bradykinin B2/physiology
, Receptor, Muscarinic M1/physiology
, Vasodilation/drug effects
, Angiotensin-Converting Enzyme Inhibitors/chemistry
, Angiotensin-Converting Enzyme Inhibitors/isolation & purification
, Animals
, CHO Cells
, Cricetinae
, Cricetulus
, Crotalid Venoms/chemistry
, Crotalid Venoms/isolation & purification
, Dose-Response Relationship, Drug
, HEK293 Cells
, Humans
, Male
, Mice
, Mice, Inbred BALB C
, Vasodilation/physiology
ABSTRACT
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.