Bradykinin-potentiating peptides: Beyond captopril

The identification of novel endogenous and exogenous molecules acting in the complex mechanism of regulating the vascular tonus has always been of great interest. The discovery of bradykinin (1949) and the bradykinin-potentiating peptides (1965) had a pivotal influence in the field, respectively, in understanding cardiovascular pathophysiology and in the development of captopril, the first active-site directed inhibitor of angiotensin-converting enzyme, and used worldwide to treat human hypertension. Both discoveries originated from studies of envenoming by the snake Bothrops jararaca. The aim of the present article is to reveal that the snake proline-rich oligopeptides, known as bradykinin-potentiating peptides, are still a source of surprising scientific discoveries, some of them useful not only to reveal potential new targets but also to introduce prospective lead molecules for drug development. In particular, we emphasize argininosuccinate synthetase as a new functional target for one of bradykinin-potentiating peptides found in B. jararaca, Bj-BPP-10c. This decapeptide leads to argininosuccinate synthetase activation, consequently sustaining increased nitric oxide production, a critical endogenous molecule to reduce the arterial blood pressure.

► Inhibition of ACE by bradykinin-potentiating peptides (BPPs) and clinical efficacy lead to the synthesis of captopril.
► In spontaneously hypertensive rats, the antihypertensive effect of BPPs is dissociated from ACE inhibition.
► In vitro, Bj-BPP-10c specifically binds to argininosuccinate synthetase (AsS) and increases its activity.
► Bj-BPP-10c increases the plasma level of l-Arg and stimulates the production of NO. ▶ The effect of BPPs is associated with other mechanisms besides the activation of AsS.