Bj-PRO-5a, a natural angiotensin-converting enzyme inhibitor, promotesvasodilatation mediated by both bradykinin B2 and M1 muscarinicacetylcholine receptors

ABSTRACT

Bradykinin-potentiating peptides (BPPs) or proline-rich oligopeptides (PROs) isolated from the venomglands of Bothrops jararaca (Bj) were the first natural inhibitors of the angiotensin-converting enzyme(ACE) described. Bj-PRO-5a (peptide family, wasessential for the development of captopril, the first site-directed ACE inhibitor used for the treatment ofhuman hypertension. Nowadays, more Bj-PROs have been identified with higher ACE inhibition potencycompared to Bj-PRO-5a. However, despite its modest inhibitory effect of ACE inhibition, Bj-PRO-5areveals strong bradykinin-potentiating activity, suggesting the participation of other mechanisms for thispeptide. In the present study, we have shown that Bj-PRO-5a induced nitric oxide (NO) productiondepended on muscarinic acetylcholine receptor M1 subtype (mAchR-M1) and bradykinin B2 receptoractivation, as measured by a chemiluminescence assay using a NO analyzer. Intravital microscopy basedon transillumination of mice cremastermuscle also showed that both bradykinin B2 receptor and mAchRM1contributed to the vasodilatation induced by Bj-PRO-5a. Moreover, Bj-PRO-5a-mediated vasodilatationwas completely blocked in the presence of a NO synthase inhibitor. The importance of this work liesin the definition of novel targets for Bj-PRO-5a in addition to ACE, the structural model for captoprildevelopment.