Proline rich-oligopeptides: diverse mechanisms for antihypertensive action

Abstract

Bradykinin-potentiating peptides from Bothrops jararaca (Bj) discovered in the early 1960s, were the first natural inhibitors of the angiotensin-converting enzyme (ACE). These peptides belong to a large family of snake venom proline-rich oligopeptides (PROs). One of these peptides, Bj-PRO-9a, was essential for defining ACE as effective drug target and development of captopril, an active site-directed inhibitor of ACE used worldwide for the treatment of human arterial hypertension. Recent experimental evidences demonstrated that cardiovascular effects exerted by different Bj-PROs are due to distinct mechanisms besides of ACE inhibition. In the present work, we have investigated the cardiovascular actions of four Bj-PROs, namely Bj-PRO-9a, -11e, -12b and -13a. Bj-PRO-9a acts upon ACE and BK activities to promote blood pressure reduction. Although the others Bj-PROs are also able to inhibit the ACE activity and to potentiate the BK effects, our results indicate that antihypertensive effect evoked by them involve new mechanisms. Bj-PRO-11e and Bj-PRO-12b involves induction of [Ca(2+)]i transients by so far unknown receptor proteins. Moreover, we have suggested argininosuccinate synthetase and M3 muscarinic receptor as targets for cardiovascular effects elicited by Bj-PRO-13a. In summary, the herein reported results provide evidence that Bj-PRO-mediated effects are not restricted to ACE inhibition or potentiation of BK-induced effects and suggest different actions for each peptide for promoting arterial pressure reduction. The present study reveals the complexity of the effects exerted by Bj-PROs for cardiovascular control, opening avenues for the better understanding of blood pressure regulation and for the development of novel therapeutic approaches.

Keywords: ([Ca(2+)](i)); 4-DAMP; 4-[(diphenylacetyl)oxy]-1,1-dimethyl-piperidinium iodide; ACE; ASS; Argininosuccinate synthetase; BK; Bj; Bothrops jararaca; C-type natriuretic peptide; CNP; CNS; HR; Heart rate; MAP; MDLA; Mean arterial pressure; Muscarinic acetylcholine receptor; NO; NOS; Nitric oxide; PAP; PRO; Proline-rich oligopeptides; SHR; angiotensin I-converting enzyme; argininosuccinate synthetase; bradykinin; central nervous system; heart rate; intracellular calcium concentration; mAChRs; mean arterial pressure; muscarinic receptors; nitric oxide; nitric oxide synthase; proline-rich oligopeptide; pulsatile arterial pressure; spontaneously hypertensive rat; α-methyl-dl-aspartic acid.