Received for publication February 5, 2007.
Revised April 30, 2007.
Accepted for publication May 1, 2007.

Do the cardiovascular effects of ACEI involve ACE-independent mechanisms? New insights from proline-rich peptides of Bothrops jararaca

Abstract

ACE inhibitors were developed based on proline rich oligopeptides found in the venom of Bothrops jararaca previously known as bradykinin-potentiating peptides (BPPs). However, the exact mechanism of action of BPPs remains unclear. The role of the ACE in the cardiovascular effects of two of naturally proline-rich oligopeptides (Bj-BPP-7a and Bj-BPP-10c) was evaluated in vitro and in vivo. Bj-BPP-7a does not potentiate the cardiovascular response to bradykinin and is a weak inhibitor of ACE C- and N-site (Ki = 40,000 and 70,000 nM, respectively), while Bj-BPP-10c is a strong bradykinin potentiator and inhibitor of ACE C-site (Ki = 0.5 nM vs. 200 nM for N-site). Strikingly, both peptides in doses ranging from 0.47 to 71 nmol/Kg, produced long-lasting reduction (> 6 hours) in the mean arterial pressure of conscious SHR (maximal change 45 ± 6 and 53 ± 6 mmHg for Bj-BPP-7a and Bj-BPP-10c, respectively). The fall in blood pressure was accompanied by variable degrees of bradycardia. In keeping with the absence of relationship between ACE inhibitory and antihypertensive activities, no changes in the pressor effect of Ang I or in the hypotensive effect of bradykinin were observed at the peak of the cardiovascular effects of both peptides. Our results indicate that the antihypertensive effect of two Bj-BPPs containing the motif Ile-Pro-Pro, is unrelated to their ability for inhibiting ACE or potentiating BK indicating as a major component, ACE and BK-independent mechanisms. These results are in line with previous observations suggesting ACE inhibition-independent mechanisms for ACEI.

Key words: Bothrops jararaca venom, Bradykinin Potentiating Peptides, Proline-rich peptides, SHR, angiotensin-converting enzyme inhibitors, blood pressure