title: Do the cardiovascular effects of angiotensin-converting enzyme (ACE) I involve ACE-independent mechanisms? new insights from proline-rich peptides of Bothrops jararaca.
abstract: Angiotensin-converting enzyme (ACE) inhibitors were developed based on proline-rich oligopeptides found in the venom of Bothrops jararaca (Bj) 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 sites (K(i) = 40,000 and 70,000 nM, respectively), whereas Bj-BPP-10c is a strong bradykinin potentiator and inhibitor of the ACE C site (K(i) = 0.5 versus 200 nM for N site). Strikingly, both peptides, in doses ranging from 0.47 to 71 nmol/kg, produced long-lasting reduction (>6 h) in the mean arterial pressure of conscious spontaneously hypertensive rats (maximal change, 45 +/- 6 and 53 +/- 6 mm Hg 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 angiotensin 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 bradykinin (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 angiotensin I-converting enzyme inhibitor.
authors.affiliation: Center for Applied ToxinologyCentro de Pesquisa, Inovac çãoe Difusão, Laboratório Especial de Toxinologia Aplicada, Instituto Butantan, Sao Paulo, Brazil.
authors.forename: Danielle
authors.initials: D
authors.lastname: Ianzer
authors.forename: Robson Augusto Souza
authors.initials: RA
authors.lastname: Santos
authors.forename: Gisele Maia
authors.initials: GM
authors.lastname: Etelvino
authors.forename: Carlos Henrique
authors.initials: CH
authors.lastname: Xavier
authors.forename: Jerusa
authors.initials: J
authors.lastname: de Almeida Santos
authors.forename: Elizabeth Pereira
authors.initials: EP
authors.lastname: Mendes
authors.forename: Leonor Tapias
authors.initials: LT
authors.lastname: Machado
authors.forename: Benedito Carlos
authors.initials: BC
authors.lastname: Prezoto
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
authors.forename: Antônio Carlos Martins
authors.initials: AC
authors.lastname: de Camargo
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D017837:Bothrops; D001920:Bradykinin / Q000494:pharmacology; D016466:CHO Cells; D002319:Cardiovascular System / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D003435:Crotalid Venoms / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D003435:Crotalid Venoms; D009842:Oligopeptides; C006791:bradykinin potentiating factors; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin