Do the cardiovascular effects of angiotensin-converting enzyme (ACE) I involve ACE-independent mechanisms? new insights from proline-rich peptides of Bothrops jararaca.
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.
Ianzer
Danielle
D
Center for Applied ToxinologyCentro de Pesquisa, Inovac çãoe Difusão, Laboratório Especial de Toxinologia Aplicada, Instituto Butantan, Sao Paulo, Brazil.
Santos
Robson Augusto Souza
RA
Etelvino
Gisele Maia
GM
Xavier
Carlos Henrique
CH
de Almeida Santos
Jerusa
J
Mendes
Elizabeth Pereira
EP
Machado
Leonor Tapias
LT
Prezoto
Benedito Carlos
BC
Dive
Vincent
V
de Camargo
Antônio Carlos Martins
AC
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
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