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CARDIOVASCULAR

Do the Cardiovascular Effects of Angiotensin-Converting Enzyme (ACE) I Involve ACE-Independent Mechanisms? New Insights from Proline-Rich Peptides of Bothrops jararaca

Center for Applied Toxinology/Centro de Pesquisa, Inovac çãoe Difusão, Laboratório Especial de Toxinologia Aplicada (D.I., A.C.M.d.C.) and Laboratório de Farmacologia, Departamento de Farmacologia (B.C.P.), Instituto Butantan, Sao Paulo, Brazil; Laboratório de Hipertensão, Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gevais, Belo Horizonte, Brazil (R.A.S.S., G.M.E., C.H.X., J.d.A.S., E.P.M., L.T.M.); and CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Gif sur Yvette, France (V.D.)

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.

Address correspondence to: Dr. Antonio C.M. Camargo, Center for Applied Toxinology-CAT/CEPID, Instituto Butantan, Av. Vital Brasil, 1500, São Paulo, SP 05530-900, Brazil. E-mail: camur{at}macbbs.com.br