Ianzer Danielle, Santos Robson Augusto Souza, Etelvino Gisele Maia, Xavier Carlos Henrique, de Almeida Santos Jerusa, Mendes Elizabeth Pereira, Machado Leonor Tapias, Prezoto Benedito Carlos, Dive Vincent, de Camargo Antônio Carlos Martins
Center for Applied ToxinologyCentro de Pesquisa, Inovac çãoe Difusão, Laboratório Especial de Toxinologia Aplicada, Instituto Butantan, Sao Paulo, Brazil.
J Pharmacol Exp Ther. 2007 Aug;322(2):795-805. doi: 10.1124/jpet.107.120873. Epub 2007 May 2.
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.
血管紧张素转换酶（ACE）抑制剂是基于在矛头蝮蛇毒液中发现的富含脯氨酸的寡肽开发而来，这些寡肽以前被称为缓激肽增强肽（BPPs）。然而，BPPs的确切作用机制仍不清楚。在体外和体内评估了ACE在两种天然富含脯氨酸的寡肽（Bj-BPP-7a和Bj-BPP-10c）心血管效应中的作用。Bj-BPP-7a不能增强对缓激肽的心血管反应，是ACE C和N位点的弱抑制剂（K(i)分别为40,000和70,000 nM），而Bj-BPP-10c是一种强效的缓激肽增强剂和ACE C位点的抑制剂（N位点的K(i)为200 nM，而C位点为0.5 nM）。令人惊讶的是，两种肽在剂量为0.47至71 nmol/kg时，均可使清醒的自发性高血压大鼠的平均动脉压产生持久降低（>6小时）（Bj-BPP-7a和Bj-BPP-10c的最大变化分别为45±6和53±6 mmHg）。血压下降伴随着不同程度的心动过缓。与ACE抑制活性和降压活性之间缺乏相关性一致，在两种肽的心血管效应峰值时，未观察到血管紧张素I的升压作用或缓激肽的降压作用发生变化。我们的结果表明，两种含有Ile-Pro-Pro基序的Bj-BPPs的降压作用与其抑制ACE或增强缓激肽（BK）的能力无关，表明主要成分是不依赖于ACE和BK的机制。这些结果与先前的观察结果一致，提示血管紧张素I转换酶抑制剂存在不依赖于ACE抑制的机制。
