BPP-5a produces a potent and long-lasting NO-dependent antihypertensive effect

Therapeutic Advances in Cardiovascular Disease http://tak.sagepub.com/

BPP-5a produces a potent and long-lasting NO-dependent antihypertensive effect Danielle Ianzer, Carlos Henrique Xavier, Fabiana Costa Fraga, Roberto Queiroga Lautner, Juliano Rodrigo Guerreiro, Leonor Tapias Machado, Elizabeth Pereira Mendes, Andônio Carlos Martins de Camargo and Robson Augusto Souza Santos Ther Adv Cardiovasc Dis 2011 5: 281 originally published online 27 October 2011 DOI: 10.1177/1753944711427318 The online version of this article can be found at: http://tak.sagepub.com/content/5/6/281

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TAK561753944711427318D IanzerTherapeutic Advances in Cardiovascular Disease

Therapeutic Advances in Cardiovascular Disease

BPP-5a produces a potent and long-lasting NO-dependent antihypertensive effect Danielle Ianzer, Carlos Henrique Xavier, Fabiana Costa Fraga, Roberto Queiroga Lautner, Juliano Rodrigo Guerreiro, Leonor Tapias Machado, Elizabeth Pereira Mendes, Ant™nio Carlos Martins de Camargo and Robson Augusto Souza Santos

Abstract:  Background:  The bradykinin potentiating peptides (BPPs) are oligopeptides found in different animal venoms. BPPs isolated from Bothrops jararaca venom were the first natural inhibitors described for somatic angiotensin I-converting enzyme (ACE). They were used in the structural modeling for captopril development, a classical ACE inhibitor widely used to treat human hypertension. Methods:  We evaluated the effect of BPP-5a on cardiovascular parameters of conscious Wistar (WTs) and spontaneously hypertensive rats (SHRs). Results:  In SHR, BPP-5a showed potent cardiovascular effects, at doses ranging from 0.47 to 710 nmol/kg. The maximal changes in mean arterial pressure (MAP) and heart rate (HR) were found at the dose of 2.37 nmol/kg (Δ MAP: −38 ± 4 mmHg, p < 0.01; Δ HR: −71 ± 17 bpm, p < 0.05). Reductions in MAP and HR occurred throughout 6 hours of post-injection period. In contrast to active site-directed ACE inhibitors, no ACE inhibition, evaluated by the Ang I pressor effect, or bradykinin potentiation was observed during the antihypertensive effect of the pentapeptide. In vitro assays showed no effects of BPP-5a upon argininosuccinate synthetase and B1, B2, AT1, AT2 or Mas receptors. Ex vivo assays showed that BPP-5a induced endothelium-dependent vasorelaxation in isolated aortic rings of SHRs and WTs. Conclusions: Although the BPP-5a is considered an ACE inhibitor, our results indicate that its antihypertensive effect is exerted via a unique target, a nitric-oxide-dependent mechanism. Keywords:  angiotensin I-converting enzyme (ACE) inhibitor, blood pressure, bradykinin potentiating peptides, bradykinin receptors, nitric oxide Introduction The study of the pathophysiological mechanisms of poisoning and molecular characterization of toxins from Bothrops jararaca venom, resulted in two major relevant scientific contributions: the discovery of the potent vasodilator, bradykinin (Bk) [Rocha et al. 1949], and peptides that display Bk-potentiating activity [Ferreira, 1965; Ferreira et al. 1970a] and inhibition of somatic angiotensin I-converting enzyme (ACE) [Ferreira et al. 1970b]. These peptides were not only useful in validating ACE as a target to treat human hypertension, but also as model for captopril development, the first commercial ACE inhibitor [Ondetti and Cushman, 1981; Ondetti et al. 1977].

B. jararaca were identified using different approaches, such as functional assays followed by mass spectroscopy and molecular biology tools [Hayashi et al. 2003; Ianzer et al. 2004; Ondetti et al. 1977]. Typically, BPPs found in the B. jararaca venom [Ferreira et al. 1970a; Ianzer et al. 2004] and brain [Hayashi et al. 2003] are oligopeptides of 5 to 14 amino acid residues characterized by pyroglutamyl (