Navegando por Palavras-chave "Angiotensin I-converting enzyme"
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- ItemAcesso aberto (Open Access)Carbamazepine inhibits angiotensin I-converting enzyme, linking it to the pathogenesis of temporal lobe epilepsy(Nature Publishing Group, 2012-03-01) Almeida, Sandro Soares [UNIFESP]; Naffah-Mazzacoratti, Maria da Graca [UNIFESP]; Guimarães, Paola Bianchi [UNIFESP]; Wasinski, Frederick [UNIFESP]; Pereira, Flavia Enira Gomes [UNIFESP]; Canzian, Mauro [UNIFESP]; Centeno, Ricardo Silva [UNIFESP]; Carrete Junior, Henrique [UNIFESP]; Yacubian, Elza Márcia Targas [UNIFESP]; Carmona, Adriana Karaoglanovic [UNIFESP]; Vieira, Renata de Freitas Fischer [UNIFESP]; Nakaie, Clovis Ryuichi [UNIFESP]; Sabatini, Regiane Angelica [UNIFESP]; Perosa, Sandra Regina [UNIFESP]; Bacurau, Reury Frank Pereira; Gouveia, Telma Luciana Furtado [UNIFESP]; Gallo, Gloria [UNIFESP]; Wuertele, Martin [UNIFESP]; Cavalheiro, Esper Abrão [UNIFESP]; Silva Junior, Jose Antonio [UNIFESP]; Pesquero, João Bosco [UNIFESP]; Araujo, Ronaldo de Carvalho [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Universidade de São Paulo (USP); Nove de Julho Univ UNINOVEWe find that a common mutation that increases angiotensin I-converting enzyme activity occurs with higher frequency in male patients suffering from refractory temporal lobe epilepsy. However, in their brains, the activity of the enzyme is downregulated. As an explanation, we surprisingly find that carbamazepine, commonly used to treat epilepsy, is an inhibitor of the enzyme, thus providing a direct link between epilepsy and the renin-angiotensin and kallikrein-kinin systems. Translational Psychiatry (2012) 2, e93; doi:10.1038/tp.2012.21; published online 13 March 2012
- ItemAcesso aberto (Open Access)The chronic blockade of angiotensin I-converting enzyme eliminates the sex differences of serum cytokine levels of spontaneously hypertensive rats(Assoc Bras Divulg Cientifica, 2013-02-01) Dalpiaz, Polyana Lima Meireles; Lamas, Aline Zandonadi; Caliman, Izabela Facco; Medeiros, Ana Raquel Santos de; Abreu, Glaucia Rodrigues de; Moyses, Margareth Ribeiro; Andrade, Tadeu Uggere; Alves, Márcio Fernando [UNIFESP]; Carmona, Adriana Karaoglanovic [UNIFESP]; Bissoli, Nazare Souza; Univ Fed Espirito Santo; Inst Fed Espirito Santo; Ctr Univ Vila Velha; Universidade Federal de São Paulo (UNIFESP)Sex hormones modulate the action of both cytokines and the renin-angiotensin system. However, the effects of angiotensin I-converting enzyme (ACE) on the proinflammatory and anti-inflammatory cytokine levels in male and female spontaneously hypertensive rats (SHR) are unclear. We determined the relationship between ACE activity, cytokine levels and sex differences in SHR. Female (F) and male (M) SHR were divided into 4 experimental groups each (n = 7): sham + vehicle (SV), sham + enalapril (10 mg/kg body weight by gavage), castrated + vehicle, and castrated + enalapril. Treatment began 21 days after castration and continued for 30 days. Serum cytokine levels (ELISA) and ACE activity (fluorimetry) were measured. Male rats exhibited a higher serum ACE activity than female rats. Castration reduced serum ACE in males but did not affect it in females. Enalapril reduced serum ACE in all groups. IL-10 (FSV = 16.4 +/- 1.1 pg/mL; MSV = 12.8 +/- 1.2 pg/mL), TNF-alpha (FSV = 16.6 +/- 1.2 pg/mL; MSV = 12.8 +/- 1 pg/mL) and IL-6 (FSV = 10.3 +/- 0.2 pg/mL; MSV = 7.2 +/- 0.2 pg/mL) levels were higher in females than in males. Ovariectomy reduced all cytokine levels and orchiectomy reduced IL-6 but increased IL-10 concentrations in males. Castration eliminated the differences in all inflammatory cytokine levels (IL-6 and TNF-alpha) between males and females. Enalapril increased IL-10 in all groups and reduced IL-6 in SV rats. in conclusion, serum ACE inhibition by enalapril eliminated the sexual dimorphisms of cytokine levels in SV animals, which suggests that enalapril exerts systemic anti-inflammatory and anti-hypertensive effects.
- ItemAcesso aberto (Open Access)A diversidade estrutural de peptídeos potenciadores da bradicinina da Bothrops jararaca (Bj-BPPs) proporciona ações sinérgicas no sistema cardiovascular(Universidade Federal de São Paulo (UNIFESP), 2010-03-31) Morais, Kátia Luciano Pereira [UNIFESP]; Camargo, Antonio Carlos Martins de [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Our laboratory has shown that one gene codes for the protein precursor that yields the natriuretic peptide type C (CNP) after having been processed, along with a variety of proline-rich peptides, known as bradykinin-potentiating peptides or BPPs. Showing little differences, this precursor is expressed in the venom gland and the neuroendocrine region of the Bothrops jararaca brain. All processing products have in common that they act on the cardiovascular system, lowering arterial blood pressure and heart frequency. This intriguing fact led us to question whether the different peptides display similar mechanisms of action. Surprisingly, the present study showed that the answer is negative, although we cannot, at the present time, explain in full detail how each peptide acts in the complex mechanism, responsible for vascular tonus and cardiac frequency. Historically, the demonstration that the Bradykinin-Potentiating Peptides from Bothrops jararaca (Bj-BPPs) were natural inhibitors of the angiotensin converting enzyme (ACE) had a wide medical impact. In fact, this inhibition seemed to fully explain the strong anti-hypertensive action of these peptides, therefore being employed as structural models for the development of a site-directed inhibitor, Captopril, a drug used worldwide for the treatment of systemic human arterial hypertension. Recent experimental evidences, however, suggest that the anti-hypertensive activity of the Bj-BPPs is not due exclusively to the inhibition of the ACE. Our group demonstrated that the antihypertensive action of Bj-BPP-10c, for instance, is due to the activation of L-arginine generation, which is essential for NO production, a potent vasodilator. Moreover, it also regulates the arterial baroreflex and intracellular calcium signaling, which contribute to NO production in endothelial and neuronal cells. In the present work we studied the mechanism of action of other Bj-BPPs found in the above mentioned precursor. We showed that the mechanism of action of Bj-BPP-5a involves bradykinin B2 receptor, the muscarinic receptor, subtype M1, and NO production. Bj-BPP-11e probably acts on a membrane receptor, thereby explaining its effects on cardiovascular parameters. The mechanism of action of Bj-BPP-12b might be explained by Bk potentiation and/or by ACE inhibition and Bj- BPP-13a action on by muscarinic receptor subtype M3 and the ASS. Interestingly, Bj-BPP-9a, which was the model molecule for the synthesis of Captopril, seems to act predominantly as a classic ACE inhibitor. Beside the pharmacological interest, our work also revealed, for the first time, that snake toxins also employ the well-known strategy in hormone-peptide generation, that is, they use the processing of a polyprotein to generate peptides which display a synergistic action.
- ItemSomente MetadadadosParamagnetic bradykinin analogues as substrates for angiotensin I-converting enzyme: Pharmacological and conformation studies(Academic Press Inc Elsevier Science, 2016) Teixeira, Luis Gustavo de Deus [UNIFESP]; Malavolta, Luciana; Bersanetti, Patricia Alessandra [UNIFESP]; Schreier, Shirley; Carmona, Adriana Karaoglanovic [UNIFESP]; Nakaie, Clovis Ryuichi [UNIFESP]This study uses EPR, CD, and fluorescence spectroscopy to examine the structure of bradykinin (BK) analogues attaching the paramagnetic amino acid-type Toac (2,2,6,6-tetramethylpiperidine-1-oxyl-4-a mino-4-carboxylic acid) at positions 0, 3, 7, and 9. The data were correlated with the potencies in muscle contractile experiments and the substrate properties towards the angiotensin I-converting enzyme (ACE). A study of the biological activities in guinea pig ileum and rat uterus indicated that only Toac(0)-BK partially maintained its native biological potency among the tested peptides. This and its counterpart, Toac3-BK, maintained the ability to act as ACE substrates. These results indicate that peptides bearing Toac probe far from the ACE cleavage sites were more susceptible to hydrolysis by ACE. The results also emphasize the existence of a finer control for BK-receptor interaction than for BK binding at the catalytic site of this metallodipetidase. The kinetic kcat/ Km values decreased from 202.7 to 38.9 mu M-1 min(-1) for BK and Toac3-BK, respectively. EPR, CD, and fluorescence experiments reveal a direct relationship between the structure and activity of these paramagnetic peptides. In contrast to the turn-folded structures of the Toac-internally labeled peptides, more extended conformations were displayed by N-or C-terminally Toac-labeled analogues. Lastly, this work supports the feasibility of monitoring the progress of the ACE-hydrolytic process of Toac-attached peptides by examining time-dependent EPR spectral variations. (C) 2016 Elsevier Inc. All rights reserved.
- ItemSomente MetadadadosPlasma Kallikrein and Angiotensin I-converting enzyme N- and C-terminal domain activities are modulated by the insertion/deletion polymorphism(Churchill Livingstone, 2010-04-01) Almeida, S. S. [UNIFESP]; Barros, C. C. [UNIFESP]; Moraes, M. R. [UNIFESP]; Russo, F. J. [UNIFESP]; Haro, A. S. [UNIFESP]; Rosa, T. S. [UNIFESP]; Alves, M. F. [UNIFESP]; Pesquero, J. B. [UNIFESP]; Carmona, A. K. [UNIFESP]; Bacurau, Reury Frank Pereira; Araujo, R. C. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Universidade de São Paulo (USP)Angiotensin I-converting enzyme (ACE) is recognized as one of the main effector molecules involved in blood pressure regulation. in the last few years some polymorphisms of ACE such as the insertion/deletion (I/D) polymorphism have been described, but their physiologic relevance is poorly understood. in addition, few studies investigated if the specific activity of ACE domain is related to the I/D polymorphism and if it can affect other systems. the aim of this study was to establish a biochemical and functional characterization of the I/D polymorphism and correlate this with the corresponding ACE activity. for this purpose, 119 male brazilian army recruits were genotyped and their ACE plasma activities evaluated from the C- and N-terminal catalytic domains using fluorescence resonance energy transfer (FRET) peptides, specific for the C-domain (Abz-LFK(Dnp)OH), N-domain (Abz-SDK(Dnp)P-OH) and both C- and N-domains (Abz-FRK(Dnp)P-OH). Plasma kallikrein activity was measured using Z-Phe-Arg-AMC as substrate and inhibited by selective plasma kallikrein inhibitor (PKSI). Some physiological parameters previously described related to the I/D polymorphism such as handgrip strength, blood pressure, heart rate and BMI were also evaluated. the genotype distribution was II n = 27, ID n = 64 and DD n = 28. Total plasma ACE activity of both domains in II individuals was significantly lower in comparison to ID and DD. This pattern was also observed for C- and N-domain activities. Difference between ID and DD subjects was observed only with the N-domain specific substrate. Blood pressure, heart rate, handgrip strength and BMI were similar among the genotypes. This polymorphism also affected the plasma kallikrein activity and DD group presents high activity level. Thus, our data demonstrate that the I/D ACE polymorphism affects differently both ACE domains without effects on handgrip strength. Moreover, this polymorphism influences the kallikrein-kinin system of normotensive individuals. (C) 2009 Elsevier B.V. All rights reserved.
- ItemSomente MetadadadosSpectroscopic and structural analysis of somatic and N-domain angiotensin I-converting enzyme isoforms from mesangial cells from Wistar and spontaneously hypertensive rats(Elsevier B.V., 2010-08-01) Andrade, Maria C. C. de [UNIFESP]; Affonso, Regina [UNIFESP]; Fernandes, Fernanda B. [UNIFESP]; Febba, Andreia C. [UNIFESP]; Silva, Ismael D. C. G. da [UNIFESP]; Stella, Regina C. R. [UNIFESP]; Marson, Odair [UNIFESP]; Jubilut, Guita N. [UNIFESP]; Hirata, Izaura Y. [UNIFESP]; Carmona, Adriana K. [UNIFESP]; Corradi, Hazel; Acharya, K. Ravi; Sturrock, Edward D.; Casarini, Dulce E. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); IPEN CNEN SP; Univ Bath; Univ Cape TownAngiotensin I-converting enzyme (ACE) plays a key role in the renin-angiotesin aldosterone cascade. We analysed the secondary structure and structural organization of a purified 65 kDa N-domain ACE (nACE) from Wistar rat mesangial cells, a 90 kDa nACE from spontaneously hypertensive rats and a 130 kDa somatic ACE. the C-terminal alignment of the 65 kDa nACE with rat ACE revealed that the former was truncated at Ser(482), and the sequence of the 90 kDa nACE ended at Pro(629). Protein's secondary structure consisted predominantly of a-helices. the 90 and 65 kDa isoforms were the most stable in guanidine and at low pH, respectively. Enzymatic activity decreased with loss in secondary structure, except in the case of guanidine HCl where the 90 kDa fragment loses its secondary structure faster than its enzymatic activity. We identified and characterized the activity and stability of these isoforms and these findings would be helpful on the understanding of the role of nACE isoforms in hypertension. (C) 2010 Elsevier B.V. All rights reserved.