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- ItemAcesso aberto (Open Access)A ação cardiovascular dos peptídeos ricos em prolina da Bothrops jararaca não está relacionada com a inibição da enzima conversora de angiotensina I e potenciação da Bradicinina(Universidade Federal de São Paulo (UNIFESP), 2006-12-31) Ianzer, Danielle Alves [UNIFESP]; Camargo, Antonio Carlos Martins de [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)In the present study, were evaluated the cardiovascular effects of four Bradykinin Potentiating Peptides (BPPs) in spontaneously hypertensive rats (SHR). The peptides were selected from a family of 19 proline-rich oligopeptides found either in the venom of Bothrops jararaca or derived from the C-type natriuretic peptide precursor of the B. jararaca brain. These peptides were chosen for their distinct features concerning the in vitro and in vivo inhibition of the somatic angiotensin converting enzyme (ACE), and the ex-vivo and in vivo potentiation of bradykinin (BK). The experiments were performed in conscious adult male hypertensive rats (SHR) and normotensive rats (WT), with polyethylene catheters implanted into the femoral artery for the mean arterial pressure (MAP) and heart rate (HR) measurements, and into the femoral vein for drug administration. The MAP and HR were monitored for 6 hours after the intravenous injection of BPPs. All four BPPs showed potent cardiovascular effects in the range between 0.47 nmol/Kg and 710 nmol/Kg. The anti-hypertensive effect of BPPs was biphasic, presenting an initial reduction of MAP in the first 20 minutes after the peptide injection (acute period), folowing by other fall in 60-80 minutes after BPP and maintained for even of 6 hours (late period). The maximal change on MAP was observed using the BPP-10c at a dose of 71 nmol/Kg (-53 ± 6 mmHg). Differently from the other three BPPs, the BPP-7a presented a weak in vitro inhibition of the somatic ACE [Ki(app) ≅ 50 μM], and was unable to potentiate the BK, even at concentrations 100-fold higher than the concentrations used for the other peptides. However, the BPP-7a at a dose of 14.2 nmol/Kg caused the maximum MAP fall of the -45 ± 6 mmHg in SHR. In contrast, was showed that during the BPP antihypertensive effect in SHR there were not alteration of the BK hypotensive and the Ang I pressure responses, during both acute and late periods. These results indicate the participation non elucidated of mechanisms in the cardiovascular effects caused by these peptides. The action mediated by an orphan receptor has not been discarded. These characteristics open new perspectives for the use of BPPs as anti-hypertensive drugs.
- ItemAcesso aberto (Open Access)Avaliação das respostas cardiovasculares e simpáticas promovidas pela injeção de moxonidina no núcleo do trato solitário comissural de rato(Universidade Federal de São Paulo (UNIFESP), 2015-03-31) Alves, Thales Biffe [UNIFESP]; Colombari, Eduardo Colombari [UNIFESP]; Moreira, Thiago dos Santos [UNIFESP]; http://lattes.cnpq.br/0243906744273591; http://lattes.cnpq.br/4544450092427426; http://lattes.cnpq.br/0786967038980670; Universidade Federal de São Paulo (UNIFESP)Importantes drogas de ação anti-hipertensiva utilizadas na clínica médica são os agonistas adrenérgicos alfa2 e imidazólicos. Várias evidências têm sugerido que o efeito anti-hipertensivo desses fármacos é mediado, pelo menos em parte, pela ativação de receptores imidazólicos do tipo I1 presentes na região rostroventrolateral (RVL) do bulbo. Resultados do nosso grupo mostraram que a moxonidina pode produzir hipotensão por agir na região do núcleo do trato solitário comissural (NTScom). Experimentos in vitro mostraram que os efeitos hiperpolarizantes produzidos pela clonidina eram abolidos após a aplicação prévia do antagonista de receptores GABA-A bicuculina. Ademais, alguns trabalhos na literatura demonstraram que o bloqueio de receptores glutamatérgicos ionotrópicos no RVL foi capaz de prevenir a hipotensão produzida pela rilmenidina em ratos espontaneamente hipertensos. Desse modo, a nossa hipótese foi que a moxonidina, atuando em neurônios do NTScom e mediante sua ação integrada com receptores GABAérgicos e glutamatérgicos, poderia exercer os seus efeitos de hipotensão e simpato-inibição. Para isso, foram registrados a pressão arterial media e a atividade simpática do nervo esplâncnico. Foram utilizados ratos Wistar (250-350g, n = 6/grupo) anestesiados com uretano (1,2 g/kg, iv) e ventilados artificialmente. Nossos resultados evidenciaram que a injeção do antagonista de receptores adrenérgicos alfa2 ioimbina (10 nmol/50 nl) no NTScom foi capaz de bloquear as respostas hipotensora (Delta = -3 ± 2 mmHg, vs. moxonidina: Delta = -22 ± 4 mmHg) e a simpatoinibição (Delta = -2 ± 5%, vs. moxonidina: Delta = -26 ± 3% do basal) produzida pela injeção de moxonidina (5 nmol/50 nl) no NTScom. Similarmente, a injeção do antagonista de receptores GABAérgicos do sub-tipo A bicuculina (25 pmol/50 nl) na região do NTScom atenuou a hipotensão (Delta = -11 ± 3, vs. moxonidina: -28 ± 5 mmHg) e a simpatoinibição (Delta = - 13 ± 3% vs. moxonidina: Delta = -24 ± 2% do basal) promovida pela injeção de moxonidina no NTScom. Contudo, a administração do antagonista de receptores glutamatérgicos ionotrópicos ácido quinurênico (2,5 nmol/50 nl) na região do NTScom não foi efetivo em atenuar a hipotensão (Delta = -24 ± 3, vs. moxonidina: Delta = - 25 ± 9 mmHg) e a simpatoinibição (Delta = -22 ± 5% vs. moxonidina: Delta = -28 ± 9%, do basal) promovida pela injeção de moxonidina no NTScom. Os nossos resultados mostram também que as respostas hipotensoras e simpatoinibitórias promovidas pela injeção de moxonidina no NTScom não dependem da integridade dos neurônios catecolaminérgicos bulbo espinais da região rostroventrolateral do bulbo, sugerindo que os neurônios C1 não são essenciais para as respostas de redução da PA e atividade simpática exercida pela moxonidina. Assim, os efeitos anti-hipertensivos da moxonidina parecem carecer de mecanismos adrenérgicos alfa2 e GABAérgicos, mas não glutamatérgicos, pelo menos ionotrópicos, para exercer de forma significante o efeito hipotensor e simpatoinibitório.
- ItemAcesso aberto (Open Access)Divergences in antihypertensive therapy in special situations in nephrology(Associação Paulista de Medicina - APM, 2008-01-01) Lemos, Marcelo Montebello [UNIFESP]; Pedrosa, Alessandra Coelho [UNIFESP]; Tavares, Alze Pereira [UNIFESP]; Góes, Miguel Ângelo [UNIFESP]; Draibe, Sergio Antonio [UNIFESP]; Sesso, Ricardo de Castro Cintra [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)CONTEXT AND OBJECTIVE: The choice of an antihypertensive drug is based on several criteria and specific situations give rise to doubt and controversy. The aim here was to evaluate physicians approaches towards treatment with antihypertensive agents in specific situations. DESIGN AND SETTING: Cross-sectional study, at Universidade Federal de São Paulo (UNIFESP), São Paulo. METHODS: A questionnaire was applied during a nephrology meeting to evaluate individual approaches towards each hypothetical clinical situation. The questionnaire consisted of five multiple-choice questions (clinical cases) concerning controversial aspects of antihypertensive therapy. RESULTS: A total of 165 questionnaires were analyzed. Most participants were nephrologists (93.2%). There was a preference for angiotensin-converting enzyme (ACE) inhibitors in at least two of the cases. Only 57.2% of the physicians were correct in choosing beta-blockers as the first-line drugs for patients with ischemic coronary disease. Moreover, 66.2% chose ACE inhibitors as the first-line drugs for patients with chronic kidney disease and proteinuria. About 5% of the physicians did not follow the current recommendations for the use of ACE inhibitors in diabetic patients with microalbuminuria. The most controversial question concerned the first-line drug for advanced chronic kidney disease. Most physicians were correct in choosing calcium channel blockers and avoiding ACE inhibitors in renovascular hypertension in the case of a patient with a single functioning kidney. CONCLUSIONS: Most physicians adopted the correct approach, but some had an alternative strategy for the same situations that was not based on evidence.
- 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.
- ItemAcesso aberto (Open Access)Eficácia de hipotensores oculares tópicos após capsulotomia posterior(Conselho Brasileiro de Oftalmologia, 2008-10-01) Minello, Antonieta Antunes Pereira [UNIFESP]; Prata Junior, João Antonio [UNIFESP]; Mello, Paulo Augusto de Arruda [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)PURPOSE: To analyze and compare the effects on intraocular pressure (IOP) of several topic hypotensive agents after posterior capsulotomy with Nd:YAG laser in non glaucoma patients. METHODS: 145 pseudophakic eyes underwent to Nd:YAG laser posterior capsulotomy. Before capsulotomy. 21 were treated with apraclonidine, 20 with brimonidine, 23 with dorzolamide, 20 with latanoprost, 20 with pilocarpine, and 20 with timolol. Controls (21 eyes) received placebo. IOP measurements (Goldmann applanation tonometry) were taken under masked conditions 1 hour before procedure and after 1 and 2 hours. If postoperative PIO was above 20 mmHg its measurements were extended to 4 and 24 hours. Capsulotomy was performed with Abraham lens, under topic anesthetic, using Nd:YAG laser. Ocular hypertension would be considered if the IOP had suffered an increase of 4 mmHg above the initial. Mean total energy used was 2.1 ± 1 mJ. RESULTS: The preoperative IOP did not differ statistically among groups. Mean IOPs of treated eyes 1h (11.9 ± 3.8) and 2h (11.5 ± 3.0) were statistically lower than IOP compared with control group (12,6 ± 2,8) (p=0.001). There were no statistically significant differences for the other measurements. Control and pilocarpine had a percentual IOP increase after 2 hours of 8.7 ± 19.1% (13.5 ± 3.2 mmHg) and 1.2 ± 26.3% (12.5 ± 3.6 mmHg) respectively. Mean percentual postoperative IOP reduction was detected in the apraclonidine group -24.7 ± 15.5% (9.8 ± 2.6 mmHg), in the brimonidine group -8.9 ± 15.5% (10.1 ± 1.7 mmHg), in the dorzolamide group -6.9 ± 20.3% (12.1 ± 2.8 mmHg), in the latanoprost group -0.4 ± 25.9% (12.1 ± 2.9 mmHg) and in timolol group -16.2 ± 14.1% (10.3 ± 1.7 mmHg). These differences were statistically significant (p=0.001). There was no significant difference between frequencies of hypertension (p=0.148). CONCLUSION: Apraclonidine caused higher hypotensive effect after capsulotomy with YAG laser when compared with brimonidine, dorzolamide, latanoprost, pilocarpine, timolol and control group.
- ItemSomente MetadadadosEnvolvimento do óxido nítrico(NO) no relaxamento vascular produzido por frações da Cecropia glazioui Sneth com atividade hipertensora(Universidade Federal de São Paulo (UNIFESP), 2003) Ribeiro, Luciana Takahashi Carvalho [UNIFESP]; Lima-Landman, Maria Teresa Riggio de [UNIFESP]OBJETIVOS: O presente estudo teve como objetivos: 1) avaliar a participacao da via do oxido nitrico (NO) no relaxamento vascular produzido por fracoes da Cecropia glazioui Sneth em aneis de aorta de ratos normotensos (N) e espontaneamente hipertensos (SHR) e 2) quantificar a producao de NO por celulas endoteliais da linhagem CLPs na presenca do EA e da Fbut da planta. METODOS: Aneis de aorta toracica de ratos N e SHR, com ou sem endotelio, previamente contraidos por noradrenalina (10-7 M ou 10-6 M) foram incubados com concentracoes crescentes de EA (0,01 - 1 mg/mL) e de Fbut (1 - 100 mg/mL) da C. glazioui, na ausencia ou na presenca de atropina (10-6 M), de L-NAME (10-5 M) ou de indometacina (10-5 M). A concentracao de NO presente no sobrenadante das celulas endoteliais em cultura apos incubacao com o EA (0,01 - 1 mg/mL) ou com a Fbut (1 - 100 mg/mL) foi quantificada por um metodo amperometrico (NO-Meter). RESULTADOS: Aneis de aorta de ratos N ou de ratos SHR, relaxaram de forma concentracao-dependente na presenca do EA e da Fbut da C. glazioui. A incubacao com L-NAME ou a retirada do endotelio impediram o relaxamento induzido pelo EA e pela Fbut, demonstrando a dependencia de endotelio e o envolvimento do NO no efeito das fracoes. O efeito da Fbut, entretanto, tambem foi parcialmente bloqueado pela atropina, indicando a participacao de receptores muscarinicos nesta acao. Nas culturas de celulas endoteliais da linhagem CLPS, o EA (0,01 - 1 mg/mL), mas nao a Fbut (1 - 100 mg/mL), aumentou a producao de NO de forma concentracao-dependente. Este efeito foi bloqueado pela incubacao de L-NAME (10-5 M), indicando mais uma vez a participacao do NO no efeito vascular do EA. CONCLUSOES: Baseado nos resultados acima, podemos concluir que o EA da C. glazioui produz vasodilatacao atraves da producao de NO por estimulo da NOS ou fornecimento de substrato para a sintese de NO. Alem disso, o EA poderia agir tambem como anti-oxidante, aumentando, desta forma, a disponibilidade do NO. Em relacao a Fbut, apesar de ter seu efeito bloqueado pela remocao de endotelio vascular e pelo LNAME, esta fracao nao estimulou a producao de NO pelas celulas CLPs, indicando que no efeito da Fbut o envolvimento do NO nao seria o unico responsavel pela vasodilatacao promovida pela fracao
- ItemAcesso aberto (Open Access)A evolução do mercado farmacêutico brasileiro no tratamento do glaucoma nos últimos 30 anos(Conselho Brasileiro de Oftalmologia, 2003-12-01) Souza Filho, João Pessoa de [UNIFESP]; Dias, Ana Beatriz Toledo [UNIFESP]; Lima Filho, Acácio Alves de Souza [UNIFESP]; Sartori, Marta Filippi; Martins, Maria Cristina [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Faculdade de Medicina de JundiaíPURPOSE: To analyze price variations of drugs used to control glaucoma, during the last 30 years, at 10-year intervals. METHODS: Drugs to treat glaucoma, as well as their presentations and laboratories were selected from the 1972, 1982, 1992 and 2002 editions of the Dictionary of Pharmaceutical Specialties. The price of medicines in the Brazilian market were analyzed, in the different decades, using the pharmaceutical guide Brasíndice. For analysis of the data, the prices were converted to American dollars and the relationship between the medicine and the minimum wage was analyzed. As unit of the product, the values per milliliter, oral tablet or gram, depending on the presentation, were considered. RESULTS: The number of laboratories and antiglaucoma medications varied in the last thirty years. Drugs such as acetazolamide and pilocarpine still continue to be used. Parasympathomimetic drugs have predominantly been used in the first years of the study, and the beta-blockers in the last years. The average cost of available medications in the market has increased in the last decade. CONCLUSION: The price of antiglaucoma drugs varied considerably in the studied period as well as the type of drug used in the treatment.
- ItemSomente MetadadadosMicropartículas e doença cardiovascular hipertensiva: efeitos do tratamento anti-hipertensivo e hipolipemiante em micropartículas circulantes(Universidade Federal de São Paulo (UNIFESP), 2018-04-26) Massunaga, Nayara Dantas [UNIFESP]; Fonseca, Francisco Antonio Helfenstein [UNIFESP]; França, Carolina Nunes; http://lattes.cnpq.br/6580677601405775; http://lattes.cnpq.br/2393476657163442; http://lattes.cnpq.br/1470279541149956; Universidade Federal de São Paulo (UNIFESP)Introduction: Patients with hypertension on stage 2 are usually treated with a combination of two antihypertensive drugs. However, the combination including a diuretic or a calcium channel blocker may determine different effects on vessels, despite similar decrease on blood pressure. Objectives: This study aimed to compare the effects of amlodipinebased treatment with that obtained by hydrochlorothiazide monotherapy or sequentially combined with valsartan and addition and subsequent withdrawal of rosuvastatin on circulating microparticles. An exploratory analysis was also performed on the effects on central blood pressure parameters and vascular compliance. Methods: Prospective, randomized, openlabel with blinded outcomes study included patients of both sexes on stage 2 hypertension who remained for four weeks on the use of amlodipine (n = 24) or hydrochlorothiazide (n = 22) monotherapy. At the end of this period, blood samples were collected for protocol analyses and blood pressure data were obtained. Three sequential fourweek periods were followed at the end of which the mentioned laboratory and blood pressure parameters were obtained. In the second period valsartan 160 mg was added in both arms of the study, in the third rosuvastatin 20 mg and in the last rosuvastatin was suspended, and the antihypertensive treatment was maintained for four weeks. Monocytic, endothelial and platelet microparticles were quantified by flow cytometry and specific antibodies at the end of each intervention period. Results: Biochemical parameters and peripheral blood pressure were similar between the two groups at the end of treatment as monotherapy, as well as throughout the study. However, central pressure parameters were lower in the anlodipine arm from the addition of valsartan (p = 0.002) and did not change in the hydrochlorothiazide arm. The pulse wave velocity was not changed in both treatment groups. Circulating monocytic microparticles remained unchanged in the amlodipine group, but increased in the hydrochlorothiazide group (p = 0.02). For the circulating endothelial microparticles, a reduction with the hydrochlorothiazide group was observed throughout the study. With regard to circulating platelet microparticles, a greater amount was observed after suspension of rosuvastatin in the anlodipine arm. Conclusions: The choice of combination treatment based on amlodipine or hydrochlorothiazide has different effects on both circulating microparticles and synergism with other drugs. In addition, they show important differences in central hemodynamic parameters. These findings suggest differences in cardiovascular protection.
- ItemAcesso aberto (Open Access)Oral drugs for hypertensive urgencies: systematic review and meta-analysis(Associação Paulista de Medicina - APM, 2009-11-01) Souza, Luciana Mendes de [UNIFESP]; Riera, Rachel [UNIFESP]; Saconato, Humberto; Demathé, Adriana; Atallah, Álvaro Nagib [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Brazilian Cochrane Center; Universidade Federal do Rio Grande do Norte Department of Medicine; Universidade Estadual de São Paulo Department of Pathology and PropaedeuticsCONTEXT AND OBJECTIVE: Hypertensive urgencies are defined as severe elevations in blood pressure without evidence of acute or progressive target-organ damage. The need for treatment is considered urgent but allows for slow control using oral or sublingual drugs. If the increase in blood pressure is not associated with risk to life or acute target-organ damage, blood pressure control must be implemented slowly over 24 hours. For hypertensive urgencies, it is not known which class of antihypertensive drug provides the best results and there is controversy regarding when to use antihypertensive drugs and which ones to use in these situations. The aim of this review was to assess the effectiveness and safety of oral drugs for hypertensive urgencies. METHODS: This systematic review of the literature was developed at the Brazilian Cochrane Center, and in the Discipline of Emergency Medicine and Evidence-Based Medicine at the Universidade Federal de São Paulo (UNIFESP) - Escola Paulista de Medicina (UNIFESP-EPM), in accordance with the methodology of the Cochrane Collaboration. RESULTS: Sixteen randomized clinical trials including 769 participants were selected. They showed that angiotensin-converting enzyme inhibitors had a superior effect in treating hypertensive urgencies, evaluated among 223 participants. The commonest adverse event for calcium channel blockers were headache (35/206), flushing (17/172) and palpitations (14/189). For angiotensin-converting enzyme inhibitors, the principal side effect was bad taste (25/38). CONCLUSIONS: There is important evidence in favor of the use of angiotensin-converting enzyme inhibitors for treating hypertensive urgencies, compared with calcium channel blockers, considering the better effectiveness and the lower frequency of adverse effects (like headache and flushing).