RESUMO
BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.
Assuntos
COVID-19/complicações , Inflamação/etiologia , SARS-CoV-2/genética , Tromboembolia Venosa/etiologia , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Aprotinina/administração & dosagem , Aprotinina/uso terapêutico , Bélgica/epidemiologia , Bradicinina/efeitos dos fármacos , Bradicinina/metabolismo , COVID-19/epidemiologia , COVID-19/virologia , Cuidados Críticos/estatística & dados numéricos , Quimioterapia Combinada , Feminino , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Incidência , Inflamação/epidemiologia , Inflamação/metabolismo , Inflamação/prevenção & controle , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Calicreínas/efeitos dos fármacos , Calicreínas/metabolismo , Masculino , Avaliação de Resultados em Cuidados de Saúde , SARS-CoV-2/efeitos dos fármacos , Índice de Gravidade de Doença , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/metabolismo , Tromboembolia Venosa/prevenção & controleRESUMO
Angiotensin inhibitors have been extensively evaluated in clinical trials and have demonstrated significant reductions in morbidity and mortality following myocardial infarction and stroke, as well as in patients with heart failure or who are at risk of cardiovascular disease. Further, both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are frequently prescribed for the treatment of hypertension and to preserve renal function in patients with diabetes mellitus and chronic kidney disease. Angioedema is a known, but rare, adverse effect of ACEIs and ARBs. Therefore, it is important for clinicians to have a thorough understanding of risks and benefits of prescribing these medications, particularly in patients with a history of angioedema. This review describes the literature evaluating the incidence and cross-reactivity of angioedema with ACEIs and ARBs in order to provide guidance for clinical decision making.
Assuntos
Angioedema/induzido quimicamente , Angioedema/fisiopatologia , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Angioedema/imunologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bradicinina/efeitos dos fármacos , Humanos , Hipertensão/tratamento farmacológico , Incidência , Sistema Renina-Angiotensina/fisiologiaRESUMO
We present a patient with asymmetric oro-facial angioedema following thrombolysis for acute ischaemic stroke with serial photographs of this phenomenon. We discuss the mechanism for the development of asymmetric oro-facial oedema following thrombolysis and suggest a management plan.
Assuntos
Angioedema/induzido quimicamente , Isquemia Encefálica/complicações , Face/patologia , Fibrinolíticos/efeitos adversos , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/efeitos adversos , Idoso de 80 Anos ou mais , Angioedema/terapia , Bradicinina/efeitos dos fármacos , Bradicinina/metabolismo , Fibrinolíticos/administração & dosagem , Humanos , Masculino , Acidente Vascular Cerebral/etiologia , Ativador de Plasminogênio Tecidual/administração & dosagemAssuntos
Angioedema/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Fatores de Coagulação Sanguínea/uso terapêutico , Bradicinina/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Doenças da Laringe/tratamento farmacológico , Idoso , Angioedema/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico , Doenças da Laringe/induzido quimicamente , Masculino , Perindopril/efeitos adversos , Pirazinas/efeitos adversos , Fosfato de Sitagliptina , Resultado do Tratamento , Triazóis/efeitos adversosRESUMO
To evaluate the hypothesis that sphingosine-1-phosphate (S1P) and cAMP attenuate increased permeability of individually perfused mesenteric microvessels through a common Rac1-dependent pathway, we measured the attenuation of the peak hydraulic conductivity (L(p)) in response to the inflammatory agent bradykinin (BK) by either S1P or cAMP. We varied the extent of exposure to each agent (test) and measured the ratio L(p)(test)/L(p)(BK alone) for each vessel (anesthetized rats). S1P (1 µM) added at the same time as BK (concurrent, no pretreatment) was as effective to attenuate the response to BK (L(p) ratio: 0.14 ± 0.05; n = 5) as concurrent plus pretreatment with S1P for 30 min (L(p) ratio: 0.26 ± 0.06; n = 11). The same pretreatment with S1P, but with no concurrent S1P, caused no inhibition of the BK response (L(p) ratio 1.07 ± 0.11; n = 8). The rapid on and off action of S1P demonstrated by these results was in contrast to cAMP-dependent changes induced by rolipram and forskolin (RF), which developed more slowly, lasted longer, and resulted in partial inhibition when given either as pretreatment or concurrent with BK. In cultured endothelium, there was no Rac activation or peripheral cortactin localization at 1 min with RF, but cortactin localization and Rac activation were maximal at 1 min with S1P. When S1P was removed, Rac activation returned to control within 2 min. Because of such differing time courses, S1P and cAMP are unlikely to act through fully common effector mechanisms.
Assuntos
Bradicinina/farmacologia , Permeabilidade Capilar/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Microvasos/efeitos dos fármacos , Esfingosina/análogos & derivados , Vasodilatadores/farmacologia , Animais , Bradicinina/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Colforsina/farmacologia , AMP Cíclico/farmacologia , Masculino , Microvasos/fisiologia , Modelos Animais , Ratos , Rolipram/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Esfingosina/farmacologia , Fatores de Tempo , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
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 B(1), B(2), AT(1), AT(2) 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.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bradicinina/metabolismo , Hipertensão/tratamento farmacológico , Oligopeptídeos/farmacologia , Venenos de Víboras/farmacologia , Motivos de Aminoácidos , Animais , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Subunidades Proteicas/metabolismo , Ratos , Ratos Endogâmicos SHR , Vasodilatação/efeitos dos fármacos , Peçonhas/químicaRESUMO
OBJECTIVE: The present study was conducted to assess the anti-inflammatory effect of a crude aqueous extract of Bixa orellana leaves (AEBO) and to examine the possible involvement of nitric oxide (NO) in its anti-inflammatory mechanism. MATERIALS AND METHODS: The air-dried, powdered leaves were soaked in distilled water (1:20 w/v) at 50°C for 24 h and the supernatant obtained was freeze-dried (yield 8.5% w/w). The dosage was recorded as the mass of extract per kg b.w. of rats in all inflammatory assays (bradykinin-induced paw edema, peritoneal vascular permeability and NO assay). RESULTS: Pretreatment with AEBO for 4 consecutive days exhibited significant inhibitory activity against inflammatory models, the bradykinin-induced hind paw edema model and bradykinin-induced increased peritoneal vascular permeability at both doses in dose-dependent manner. In addition, AEBO was also found to significantly suppress the production of NO at doses of 50 and 150 mg/kg. CONCLUSION: This study provides scientific data to support the traditional use of B. orellana leaves in treating inflammation. Results from this study suggest that AEBO exerts anti-inflammatory effects. Part of this anti-inflammatory effect may be associated with its antibradykinin activity and may be related to a reduction of the NO production.
Assuntos
Anti-Inflamatórios/uso terapêutico , Bixaceae/química , Bradicinina/antagonistas & inibidores , Inflamação/tratamento farmacológico , Óxido Nítrico/antagonistas & inibidores , Extratos Vegetais/uso terapêutico , Análise de Variância , Animais , Bioensaio , Bradicinina/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Edema/tratamento farmacológico , Masculino , Óxido Nítrico/biossíntese , Ratos , Ratos Sprague-DawleyRESUMO
Angiotensin-converting enzyme (ACE) inhibitors improve outcomes in patients with coronary artery disease (CAD), heart failure, and hypertension. This short review examines clinical evidence for such effects and the underlying mechanism of action. One potential mode of action for ACE inhibitors in CAD is blood pressure reduction. However, recent data suggest that the effects of ACE inhibitors on the endothelium may also be relevant in attenuating the progression of atherosclerosis. In CAD, chronic overexpression of tissue ACE disrupts the angiotensin II/bradykinin balance with a net result of endothelial dysfunction, mainly due to an increased rate of apoptosis. An imbalance between endothelial apoptosis (death) and its renewal from the bone marrow (life) causes discontinuity of the endothelial layer, favoring the initiation and progression of a biochemical sequence that leads to atherosclerosis, plaque rupture, and eventually acute coronary syndromes. There is clinical and experimental evidence that ACE inhibition improves the life and death cycle of the endothelium. By restoring the bradykinin/angiotensin II balance, ACE inhibition reduces the rate of endothelial apoptosis and experimental results suggest that ACE inhibition can also improve the production and mobilization of endothelial progenitor cells from bone marrow. We report our experience in this context with perindopril.
Assuntos
Síndrome Coronariana Aguda/prevenção & controle , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doença da Artéria Coronariana/terapia , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Insuficiência Cardíaca/terapia , Hipertensão/terapia , Prevenção Secundária , Angiotensina II/efeitos dos fármacos , Angiotensina II/metabolismo , Apoptose/efeitos dos fármacos , Aterosclerose/complicações , Aterosclerose/metabolismo , Bradicinina/efeitos dos fármacos , Bradicinina/metabolismo , Cardiotônicos/uso terapêutico , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/fisiopatologia , Progressão da Doença , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiologia , Endotélio Vascular/fisiopatologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/etiologia , Hipertensão/fisiopatologia , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Perindopril/uso terapêutico , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/patologia , Placa Aterosclerótica/fisiopatologia , Placa Aterosclerótica/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Células-Tronco/fisiologiaRESUMO
BACKGROUND: The objective of this study was to investigate whether reduction of cyclic circumferential stretch will impair endothelial function and elevate basal levels of oxidative stress, both known risk factors linked to cardiovascular disease. METHODS: Ex vivo and in vitro models were used to perfuse porcine carotid arteries and porcine endothelial cells, respectively, for 24 h. In both cases, one group was allowed to stretch naturally when exposed to a pulse shear stress (6+/-3 dynes/cm(2)) combined with a pulse pressure of 80+/-10 mmHg, yielding a physiological cyclic stretch of 4-5%. This group was compared to a reduced stretch group, achieved by wrapping the arterial segment with a silicon band or by seeding the endothelial cells inside less compliant tubes, decreasing cyclic stretch to 1%. RESULTS: The experimentally reduced compliance caused a significant decrease in bradykinin-dependent vascular relaxation. Reduced compliance significantly decreased the phosphorylation of serine 1177 (Ser1177) on eNOS, suggesting the activity of eNOS was decreased. Overall production of reactive oxygen species was increased by reducing compliance, as visualized with DHE. Finally, p22-phox and p47-phox, key players in the superoxide-generating NAD(P)H oxidase, were also up-regulated by reduced compliance. CONCLUSIONS: These findings point out how reduced arterial compliance increases the risk of arterial disease by creating a less functional endothelium, interrupting the eNOS activation pathway, and increasing the vascular levels of oxidative stress.
Assuntos
Artéria Carótida Interna/fisiologia , Endotélio Vascular/fisiologia , Mecanotransdução Celular/fisiologia , Estresse Oxidativo , Adaptação Fisiológica , Animais , Bradicinina/efeitos dos fármacos , Artéria Carótida Interna/efeitos dos fármacos , Células Cultivadas , Complacência (Medida de Distensibilidade)/efeitos dos fármacos , Complacência (Medida de Distensibilidade)/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Mecanotransdução Celular/efeitos dos fármacos , Modelos Animais , NADPH Oxidases/biossíntese , Óxido Nítrico Sintase Tipo III/metabolismo , Fluxo Pulsátil , Espécies Reativas de Oxigênio/metabolismo , Resistência ao Cisalhamento/efeitos dos fármacos , Resistência ao Cisalhamento/fisiologia , Estresse Mecânico , Suínos , Resistência à Tração/efeitos dos fármacos , Resistência à Tração/fisiologia , Regulação para Cima , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
Hereditary angioedema (HAE) is a rare familial disease characterized by recurrent self-limiting episodes of soft tissue swelling affecting different parts of the body. Acute HAE attacks range from benign, but disfiguring skin edema, to painful abdominal, and even life-threatening laryngeal attacks. The disease is caused by an aberrant C1 esterase inhibitor (C1-INH), which regulates complement, fibrinolytic, and contact pathways. Elevated serum level of bradykinin as a result of contact pathway activation is thought to be the major mediator of pain and edema formation in HAE. Current therapy of acute HAE attacks is limited and mainly offers symptom control. In the United States only fresh frozen plasma provides some reconstitution of C1-INH, but the efficacy and safety of this treatment is controversial. In some European countries two human derived C1-INH concentrates have been used successfully. Prophylactic therapy for patients with frequent HAE attacks is confined to attenuated androgens and in some countries anti-fibrinolytics and C1-INH are also used. To satisfy the unmet needs, investigation of one recombinant C1-INH, two drugs working on bradykinin pathway and two human derived C1-INH concentrates are underway. This review article also discusses some recent patents related to the filed.
Assuntos
Angioedema/terapia , Bradicinina/efeitos dos fármacos , Proteínas Inativadoras do Complemento 1/uso terapêutico , Androgênios/uso terapêutico , Angioedema/genética , Angioedema/fisiopatologia , Animais , Antifibrinolíticos/uso terapêutico , Bradicinina/sangue , Proteínas Inativadoras do Complemento 1/metabolismo , Europa (Continente)/epidemiologia , Humanos , Patentes como Assunto , Plasma , Proteínas Recombinantes , Estados Unidos/epidemiologiaRESUMO
The roles of kinin and protease-activated receptors (PAR) in endothelium-dependent relaxations to the serine protease, trypsin, were examined in rings of bovine left anterior descending coronary artery (LAD). Trypsin (0.01-30 U/ml) caused biphasic, endothelium-dependent relaxations-a high potency (0.01-0.3 U/ml), low efficacy relaxation [maximum relaxation (R (max)), 9.0 +/- 5.1%] followed by a lower potency (1-30 U/ml) but high efficacy (R (max), 90.4 +/- 5.5%) relaxation, which was abolished by aprotinin. Captopril (10 microM) caused an approximately 10-fold leftward shift of the second phase response such that the first phase was masked. The second phase relaxation to trypsin was inhibited in a concentration-dependent, non-surmountable manner by the B2 antagonist, HOE-140. At 3 nM HOE-140, the second phase response to trypsin was abolished unmasking the first phase. Kallikrein (0.0003-0.3 U/ml) caused monophasic, endothelium-dependent relaxations (R (max), 33.7 +/- 14.6%), which were potentiated by captopril (R (max), 94.2 +/- 1.0%) and abolished by HOE-140. In the presence of captopril, the second phase relaxation to trypsin was only minimally inhibited by either N(G)-nitro-L: -arginine (100 microM) or 67 mM [K(+)](o) alone but markedly reduced when these two treatments were combined (R (max), 26.1 +/- 11.6% versus 98.6 +/- 2.9% in controls). The PAR1-activating peptide, SFLLRN (0.1-30 microM), but not the PAR2-activating peptide, SLIGRL, caused concentration-dependent relaxations (pEC(50), 5.9 +/- 0.0%; R (max), 43.3 +/- 8.3%). In conclusion, trypsin causes endothelium-dependent relaxations in the bovine LAD predominantly via release of endogenous BK, which in turn activates endothelial B2 receptors. Only a minor role for PAR1-like receptors was evident in this tissue.
Assuntos
Bradicinina/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Receptor B2 da Bradicinina/efeitos dos fármacos , Tripsina/farmacologia , Animais , Bradicinina/administração & dosagem , Bradicinina/análogos & derivados , Bradicinina/metabolismo , Bradicinina/farmacologia , Captopril/farmacologia , Bovinos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Calicreínas/administração & dosagem , Calicreínas/farmacologia , Receptor B2 da Bradicinina/metabolismo , Receptor PAR-1/efeitos dos fármacos , Receptor PAR-1/metabolismo , Tripsina/administração & dosagem , Vasodilatação/efeitos dos fármacosRESUMO
Regulation of the kallikrein-kinin system in cerebral inflammation is still unclear. Here, we used reverse-transcription polymerase chain reaction (RT-PCR) techniques to show that lipopolysaccharide (LPS) activates the kallikrein-kinin system by enhancing liberation of bradykinin (BK), and alters mRNA levels of kallikrein-kinin system components, including high molecular weight (H-) and low molecular weight (L-) kininogens, in ECPC4 cells, a cell line of mouse choroid plexus epithelium. LPS treatment increased liberation of immunoreactive bradykinin in the supernatant of ECPC4 cells, and addition of LPS (500 ng/ml) to cultures resulted in elevation of H- and L-kininogen mRNA levels in ECPC4 cells within 24-48 h. Furthermore, LPS treatment elevated bradykinin type 2 and type 1 receptor mRNA levels within 4h, but did not change tissue kallikrein or plasma kallikrein mRNA levels. On the other hand, expression of pro-inflammatory mediators interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and cyclooxygenase-2 mRNA increased within 4-8h after addition of LPS to ECPC4 cells. The addition of IL-1beta and TNF-alpha to investigate the major mediator for kininogen expression in ECPC4 cells remarkably induced expression of H- and L-kininogen mRNAs in ECPC4 cells. These results suggest that LPS activates the kallikrein-kinin system in the choroid plexus via autocrine induction of IL-1beta and TNF-alpha.
Assuntos
Plexo Corióideo/metabolismo , Citocinas/genética , Encefalite/líquido cefalorraquidiano , Mediadores da Inflamação/metabolismo , Calicreínas/líquido cefalorraquidiano , Cininas/líquido cefalorraquidiano , Animais , Bradicinina/líquido cefalorraquidiano , Bradicinina/efeitos dos fármacos , Bradicinina/genética , Linhagem Celular , Líquido Cefalorraquidiano/metabolismo , Plexo Corióideo/efeitos dos fármacos , Plexo Corióideo/fisiopatologia , Ciclo-Oxigenase 2/genética , Encefalite/induzido quimicamente , Encefalite/fisiopatologia , Interleucina-1beta/genética , Interleucina-1beta/farmacologia , Calicreínas/efeitos dos fármacos , Calicreínas/genética , Cininas/efeitos dos fármacos , Cininas/genética , Lipopolissacarídeos , Camundongos , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores da Bradicinina/efeitos dos fármacos , Receptores da Bradicinina/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
Kinins have been suggested to be involved in human airway diseases such as asthma and rhinitis. MEN16132 is a non-peptide kinin B(2) receptor antagonist able to inhibit the responses produced by intravenous bradykinin into the airways, as bronchoconstriction and microvascular leakage; we tested the effect of MEN16132 on endogenously generated bradykinin through the dextran sulfate-induced contact activation of kinin-kallikrein cascade in guinea-pigs. After dextran sulfate administration (1.5 mg/kg i.v.), the pulmonary insufflation pressure was monitored and the microvascular leakage of upper and lower airways was assessed using Evans blue as tracer of plasma protein extravasation. Our results demonstrated that topical MEN16132 strongly inhibited the dextran sulfate-induced bronchoconstriction (0.3 mM solution aerosol for 5 min) and plasma protein extravasation in both lower airways (3-10 microM solution aerosol for 5 min) and nasal mucosa (0.3 nmol/nostril); Icatibant, the peptide antagonist of kinin B(2) receptor, exerted a 3-30-fold less potent inhibitory effect than MEN16132. We conclude that local application of MEN16132 into the airways abolishes the responses produced by the endogenous generation of bradykinin and it can be useful as new pharmacological tool to check the role of kinins in human diseases.
Assuntos
Antagonistas de Receptor B2 da Bradicinina , Bradicinina/efeitos dos fármacos , Broncoconstrição/efeitos dos fármacos , Ornitina/análogos & derivados , Sulfonamidas/farmacologia , Administração Intranasal , Aerossóis , Animais , Proteínas Sanguíneas/metabolismo , Bradicinina/administração & dosagem , Bradicinina/análogos & derivados , Bradicinina/metabolismo , Bradicinina/farmacologia , Sulfato de Dextrana , Relação Dose-Resposta a Droga , Cobaias , Sistema Calicreína-Cinina/efeitos dos fármacos , Masculino , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Ornitina/administração & dosagem , Ornitina/farmacologia , Sulfonamidas/administração & dosagemRESUMO
BACKGROUND AND PURPOSE: Inhibition of bradykinin metabolizing enzymes (BMEs) can cause acute angioedema, as demonstrated in a recent clinical trial in patients administered the antihypertensive, omapatrilat. However, the relative contribution of specific BMEs to this effect is unclear and confounded by the lack of a predictive pre-clinical model of angioedema. EXPERIMENTAL APPROACH: Rats were instrumented to record blood pressure and heart rate; inhibitors were infused for 35 min and bradykinin was infused during the last 5 min to elicit hypotension, as a functional marker of circulating bradykinin and relative angioedema risk. KEY RESULTS: In the presence of omapatrilat bradykinin produced dose-dependent hypotension, an effect abolished by B(2) blockade. In the presence of lisinopril (ACE inhibitor), but not candoxatril (NEP inhibitor) or apstatin (APP inhibitor), bradykinin also elicited hypotension. Lisinopril-mediated hypotension was unchanged with concomitant blockade of NEP or NEP/DPPIV (candoxatril+A-899301). However, hypotension was enhanced upon concomitant blockade of APP and further intensified in the presence of NEP inhibition to values not different from omapatrilat alone. CONCLUSIONS AND IMPLICATIONS: We demonstrated that bradykinin is degraded in vivo with an enzyme rank-efficacy of ACE>APP>>NEP or DPPIV. These results suggest the effects of omapatrilat are mediated by inhibition of three BMEs, ACE/APP/NEP. However, dual inhibition of ACE/NEP or ACE/NEP/DPPIV elicits no increased risk of angioedema compared to ACE inhibition alone. Thus, novel BME inhibitors must display no activity against APP to avoid angioedema risk due to high prevalence of ACE inhibitor therapy in patients with diabetes and cardiovascular disease.
Assuntos
Angioedema/etiologia , Bradicinina/metabolismo , Inibidores Enzimáticos/farmacologia , Hipotensão/etiologia , Aminopeptidases/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Bradicinina/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Indanos/farmacologia , Lisinopril/farmacologia , Masculino , Neprilisina/antagonistas & inibidores , Peptídeos/farmacologia , Propionatos/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Tiazepinas/administração & dosagem , Tiazepinas/farmacologiaRESUMO
The prevalence of type 2 diabetes is increasing worldwide, and prevention of the disease is a key objective. Several clinical trials reported a consistent reduction in the incidence of newly diagnosed diabetes in high-risk patients treated with renin-angiotensin system-inhibiting drugs. In all those trials, however, diabetes reduction was either a post-hoc analysis result or a secondary endpoint. Therefore, we need the results of ongoing specific prospectively designed trials, with new-onset diabetes as the principal endpoint.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Tecido Adiposo/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Bradicinina/sangue , Bradicinina/efeitos dos fármacos , Doenças Cardiovasculares/mortalidade , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Resistência à Insulina , Pâncreas/irrigação sanguínea , Potássio/sangue , Sistema Renina-Angiotensina/efeitos dos fármacosAssuntos
Angioedema/induzido quimicamente , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Angioedema/diagnóstico , Angioedema/fisiopatologia , Angioedema/terapia , Antagonistas de Receptores de Angiotensina , Anti-Hipertensivos/efeitos adversos , Bradicinina/efeitos dos fármacos , Bradicinina/fisiologia , Dipeptidil Peptidase 4/efeitos dos fármacos , Dipeptidil Peptidase 4/fisiologia , Monitoramento de Medicamentos , Humanos , Incidência , Lisina Carboxipeptidase/efeitos dos fármacos , Lisina Carboxipeptidase/fisiologia , Seleção de Pacientes , Sistema Renina-Angiotensina/efeitos dos fármacos , Fatores de RiscoRESUMO
OBJECTIVE: Brief reversible ischemic episodes (ischemic preconditioning, IPC) protect the heart against arrhythmias during a subsequent prolonged low-flow ischemia. We have recently shown that this protection involves release of bradykinin, activation of bradykinin B2 receptors followed by opening of sarcolemmal, but not mitochondrial ATP-sensitive K+ channels. The goal of this study was to clarify a trigger and/or mediator role of bradykinin in the antiarrhythmic effects of IPC during low-flow ischemia. METHODS: Isolated perfused rat hearts underwent 60 minutes of low-flow ischemia induced by reducing perfusion pressure followed by 60 minutes of reperfusion. Preconditioning was induced by 2 x 5 minutes episodes of zero-flow ischemia. In yet other groups, preconditioned or non-preconditioned hearts were treated either with bradykinin (10 nmol/L) or with HOE 140 (bradykinin B2 receptor antagonist, 100 nmol/L). RESULTS: IPC reduced the number of ventricular premature beats, as well as the incidence of ventricular tachycardia and of ventricular fibrillation during low-flow ischemia. In addition, this protection was abolished by HOE 140 given during low-flow ischemia. Pharmacological preconditioning using short bradykinin perfusion instead of IPC did not show antiarrhythmic effects. However, bradykinin administered during low-flow ischemia and reperfusion reduced the number of ventricular premature beats and the incidence of ventricular tachycardia and of ventricular fibrillation during low-flow ischemia. CONCLUSION: Bradykinin is a mediator, but unlikely a trigger, of antiarrhythmic effects of IPC during low-flow ischemia.
Assuntos
Bradicinina/metabolismo , Ventrículos do Coração/metabolismo , Precondicionamento Isquêmico Miocárdico/métodos , Taquicardia Ventricular/etiologia , Fibrilação Ventricular/etiologia , Animais , Bradicinina/análogos & derivados , Bradicinina/efeitos dos fármacos , Bradicinina/farmacologia , Antagonistas dos Receptores da Bradicinina , Modelos Animais de Doenças , Progressão da Doença , Eletrocardiografia , Frequência Cardíaca/fisiologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Masculino , Projetos Piloto , Prognóstico , Ratos , Ratos Sprague-Dawley , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/prevenção & controle , Fibrilação Ventricular/metabolismo , Fibrilação Ventricular/prevenção & controleRESUMO
BACKGROUND: The beneficial effects of angiotensin converting enzyme (ACE)-inhibitors are in part mediated through the inhibition of the degradation of the vasodilator bradykinin. The bradykinin effect is counteracted by cyclooxygenase-inhibitors. Angiotensin receptor blockers (ARBs) do not affect bradykinin. AIMS: To test the hypothesis that renal counteraction from a cyclooxygenase-inhibitor, diclofenac, is different in subjects treated with an ACE-inhibitor, enalapril compared with an ARB, losartan. METHODS: Twelve elderly, healthy, slightly over-hydrated subjects received diclofenac orally after pre-treatment with a diuretic, bendroflumethiazide, and enalapril or bendroflumethiazide and losartan, in a double-blind cross-over fashion, with a wash-out period of at least 1 week. RESULTS: Diclofenac reduced GFR significantly from 81(64-98) ml/min at first observations after dose for enalapril to 29(16-42) and from 76(64-88) after losartan to 35(24-46). There was no significant difference between enalapril and losartan in GFR. Diclofenac induced decreases in urine flow, excretion rates and clearances of sodium, osmolality clearance and free water clearance, irrespective of treatment with enalapril or losartan. However, serum potassium and handling of potassium were significantly lower after losartan-treatment. CONCLUSION: The negative renal effects of diclofenac administration in subjects with activation of the renin-angiotensin system and enalapril treatment are the same in subjects with activation of the renin-angiotensin system and losartan treatment.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bradicinina/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Diclofenaco/efeitos adversos , Enalapril/farmacologia , Insuficiência Cardíaca/fisiopatologia , Losartan/farmacologia , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Diuréticos/farmacologia , Diuréticos/uso terapêutico , Enalapril/uso terapêutico , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Rim/fisiopatologia , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina/efeitos dos fármacos , Fatores de TempoRESUMO
Advances in our understanding of the molecular mechanisms underlying hereditary angioedema (HAE) have led to the development of new treatment modalities. Five new drugs for the treatment of HAE are currently undergoing clinical testing in the United States. These novel therapeutics can be divided into two groups: drugs that replace C1 inhibitor (C1INH) functional activity and drugs that abrogate the bradykinin-mediated increase in vascular permeability associated with HAE attacks. The first group includes two plasma-derived C1INH concentrates as well as a recombinant transgenic human C1INH protein, and the second group includes an engineered plasma kallikrein inhibitor as well as a B2 bradykinin receptor antagonist. This article reviews the rationale, development, and potential use of these novel therapeutics.
Assuntos
Angioedema/tratamento farmacológico , Animais , Bradicinina/antagonistas & inibidores , Bradicinina/efeitos dos fármacos , Ensaios Clínicos como Assunto , Proteína Inibidora do Complemento C1/metabolismo , Proteína Inibidora do Complemento C1/uso terapêutico , Humanos , Calicreínas/antagonistas & inibidores , Calicreínas/efeitos dos fármacos , Proteínas Recombinantes/uso terapêuticoRESUMO
Traumatic brain injury (TBI) mortality and morbidity remains a public health challenge. Because experimental studies support an important role of bradykinin (BK) in the neurological deterioration that follows TBI, a double-blind, randomized, placebo-controlled study of Anatibant (LF16- 0687Ms), a selective and potent antagonist of the BK B(2) receptor, was conducted in severe (Glasgow Coma Scale [GCS] < 8) TBI patients (n = 25) at six sites in the United States. At 8-12 h after injury (9.9 +/- 2.8 h), patients received a single subcutaneous injection of Anatibant (3.75 mg or 22.5 mg, n = 10 each) or placebo (n = 5). The primary objective was to investigate the pharmacokinetics of Anatibant; general safety, local tolerability, levels of the bradykinin metabolite BK1-5 in plasma and cerebrospinal fluid (CSF), intracranial pressure (ICP), and cerebral perfusion pressure were also assessed. We observed a dose-proportionality of the pharmacokinetics, Cmax, and AUC of Anatibant. V(d)/F, Cl/F, and t(1/2) were independent on the dose and protein binding was >97.7%. Anatibant, administered as single subcutaneous injections of 3.75 g and 22.5 mg, was well tolerated in severe TBI patients with no unexpected clinical adverse events or biological abnormalities observed. Interestingly, plasma and CSF levels of BK1-5 were significantly and markedly increased after trauma (e.g., 34,700 +/- 35,300 fmol/mL in plasma vs. 34.9 +/- 5.6 fmol/mL previously reported for normal volunteers), supporting the use of Anatibant as a treatment of secondary brain damage. To address this issue, a dose-response trial that would investigate the effects of Anatibant on the incidence of raised ICP and on functional outcome in severe TBI patients is needed.