RESUMO
INTRODUCTION: Amiodarone is the gold standard in the prevention of recurrence of atrial fibrillation (AF), but the causes for its superior clinical efficacy are not understood. We hypothesized that atrial electrical remodeling increases the atrial efficacy of amiodarone. METHODS AND RESULTS: We investigated the effect of an acute intravenous dose of amiodarone on atrial refractory periods (AERP) in sinus rhythm (SR) and after 5, 24, and 72 hours of atrial tachypacing in comparison with the I(Kr) blocker dofetilide and the I(to)/IKur blockers AVE1231 and AVE0118 in five instrumented goats. Electrical remodeling progressively increased the AERP-prolonging effect of 3 mg/kg of AVE1231 and AVE0118 (2-fold increase in AERP at 72 hours vs SR, P < 0.01), but strongly decreased that of 10 mug/kg dofetilide (<0.5-fold, P < 0.05, at 300 and 400 ms basic cycle length). After 5 and 24 hours of tachypacing, the effect of 3 mg/kg amiodarone strongly increased (2-fold, P < 0.01 after 24 hours vs SR). This early gain in AERP prolongation was confirmed in anesthetized pigs with 3.5 hours of atrial tachypacing (2.4-fold increase, P < 0.01). At 72 hours of atrial tachypacing in the goat, however, the early gain was lost and the effect of amiodarone was similar again to that in SR. CONCLUSION: Atrial electrical remodeling changed the efficacy of the antiarrhythmic agents in a different way. The favorable efficacy profile of amiodarone during electrical remodeling, particularly the marked increase in AERP prolongation in early electrical remodeling, may explain its superior clinical efficacy over existing antiarrhythmic drugs.
Assuntos
Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Função Atrial/efeitos dos fármacos , Compostos de Bifenilo/administração & dosagem , Sistema de Condução Cardíaco/fisiologia , Fenetilaminas/administração & dosagem , Bloqueadores dos Canais de Potássio/administração & dosagem , Sulfonamidas/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Feminino , Cabras , Sistema de Condução Cardíaco/efeitos dos fármacos , Injeções Intravenosas , Masculino , SuínosRESUMO
The reduction and control of allergens in the animal facility is important for staff working with laboratory animals. This study was designed to evaluate the efficiency of perforated Makrolon curtains in front of racks as a method to reduce the amount of allergen in the animal room. The experimental situation we studied provides some information regarding allergen disposition in animal rooms but is clearly artificial and does not reflect a typical, 'real-world' environment in terms of preventing exposure of workers to allergens. Plastic curtains with holes were placed in front of racks, and a corridor between the racks and a curtain was present. The room was ventilated with air, which was blown into the room through the middle of the corridor, flowing downstream and passing through the holes in the curtain. This set-up resulted in air flow from the corridor through the curtain. Air samples were collected from sites in the corridor and behind the curtain. The samples were analyzed for the allergen Mus m1, and the amount of allergen was calculated. The results show air flow from the aisle through the holes in the curtains and through the racks behind the curtains, and this flow keeps allergen behind the curtains and prevents its spread from the cages into the aisle. The present study shows that the use of curtains in front of the cage racks is an efficient way to prevent spread of allergens from rodent cages to the entire animal room.
Assuntos
Poluentes Ocupacionais do Ar/análise , Poluição do Ar em Ambientes Fechados/prevenção & controle , Alérgenos/análise , Abrigo para Animais , Camundongos/imunologia , Exposição Ocupacional/prevenção & controle , Animais , Animais de Laboratório , Humanos , Exposição por Inalação , Pessoal de Laboratório Médico , VentilaçãoRESUMO
A markedly decreased aortic nitric oxide (NO) availability, probably due to impaired endothelial nitric oxide synthase activity with enhanced O2- and peroxynitrite production, seems to be attributable to endothelial dysfunction in spontaneously hypertensive rats (SHR) with severe congestive heart failure (CHF). In this study, we investigated the chronic effect of the angiotensin-converting enzyme inhibitor, ramipril (RA) and the loop diuretic, frusemide (FU), as well as the combination of both on endothelial NO, O2- and peroxynitrite production in aortae from SHR with failing hearts after myocardial infarction (MI). Heart failure was induced by permanent occlusion of the left coronary artery. SHR were randomised to receive either placebo, RA, (1 mg/kg/day), FU (4 mg/kg/day) or RA+FU (1 and 4 mg/kg/day, respectively). Treatments were started two weeks following MI and continued for six weeks. Reduced aortic and coronary flow indices in the working heart, which can be considered as markers for endothelial function, were significantly normalised and improved, respectively, by RA, FU or RA+FU-treatment. Similarly, all three treatment regimens significantly enhanced the reduced calcium ionophore (CaI)-induced NO-release (assessed by a NO-sensitive microsensor) from aortic endothelial cells of placebo-treated animals with CHF. Concomitantly, the increased CaI-stimulated O2- production (assessed by an electrochemical sensor) in aortic endothelial cells of placebo-treated animals with CHF was significantly reduced by RA and RA+FU-treatment. Treatment with RA and RA+FU also attenuated the dramatic increase in endothelial peroxynitrite concentration (chemiluminescence method), which was observed in placebo-treated rats with CHF. FU did not counteract improved haemo- and cardiodynamic parameters by RA. Thus, RA and FU act synergistically to enhance bioavailability of endothelium-derived NO, and this may contribute to the clinical usefulness of the combination of these drugs in treatment of heart failure.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Hipertensão/tratamento farmacológico , Infarto do Miocárdio/complicações , Óxido Nítrico/metabolismo , Ramipril/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Endotélio Vascular/metabolismo , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/metabolismo , Masculino , Contração Miocárdica/efeitos dos fármacos , Ácido Peroxinitroso/metabolismo , Ratos , Ratos Endogâmicos SHR , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Cardiac angiotensin converting enzyme (ACE) is activated by an increase in wall stress and is involved in remodeling processes. Heart failure is often treated with ACE inhibitors and diuretics although diuretic treatment could activate the renin-angiotensin system (RAS). AIMS: To examine the effects of diuretic treatment on cardiac and circulating RAS in post-infarction chronic heart failure. METHODS: Myocardial infarction was produced by coronary artery ligation in spontaneously hypertensive rats. The rats were randomly assigned to receive either ramipril (1 mg/kg/day), furosemide (4 mg/kg/day), or combination therapy for 6 weeks, commencing 2 weeks after infarction. RESULTS: All three treatment protocols equivalently attenuated reactive hypertrophy of the right ventricle and ventricular septum and improved left ventricular systolic function. Both cardiac ACE mRNA and activity were significantly increased in untreated rats. This increase was attenuated by both ramipril and furosemide and further depressed by the combination. The increase in activity was completely inhibited by either agent alone. Plasma renin activity was upregulated by ramipril or ramipril plus furosemide but not influenced by infarction or furosemide alone. CONCLUSIONS: Furosemide and ramipril significantly reduced cardiac ACE and remodeling. Diuretics work favorably and do not interfere with the effects of ACE inhibitors. Possibly, a reduction in wall stress due to decreased volume overload accounts for the effects of diuretics on cardiac ACE in the treatment of post-infarction remodeling in hypertensive hearts. These data suggest a new mechanism for the frequently observed beneficial effect of diuretics in heart failure.
Assuntos
Diuréticos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Doença Crônica , Modelos Animais de Doenças , Quimioterapia Combinada , Furosemida/uso terapêutico , Insuficiência Cardíaca/mortalidade , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/mortalidade , Masculino , Modelos Cardiovasculares , Infarto do Miocárdio/mortalidade , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Placebos , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ramipril/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Ratos Endogâmicos SHR , Renina/sangue , Renina/efeitos dos fármacos , Estatística como Assunto , Análise de Sobrevida , Resultado do Tratamento , Pressão Ventricular/efeitos dos fármacos , Pressão Ventricular/fisiologia , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/fisiologiaRESUMO
Extracellular matrix (ECM) remodeling and increased matrix metalloproteinase (MMP) expression and activity have been observed to be relevant in the development of heart failure (HF). We examined the effects of ramipril alone or with furosemide on ECM in a heart failure model. HF was induced by occlusion of the left coronary artery in spontaneously hypertensive rats (SHR). Rats were assigned to placebo (n=9), ramipril 1 mg/kg/day (n=11), furosemide 2 x 2 mg/kg/day (n=7) or both (1 mg/kg/day + 2 x 2 mg/kg/day n=8). LV-function, collagen content, MMP/TIMP (tissue inhibitor of matrix metalloproteinases) protein- and mRNA-expression were examined in non-infarcted LV tissue. MMP-2/TIMP-4 ratio was increased in HF. Ramipril reduced MMP-2 expression (active form), collagen type I mRNA expression and content and increased TIMP-4 levels associated with decreased left ventricular end diastolic pressure (LVEDP), mortality rate and increased LV pressure (LVP). Combination therapy with furosemide is less efficient with regard to collagen content and MMP-2 (active form) reduction but did not worsen beneficial effects of ramipril on LV function and mortality rate. Furosemide alone had no effect on MMP-2 (active form) expression, collagen content, LV function and mortality rate. Prevention of LV dilatation by ramipril was associated with decreased gelatinolytic activity and increased MMP-inhibition in heart failure SHR. Furthermore, ramipril reduced fibrosis by enhanced interstitial collagenase expression. Furosemide did not show the beneficial effects of ramipril on ECM remodeling but did not worsen LV function. Positive effects of furosemide treatment alone on LV remodeling and function were not observed.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Diuréticos/farmacologia , Furosemida/farmacologia , Insuficiência Cardíaca/metabolismo , Ramipril/farmacologia , Remodelação Ventricular/fisiologia , Animais , Matriz Extracelular/fisiologia , Proteínas da Matriz Extracelular/fisiologia , Coração/fisiologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Masculino , Metaloendopeptidases/fisiologia , Infarto do Miocárdio/complicações , Miocárdio/patologia , Ratos , Ratos Endogâmicos SHRRESUMO
The expression of adrenomedullin (AM) and atrial natriuretic factor (ANF) were investigated in the myocardium of a rat model of chronic ischemic heart failure (CHF) compared with sham-operated controls. In addition, human myocardium of patients with end-stage heart failure due to idiopathic dilated cardiomyopathy compared with myocardium of normal subjects (NF) was studied. In CHF, similar AM levels but increased ANF expression were observed in left ventricular myocardium, as assessed by semiquantitative PCR. Functional experiments with freshly excised papillary muscles showed no influence of AM on myocardial contractility. In NF human myocardium, the expression of AM mRNA was threefold higher in atrial compared with ventricular tissue. In analogy, ANF mRNA was increased by approximately 15-fold in atrial tissue. In dilated cardiomyopathy, the expression of AM was significantly increased in right and left ventricles compared with NF. In parallel, ventricular ANF expression was enhanced.