RESUMO
The objective of this study was to investigate the effects of a flaxseed-supplemented diet on archaeal abundance and gene expression of methanogens in the rumen of dairy cows. In all, 11 non-lactating dairy cows were randomly divided into two groups: group A (five cows) and B (six cows). The two diets fed were: (1) the control diet, a conventional dry cow ration; and (2) the flaxseed-supplemented diet, the conventional dry cow ration adjusted with 12.16% ground flaxseed incorporated into the total mixed ration. A cross-over experiment was performed with the two groups of cows fed the two different diets for five 21-day periods, which included the first adaptation period followed by two treatment and two wash out periods. At the end of each feeding period, rumen fluid samples were collected via rumenocentesis and DNA was extracted. Quantitative PCR was utilized to analyze the gene abundance of 16S ribosomal RNA (16S rRNA) targeting the ruminal archaea population and the mcrA gene coding for methyl coenzyme-M reductase subunit A, a terminal enzyme in the methanogenesis pathway. Results demonstrated a 49% reduction of 16S rRNA and 50% reduction of mcrA gene abundances in the rumen of dairy cows fed the flaxseed-supplemented diet in comparison with those fed the control diet. This shows flaxseed supplementation effectively decreases the methanogenic population in the rumen. Future studies will focus on the mechanisms for such reduction in the rumen of dairy cattle, as well as the relationship between methanogenic gene expression and methane production.
Assuntos
Bovinos/microbiologia , Suplementos Nutricionais , Linho , Methanomicrobiales/efeitos dos fármacos , Rúmen/microbiologia , Animais , Bovinos/fisiologia , DNA Bacteriano/análise , Dieta/veterinária , Feminino , Genes Bacterianos/genética , Metano/biossíntese , Methanomicrobiales/genética , Reação em Cadeia da Polimerase/veterinária , RNA Ribossômico 16S/análise , RNA Ribossômico 16S/genética , Rúmen/efeitos dos fármacosRESUMO
BACKGROUND: Although the benefit of implantable cardioverter defibrillator (ICD) therapy in patients with hypertrophic cardiomyopathy (HCM) at risk for sudden cardiac arrest is well established, there may be a higher risk for device complications and inappropriate shocks. OBJECTIVES: To determine the incidence of inappropriate ICD shocks and device complications in HCM patients and the impact of young age at ICD implant and atrial fibrillation. METHODS: HCM patients who underwent ICD implantation between January 1988 and December 2005 were included. The frequency of device complications, including pneumothorax, pericardial effusion, haematoma, lead revisions, infection and rate of inappropriate shocks, was determined. ICD shocks were characterised as inappropriate if triggered by sinus tachycardia, atrial fibrillation or device malfunction. RESULTS: A total of 181 patients were included (mean age 44 (SD 17) years; 62% males). During a mean follow-up of 59 (42) months (4.92 years; 830.75 patient-years), 65 patients (36%) had a total of 88 device complications, including 42 (23%) patients with inappropriate shocks. The rate of inappropriate shocks was 5.3% per year (vs 4% risk of appropriate shocks), and the likelihood of inappropriate ICD shocks per 100 patient-years was 5.1. Younger age and atrial fibrillation were associated with an increased risk of inappropriate ICD discharges. CONCLUSIONS: The rate of inappropriate ICD shocks and frequency of device complications in HCM patients are not insignificant and are most common in younger patients and those with atrial fibrillation. Inappropriate ICD shocks are the most common device complication and should be accounted for when counselling high-risk HCM patients for ICD implantation.
Assuntos
Fibrilação Atrial/terapia , Cardiomiopatia Hipertrófica/complicações , Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis/efeitos adversos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatia Hipertrófica/mortalidade , Criança , Pré-Escolar , Competência Clínica , Falha de Equipamento , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Retrospectivos , Medição de Risco , Adulto JovemAssuntos
Apêndice Atrial/diagnóstico por imagem , Cardiopatias/diagnóstico por imagem , Trombose/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Ablação por Cateter , Ecocardiografia Transesofagiana , Reações Falso-Negativas , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios/métodos , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: Cardiac resynchronisation therapy (CRT) improves outcomes in selected patients with heart failure and left ventricular dysfunction. One mechanism of benefit is believed to be favourable ventricular remodelling. Whether CRT also decreases the frequency of ventricular arrhythmias and risk of sudden death is unknown. OBJECTIVE: To determine the effect of CRT on frequency of ventricular arrhythmias and appropriate ICD therapies. DESIGN: Retrospective cohort study. SETTING: Single-centre, tertiary care facility (Mayo Clinic). PATIENTS: 52 patients (46 male), aged 70 (SD 10) years, who underwent upgrade from an implantable cardioverter defibrillator (ICD) to a CRT-defibrillator were included. INTERVENTIONS: Upgrade of ICD to CRT-defibrillator. MAIN OUTCOME MEASURES: Frequency of ventricular arrhythmias prior to and following upgrade to CRT device. RESULTS: Ejection fraction increased from 22% (SD 8%) to 27% (SD 11%) following CRT. However, the frequency of non-sustained ventricular arrhythmias, sustained ventricular arrhythmias, and ventricular fibrillation was not significantly changed prior to and following CRT (2.38 (SD 9.78) vs 58.51 (SD 412.73) per patient per month, p = 0.66; 0.07 (SD 0.17) vs 0.16 (SD 0.52), p = 0.70; 0.05 (SD 0.12) vs 0.25 (SD 1.40), p = 0.12). CONCLUSIONS: CRT is not associated with a decrease in the frequency of ventricular arrhythmia or appropriate device therapy. Thus, use of CRT alone is not beneficial in decreasing the frequency of ventricular arrhythmias or the risk of appropriate ICD therapies.
Assuntos
Arritmias Cardíacas/prevenção & controle , Desfibriladores Implantáveis , Insuficiência Cardíaca/terapia , Coração Auxiliar , Marca-Passo Artificial , Idoso , Arritmias Cardíacas/etiologia , Morte Súbita Cardíaca/prevenção & controle , Feminino , Humanos , Masculino , Implantação de Prótese/métodos , Estudos Retrospectivos , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento , Remodelação Ventricular/fisiologiaAssuntos
Cardiomiopatia Hipertrófica/terapia , Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis , Taquicardia Ventricular/terapia , Cardiomiopatia Hipertrófica/mortalidade , Morte Súbita Cardíaca/epidemiologia , Humanos , Medição de Risco , Taxa de Sobrevida , Taquicardia Ventricular/mortalidadeRESUMO
OBJECTIVES: The purpose of this study was to examine the impact of sulfonylurea drug use on outcome in diabetic patients undergoing direct coronary angioplasty for acute myocardial infarction. BACKGROUND: Sulfonylurea drugs impair ischemic preconditioning. Whether sulfonylurea drugs affect outcome adversely in diabetic patients undergoing direct angioplasty for acute myocardial infarction is unknown. METHODS: Clinical outcomes after direct balloon angioplasty for acute myocardial infarction were evaluated in 67 diabetic patients taking oral sulfonylurea drugs and 118 diabetic patients not taking these drugs. RESULTS: Hospital mortality was significantly higher among diabetics treated with sulfonylurea drugs at the time of myocardial infarction (24% vs. 11%). Univariate analysis identified sulfonylurea drug, age, ventricular function, ejection fraction less than 40%, prior bypass surgery and congestive heart failure as correlates of increased in-hospital mortality. Logistic regression found sulfonylurea drug use (odds ratio 2.77, p=0.017) to be independently associated with early mortality. Congestive heart failure, but not sulfonylurea drug use, was associated with an increased incidence of in-hospital ventricular arrhythmias. Congestive heart failure, prior bypass surgery and female gender, but not sulfonylurea drug use, were associated with late adverse events. CONCLUSIONS: Sulfonylurea drug use is associated with an increased risk of in-hospital mortality among diabetic patients undergoing coronary angioplasty for acute myocardial infarction. This early risk is not explained by an increase in ventricular arrhythmias, but may reflect deleterious effects of sulfonylurea drugs on myocardial tolerance for ischemia and reperfusion. For surviving patients sulfonylurea drug use is not associated with an increased risk of serious late adverse events.
Assuntos
Angioplastia Coronária com Balão , Diabetes Mellitus Tipo 2/mortalidade , Angiopatias Diabéticas/mortalidade , Mortalidade Hospitalar , Hipoglicemiantes/efeitos adversos , Infarto do Miocárdio/mortalidade , Compostos de Sulfonilureia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/terapia , Angiopatias Diabéticas/terapia , Feminino , Seguimentos , Hemodinâmica/efeitos dos fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Razão de Chances , Análise de Regressão , Risco , Compostos de Sulfonilureia/administração & dosagem , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Myocardial ischemia and infarction are associated with substantially increased morbidity and mortality among patients with diabetes mellitus. Although many factors contribute to the increased morbidity and mortality, in patients with non-insulin-dependent (type II) diabetes mellitus, one contributor may be the use of sulfonylurea drugs, the most widely used oral hypoglycemic agents. Such a possibility, which first arose over a 25 years ago when it was observed that patients taking sulfonylurea drugs had increased cardiovascular mortality, has recently resurfaced after the discovery that sulfonylureas act by inhibiting adenosine triphosphate (ATP)-sensitive potassium channels. In the pancreas, inhibition of ATP-sensitive potassium channels induces release of insulin; but in the heart, inhibition of these channels prevents ischemic preconditioning, an endogenous cardioprotective mechanism that protects the heart from lethal injury. This review outlines the current understanding of the molecular and cellular pharmacodynamics of sulfonylurea drugs and discusses the potential clinical consequences of inhibition of ATP-sensitive potassium channels in the heart of diabetic patients with cardiac disease in whom the use of sulfonylureas may be harmful.
Assuntos
Complicações do Diabetes , Cardiopatias/complicações , Coração/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Compostos de Sulfonilureia/farmacologia , Animais , Diabetes Mellitus/fisiopatologia , Coração/fisiopatologia , Cardiopatias/tratamento farmacológico , Cardiopatias/fisiopatologia , Humanos , Hipoglicemiantes/uso terapêutico , Precondicionamento Isquêmico Miocárdico , Pâncreas/efeitos dos fármacos , Bloqueadores dos Canais de Potássio , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/fisiologia , Compostos de Sulfonilureia/uso terapêuticoRESUMO
OBJECTIVES: The purpose of this study was to determine the risk of epicardial lead failure during long-term follow-up and its mode of presentation. BACKGROUND: Despite the high prevalence of epicardial lead-based implantable cardioverter-defibrillators, their long-term performance is unknown, and appropriate follow-up has not been established. METHODS: The study group comprised all patients in whom an epicardial lead system was implanted at the Mayo Clinic between October 31, 1984 and November 3, 1994. The number of lead fractures and leads with fluid within the insulation and the mode of presentation were determined retrospectively by review of patient visits, radiographs of lead systems and data derived from formal lead testing. RESULTS: At 4 years, the survival rate free of lead malfunction, using formal lead testing, for 160 Medtronic epicardial patches (models 6897 and 6921) was 72% compared with 92.5% for the 179 Cardiac Pacemaker, Inc. (CPI) patches (models 0040 and 0041) (p = 0.01). In addition, five Medtronic patches in three patients had fluid within the lead insulation but no obvious fracture. No CPI patches had fluid identified within the leads. Of 330 Medtronic epicardial pace/sense leads (model 6917), the 4-year survival rate free of lead malfunction as assessed by lead testing was 96%. In all, 19 presentations of lead malfunction were found in 17 patients (2 patients had more than one lead fracture at different times). In 11 (58%) of these presentations, the patients were asymptomatic despite the presence of obvious lead fracture. CONCLUSIONS: Epicardial lead malfunction is common on long-term follow-up, and some leads have a failure rate of 28% at 4 years. Many patients with fractured leads remain asymptomatic, despite involvement of multiple leads in some cases. Therefore, consideration should be given to regular periodic lead testing in addition to routine X-ray examination, as asymptomatic lead malfunction can present with normal chest X-ray findings.
Assuntos
Desfibriladores Implantáveis/estatística & dados numéricos , Idoso , Fatores de Confusão Epidemiológicos , Falha de Equipamento/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , PericárdioAssuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Coração/efeitos dos fármacos , Hipoglicemiantes/efeitos adversos , Infarto do Miocárdio/mortalidade , Canais de Potássio/efeitos dos fármacos , Compostos de Sulfonilureia/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Diabetes Mellitus Tipo 2/complicações , Seguimentos , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Ativação do Canal Iônico/efeitos dos fármacos , Tábuas de Vida , Infarto do Miocárdio/complicações , Compostos de Sulfonilureia/farmacologia , Compostos de Sulfonilureia/uso terapêutico , Análise de Sobrevida , Resultado do TratamentoRESUMO
The mechanism by which ATP-sensitive K+ (KATP) channels open in the presence of inhibitory concentrations of ATP remains unknown. Herein, using a four-state kinetic model, we found that the nucleotide diphosphate UDP directed cardiac KATP channels to operate within intraburst transitions. These transitions are not targeted by ATP, nor the structurally unrelated sulfonylurea glyburide, which inhibit channel opening by acting on interburst transitions. Therefore, the channel remained insensitive to ATP and glyburide in the presence of UDP. "Rundown" of channel activity decreased the efficacy with which UDP could direct and maintain the channel to operate within intraburst transitions. Under this condition, the channel was sensitive to inhibition by ATP and glyburide despite the presence of UDP. This behavior of the KATP channel could be accounted for by an allosteric model of ligand-channel interaction. Thus, the response of cardiac KATP channels towards inhibitory ligands is determined by the relative lifetime the channel spends in a ligand-sensitive versus -insensitive state. Interconversion between these two conformational states represents a novel basis for KATP channel opening in the presence of inhibitory concentrations of ATP in a cardiac cell.
Assuntos
Trifosfato de Adenosina/fisiologia , Ativação do Canal Iônico/fisiologia , Miocárdio/metabolismo , Canais de Potássio/metabolismo , Eletrofisiologia , Glibureto/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Cinética , Ligantes , Potenciais da Membrana/fisiologia , Modelos Biológicos , Técnicas de Patch-Clamp , Difosfato de Uridina/farmacologiaRESUMO
A defining property of ATP-sensitive K+ (K[ATP]) channels is inhibition by sulfonylurea drugs, yet the response of cardiac K[ATP] channels toward sulfonylureas during myocardial ischemia is not consistent. Altered channel sensitivity toward sulfonylureas has, in part, been ascribed to antagonism by cytosolic nucleotide diphosphates, although the mechanism of interaction remains unclear. Herein, in inside-out patches excised from cardiomyocytes, we observed a dual response of K[ATP] channels toward the sulfonylurea drug, glyburide, in the presence of cytosolic UDP. Specifically, glyburide failed to inhibit spontaneous K[ATP] channel activity in the presence of UDP but inhibited UDP-induced channel activity after rundown of spontaneous channel openings. Such behavior of K[ATP] channels cannot be explained by differences in the level of channel activity or by UDP-induced displacement of glyburide. Rather, the dual response toward the sulfonylurea could be attributed to a property of K[ATP] channels to switch between operative conditions (spontaneous versus UDP-induced) each associated with a distinct responsiveness toward ligands. Conversion of post-rundown K[ATP] channels to the spontaneously operative channel condition, by Mg-ATP, restored the ability of UDP to antagonize the inhibitory action of glyburide lost after rundown, suggesting that the response of the channel to glyburide is phosphorylation dependent. The existence of distinct operative conditions of cardiac K[ATP] channels could be the basis for the inconsistent response of the channel toward sulfonylurea drugs and should be considered when sulfonylureas are used to implicate the opening of K[ATP] channels in the myocardium.
Assuntos
Trifosfato de Adenosina/fisiologia , Miocárdio/metabolismo , Canais de Potássio/metabolismo , Compostos de Sulfonilureia/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Interações Medicamentosas , Glibureto/farmacologia , Cobaias , Miocárdio/citologia , Bloqueadores dos Canais de Potássio , Canais de Potássio/efeitos dos fármacos , Difosfato de Uridina/farmacologiaRESUMO
Opening of ATP-sensitive K+ (KATP) channels by the uncoupler of oxidative phosphorylation, 2,4 dinitrophenol (DNP), has been assumed to be secondary to metabolic inhibition and reduced intracellular ATP levels. Herein, we present data which show that DNP (200 microM) can induce opening of cardiac KATP channels, under whole-cell and inside-out conditions, despite millimolar concentrations of ATP (1-2. 5 mm). DNP-induced currents had a single channel conductance (71 pS), inward rectification, reversal potential, and intraburst kinetic properties (open time constant, tauopen: 4.8 msec; fast closed time constant, tauclosed(f): 0.33 msec) characteristic of KATP channels suggesting that DNP did not affect the pore region of the channel, but may have altered the functional coupling of the ATP-dependent channel gating. A DNP analogue, with the pH-titrable hydroxyl replaced by a methyl group, could not open KATP channels. The pH-dependence of the effect of DNP on channel opening under whole-cell, cell-attached, and inside-out conditions suggested that transfer of protonated DNP across the sarcolemma is essential for activation of KATP channels in the presence of ATP. We conclude that the use of DNP for metabolic stress-induced KATP channel opening should be reevaluated.
Assuntos
Trifosfato de Adenosina/metabolismo , Dinitrofenóis/farmacologia , Coração/fisiologia , Ativação do Canal Iônico/fisiologia , Miocárdio/metabolismo , Canais de Potássio/metabolismo , Sarcolema/metabolismo , Desacopladores/farmacologia , Animais , Cobaias , Coração/efeitos dos fármacos , Técnicas In Vitro , Ativação do Canal Iônico/efeitos dos fármacos , Miocárdio/citologia , Canais de Potássio/efeitos dos fármacos , Sarcolema/efeitos dos fármacosRESUMO
This study used the colorimetric MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide)] assay to assess cell viability in isolated quiescent adult guinea-pig ventricular myocytes exposed to different insults or cardioprotective conditions, including adenosine and hyperkalemic-cardioplegia. Optical density (OD), reflecting intracellular reduction of MTT into formazan pigment formation, was a function of the number of viable cells (coefficient of linear correlation approximately 0.99), with MTT reduction preferentially carried out by rod-shaped cardiomyocytes (absorbance at 1.009 +/- 0.013 and 0.006 +/- 0.001 OD units for populations containing 50 and 0% of rod-shaped cells). Following prolonged mechanical (pressure of 1 lb/min for 40 min), chemical (10% DMSO or ethanol) or hypoxic injury (N2-saturated solution), the MTT reductase activity reflected reduction in the number of viable cells by 87%, >50%, and 77%, respectively. In cardiomyocytes exposed to a 40 min hypoxia (with CO2), the MTT reductase activity was 0.056 +/- 0.009 in the absence, and 0.074 +/- 0.008 OD units in the presence of adenosine (1 mM), i.e. adenosine reduced the number of non-viable cells. Also, the MTT assay revealed that the effect of potassium-containing solutions (16 and 32 mM K+) on cellular viability may depend on the extent of insult imposed on cardiomyocytes; i.e. a approximately 24% and 49% increase under mild hypoxia (0.03% CO2), or an 18% decrease in cell viability under severe hypoxia (N2) in pre-injured cells. Thus, the MTT assay used to assess viability of isolated adult cardiomyocytes revealed a direct cytoprotective effect of adenosine and hyperkalemic-cardioplegia by promoting cell survival under certain conditions in vitro.
Assuntos
Adenosina/farmacologia , Ventrículos do Coração/citologia , Potássio/farmacologia , Espectrofotometria/métodos , Sais de Tetrazólio/metabolismo , Fatores Etários , Animais , Soluções Cardioplégicas/farmacologia , Adesão Celular , Morte Celular/efeitos dos fármacos , Dimetil Sulfóxido/toxicidade , Cobaias , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/lesões , Hipóxia/induzido quimicamente , Hipóxia/metabolismo , Nitrogênio/toxicidade , Oxirredução , Fenótipo , Estresse MecânicoRESUMO
Ventricular hypertrophy alters transporters associated with digitalis action, but the outcome of digitalis treatment on intracellular cations in the hypertrophied human myocardium remains unknown. Using double-barreled Ca2+-selective microelectrodes, we simultaneously measured Ca2+ activity and membrane potential in myocardial samples from patients without and with ventricular hypertrophy, prior to and following exposure to strophanthidin, a prototype digitalis. We found that ventricular hypertrophy is associated with greater strophanthidin-induced increase in diastolic Ca2+ levels compared to that observed in the absence of hypertrophy. Furthermore, in hypertrophied myocardium the magnitude of the increase in Ca2+ induced by strophanthidin was inversely related to increase in myocardial mass. Thus, the extent of ventricular hypertrophy determines digitalis action on intracellular Ca2+ within the human myocardium.
Assuntos
Cálcio/metabolismo , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Miocárdio/metabolismo , Estrofantidina/uso terapêutico , Adulto , Idoso , Digitalis , Humanos , Hipertrofia Ventricular Esquerda/metabolismo , Pessoa de Meia-Idade , Plantas Medicinais , Plantas TóxicasRESUMO
Dual-chamber pacing may improve short-term hemodynamics and functional class in some patients with congestive heart failure, even in the absence of conventional indications for pacemaker implantation. However, the impact of different pacing modes on survival of patients with congestive heart failure is controversial. In this retrospective study we analyzed survival data from 546 elderly patients, aged 70 years and older, who underwent implantation of a permanent dual-chamber (DDD, n = 62, DVI, n = 102) or single-chamber (VVI) pacemaker (n = 382) between 1980 and 1985. Survival was further analyzed according to the presence of absence of congestive heart failure, and pacemaker mode (DDD vs. DVI vs. VVI). Overall, dual-chamber pacing (DDD and DVI) was associated with a more favorable long-term outcome when compared with single-chamber ventricular pacing, although differences were only significant for DDD pacing (P = 0.002). When patients with and without preexisting congestive heart failure were analyzed separately, survival following dual-chamber pacing (DDD and DVI) was significantly better than survival following single-chamber pacing in patients without congestive heart failure (P = 0.03), but not in patients with preexisting heart failure (P = 0.139). When patients were analyzed according to the electrophysiological indication for pacemaker implantation, overall survival of patients with AV block (P = 0.0025) but not sinus node dysfunction (P = 0.346) was improved with dual-chamber pacing. This survival advantage in patients with AV block following dual-chamber pacing was lost in the presence of heart failure (P = 0.11). These findings suggest that dual-chamber pacing, in particular DDD pacing, improves the survival in elderly patients without preexisting congestive heart failure. In contrast to the short-term hemodynamic improvement observed in selected patients with congestive heart failure, dual-chamber pacing in elderly patients with congestive heart failure, paced for conventional indications, is not associated with improved survival when compared with single-chamber ventricular pacing.
Assuntos
Envelhecimento/fisiologia , Estimulação Cardíaca Artificial/métodos , Insuficiência Cardíaca/cirurgia , Marca-Passo Artificial , Idoso , Idoso de 80 Anos ou mais , Feminino , Bloqueio Cardíaco/etiologia , Bloqueio Cardíaco/cirurgia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Estudos Retrospectivos , Nó Sinoatrial/fisiopatologia , Análise de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
The efficacy with which sulfonylurea drugs inhibit cardiac ATP-sensitive K+ (KATP) channels is reduced during metabolic compromise and cellular contracture. Disruption of the actin microfilament network, which occurs under similar conditions, reduces the sensitivity of the channel toward intracellular ATP. To investigate whether a disrupter of actin microfilaments could also affect the responsiveness of the KATP channel to sulfonylurea drugs, single-channel currents were measured in the inside-out configuration of excised patches from guinea pig ventricular myocytes. Treatment of the internal side of patches with deoxyribonuclease (DNase) I (100 micrograms/ml), which forms complexes with G actin and prevents actin filament formation, antagonized sulfonylurea-induced inhibition of KATP channels that was coupled with a loss of sensitivity to ATP. The apparent dissociation constant and Hill coefficient for the inhibitory effect of glyburide, a prototype sulfonylurea, on KATP-channel opening were, respectively, 0.13 microM and 0.95 before and 2.7 microM and 0.98 after DNase treatment. DNase did not alter intraburst kinetic properties of the channel. When DNase was denatured or coincubated with purified actin (200 micrograms/ml), it no longer decreased glyburide-induced channel inhibition. This suggests that sulfonylurea-inhibitory gating of cardiac KATP channels may also be regulated through a mechanism involving subsarcolemmal actin microfilament networks.
Assuntos
Citoesqueleto de Actina/efeitos dos fármacos , Actinas/efeitos dos fármacos , Trifosfato de Adenosina/farmacologia , Desoxirribonuclease I/farmacologia , Glibureto/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Miocárdio/metabolismo , Canais de Potássio/efeitos dos fármacos , Compostos de Sulfonilureia/farmacologia , Actinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Cobaias , Temperatura Alta , Cinética , Concentração Osmolar , Bloqueadores dos Canais de Potássio , Canais de Potássio/metabolismoRESUMO
Whether sulfonylurea therapy, which blocks ATP-sensitive K+ (KATP) channels, impedes endogenous cardioprotective mechanisms during cellular metabolic impairment remains controversial. Therefore, the effect of glyburide, a prototype sulphonylurea drug, on cytosolic Ca2+ concentration and KATP channel activity, was measured in 2-4-dinitrophenol-treated guinea-pig cardiomyocytes, using epifluorescent digital-imaging and cell-attached patch-clamp electrophysiology. Dinitrophenol (200 microM), which uncouples oxidative phosphorylation, induced opening of KATP channels and Ca2+ loading. Glyburide (6 microM) which reduced the opening of KATP channels, aggravated Ca2+ loading only when applied to dinitrophenol-pretreated myocytes but not when applied with dinitrophenol treatment. We conclude that a blocker of KATP channels has differential effects upon dinitrophenol-induced intracellular Ca2+ loading, which appear to depend upon the stage of metabolic insult.
Assuntos
Cálcio/metabolismo , Glibureto/farmacologia , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Bloqueadores dos Canais de Potássio , 2,4-Dinitrofenol/farmacologia , Animais , Citosol/efeitos dos fármacos , Citosol/metabolismo , Cobaias , Ativação do Canal Iônico/efeitos dos fármacos , Miocárdio/citologiaRESUMO
Concern has been raised regarding the ability of a nonthoracotomy integrated lead system to redetect ventricular fibrillation following failed defibrillation shocks due to diminution in postshock intracardiac electrogram amplitude. Whether such a problem could occur with other lead systems is not known, leading to uncertainty regarding a potential ongoing risk of sudden cardiac death in some patients despite implantable cardioverter-defibrillator therapy. To investigate this problem, we measured the amplitude of 10 consecutive ventricular fibrillation endocardial electrograms immediately before and immediately after failed defibrillation shocks in 15 patients at the time of implantation of a nonintegrated, transvenous, pace/sense/defibrillation lead. Overall, mean electrogram amplitude decreased 21%, from 10.7 +/- 4.6 mV before to 8.5 +/- 4.9 mV immediately after failed defibrillation shocks. The change in electrogram amplitude postshock was directly related to shock energy (r = 0.85, p < 0.0005), but shock waveform had no differential effect. Electrogram amplitude could also increase after failed shocks, particularly following those of low energy. No failures to redetect ventricular fibrillation were found. Thus, intracardiac electrogram amplitude is reduced following failed defibrillation shocks in this nonintegrated lead system, but by an amount less than that previously reported for some integrated lead systems. Our findings reveal that failed low energy defibrillation shocks are likely to result in less diminution in postshock intracardiac electrogram amplitude than high energy shocks, and that the postshock amplitude may even increase after some failed shocks.