RESUMO
The cardiac remodeling is a progressive response of the heart to acute and chronic insults regardless its etiology. This process is characterized by changes in the size, shape and function and is associated with a worse prognosis in patients with heart failure. The acute myocardial infarction is the most common cause of remodeling. In the first minutes after injury in the ischemic zone there is an important augment in the synthesis and release of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) interleukin-6 (IL-6), interleukin-1-beta (IL-1beta) and transforming growth factor 1-beta (TGF-1beta). This acute releasing of cytokines could regulate the survival or apoptosis of myocytes in infarcted zone and, their negative inotropic effects could represent an adaptative response to delimit the injury and to decrease myocardial energy demand. This significant upregulation of proinflammatory cytokines can extend to noninfarcted zone and triggers a second phase of elevated levels of cytokines that promote interstitial fibrosis and collagen deposition in the contralateral noninfarcted myocardium leading to a dysfunctional ventricle. This article will review the recent reports that support the idea of a cardioprotective role for this early inflammatory response and a deleterious role of the delayed response that mediate the fibrosis that is a typical feature of the remodeling process.
Assuntos
Citocinas/fisiologia , Inflamação , Remodelação Ventricular , Animais , Células Cultivadas , Cricetinae , Modelos Animais de Doenças , Humanos , Interleucina-1/fisiologia , Interleucina-6/farmacologia , Interleucina-6/fisiologia , Camundongos , Contração Miocárdica/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Músculos Papilares/citologia , Músculos Papilares/efeitos dos fármacos , Ratos , Fator de Crescimento Transformador beta1/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Remodelação Ventricular/fisiologiaRESUMO
Long-lasting cardioprotection may be attained by chronic hypoxia. The basal parameters of contractile function and their response to hypoxia/reoxygenation were measured under isometric conditions, in papillary muscles isolated from left ventricle of rats that were submitted to 53.8 kPa in a hypobaric chamber from 7 wk of age and for their lifetime and of their siblings kept at 101.3 kPa. During acclimatization, hematocrit increased, body weight gain decreased, and heart weight increased with right ventricle hypertrophy. Papillary muscle cross-sectional area was similar in both control and hypoxic groups up to 45 wk of exposure. Developed tension (DT) was 34-64% higher in rats exposed to hypoxia for 10, 26, and 45 wk than in their age-matched controls, whereas resting tension was unchanged. Maximal rates of contraction and relaxation showed a similar pattern of changes as DT. Recovery of DT and maximal rates of contraction and relaxation after 60-min hypoxia and 30-min reoxygenation was also improved in adult hypoxic rats to values similar to those of young rats. Heart acclimatization was lost after 74 wk of exposure. Results are consistent with the development of cardioprotection during high-altitude acclimatization and provide an experimental model to study the mechanisms involved, which are addressed in the accompanying paper.
Assuntos
Envelhecimento/fisiologia , Altitude , Hipóxia Celular/fisiologia , Mecanotransdução Celular/fisiologia , Contração Miocárdica/fisiologia , Músculos Papilares/citologia , Músculos Papilares/fisiologia , Aclimatação/fisiologia , Envelhecimento/patologia , Animais , Masculino , Tamanho do Órgão/fisiologia , Pressão , Ratos , Ratos Wistar , Estresse Mecânico , SobrevidaRESUMO
Mitochondrial nitric oxide (NO) production was assayed in rats submitted to hypobaric hypoxia and in normoxic controls (53.8 and 101.3 kPa air pressure, respectively). Heart mitochondria from young normoxic animals produced 0.62 and 0.37 nmol NO.min(-1).mg protein(-1) in metabolic states 4 and 3, respectively. This production accounts for a release to the cytosol of 29 nmol NO.min(-1).g heart(-1) and for 55% of the NO generation. The mitochondrial NO synthase (mtNOS) activity measured in submitochondrial membranes at pH 7.4 was 0.69 nmol NO.min(-1).mg protein(-1). Rats exposed to hypobaric hypoxia for 2-18 mo showed 20-60% increased left ventricle mtNOS activity compared with their normoxic siblings. Left ventricle NADH-cytochrome-c reductase and cytochrome oxidase activities decreased by 36 and 12%, respectively, from 2 to 18 mo of age, but they were not affected by hypoxia. mtNOS upregulation in hypoxia was associated with a retardation of the decline in the mechanical activity of papillary muscle upon aging and an improved recovery after anoxia-reoxygenation. The correlation of left ventricle mtNOS activity with papillary muscle contractility (determined as developed tension, maximal rates of contraction and relaxation) showed an optimal mtNOS activity (0.69 nmol.min(-1).mg protein(-1)). Heart mtNOS activity is regulated by O(2) in the inspired air and seems to play a role in NO-mediated signaling and myocardial contractility.
Assuntos
Envelhecimento/metabolismo , Altitude , Hipóxia Celular/fisiologia , Citocromos/metabolismo , Ventrículos do Coração/enzimologia , Mitocôndrias/metabolismo , Contração Miocárdica/fisiologia , Óxido Nítrico Sintase/metabolismo , Aclimatação/fisiologia , Envelhecimento/patologia , Animais , Masculino , Mecanotransdução Celular/fisiologia , Tamanho do Órgão/fisiologia , Músculos Papilares/citologia , Músculos Papilares/fisiologia , Pressão , Ratos , Ratos Wistar , Estresse Mecânico , SobrevidaRESUMO
In most mammalian species, an increase in stimulation frequency (ISF) produces an increase in contractility (treppe phenomenon), which results from larger Ca2+ transients at higher frequencies, due to an increase in sarcoplasmic reticulum Ca2+ load and release. The present study attempts to elucidate the contribution of the Na(+)-Ca2+ exchanger (NCX) to this phenomenon. Isolated cat ventricular myocytes, loaded with [Ca2+]i- and [Na+]i-sensitive probes, were used to determine whether the contribution of the NCX to the positive inotropic effect of ISF is due to an increase in Ca2+ influx (reverse mode) and/or a decrease in Ca2+ efflux (forward mode) via the NCX, due to frequency-induced [Na+]i elevation, or whether it was due to the reduced time for the NCX to extrude Ca2+. The results showed that the positive intropic effect produced by ISF was temporally dissociated from the increase in [Na+]i and was not modified by KB-R7943 (1 or 5 microM), a specific blocker of the reverse mode of the NCX. Whereas the ISF from 10 to 30 beats min(-1) (bpm) did not affect the forward mode of the NCX (assessed by the time to half-relaxation of the caffeine-induced Ca2+ transient), the ISF to 50 bpm produced a significant reduction of the activity of the forward mode of the NCX, which occurred in association with an increase in [Na+]i (from 4.33+/-0.40 to 7.25+/-0.50 mM). However, both changes became significant well after the maximal positive inotropic effect had been reached. In contrast, the positive inotropic effect produced by ISF from 10 to 50 bpm was associated with an increase in diastolic [Ca2+]i, which occurred in spite of a significant increase in the relaxation rate and at a time at which no increases in [Na+]i were detected. The contribution of the NCX to stimulus frequency inotropy would therefore depend on a decrease in NCX-mediated Ca2+ efflux due to the reduced diastolic interval between beats and not on [Na+]i-dependent mechanisms.
Assuntos
Frequência Cardíaca/fisiologia , Contração Miocárdica/fisiologia , Trocador de Sódio e Cálcio/fisiologia , Tioureia/análogos & derivados , Animais , Cálcio/metabolismo , Cálcio/fisiologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Cardiotônicos/farmacologia , Gatos , Citosol/metabolismo , Estimulação Elétrica , Corantes Fluorescentes , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Indóis , Contração Miocárdica/efeitos dos fármacos , Ouabaína/farmacologia , Músculos Papilares/citologia , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Sódio/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Tioureia/farmacologiaRESUMO
INTRODUCTION: The present study was designed to examine the extent to which differences in input resistance contribute to the heterogeneity of excitability in canine endocardium. METHODS AND RESULTS: The experiments were performed in isolated canine right anterior papillary muscles. The preparations were superfused with oxygenated Tyrode's solution at 36 degrees to 37 degrees C. Conventional methods were used for recording and stimulation. To obtain pertinent data, two microelectrodes were inserted into the same cell or into two contiguous cells. One microelectrode injected intracellular hyperpolarizing current to polarize the membrane; the second microelectrode recorded the changes in transmembrane potential. The two micreoelectrodes were separated by 8 to 10 microm. The procedure used provided input resistance and threshold current values for the doubly impaled cell or the two contiguous cell units. The same procedure was repeated at different sites of the preparation. The plot of input resistance versus threshold current showed a good fit (R2 = 0.97) between the experimental data and the curve for the rectangular hyperbola XY = 30 mV; therefore, the input resistance and the threshold current are inversely related. CONCLUSION: The results indicate that the canine cardiac syncytium is nonhomogeneous with respect to input resistance and that input resistance is inversely related to the minimal current needed to reach threshold. Accordingly, the electrical excitability of the cells studied also is inhomogeneous.
Assuntos
Coração/fisiologia , Animais , Limiar Diferencial , Cães , Condutividade Elétrica , Impedância Elétrica , Eletrofisiologia/instrumentação , Técnicas In Vitro , Potenciais da Membrana/fisiologia , Microeletrodos , Oscilometria , Músculos Papilares/citologia , Músculos Papilares/fisiologiaRESUMO
Myocardial stretch is a well-known stimulus that leads to hypertrophy. Little is known, however, about the intracellular pathways involved in the transmission of myocardial stretch to the cytoplasm and nucleus. Studies in neonatal cardiomyocytes demonstrated stretch-induced release of angiotensin II (Ang II). Because intracellular alkalinization is a signal to cell growth and Ang II stimulates the Na+/H+ exchanger (NHE), we studied the relationship between myocardial stretch and intracellular pH (pHi). Experiments were performed in cat papillary muscles fixed by the ventricular end to a force transducer. Muscles were paced at 0.2 Hz and superfused with HEPES-buffered solution. pHi was measured by epifluorescence with the acetoxymethyl ester form of the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5,6-carboxyfluorescein (BCECF-AM). Each muscle was progressively stretched to reach maximal developed force (Lmax) and maintained in a length that was approximately 92% Lmax (Li). During the "stretch protocol," muscles were quickly stretched to Lmax for 10 minutes and then released to Li; pHi significantly increased during stretch and came back to the previous value when the muscle was released to Li. The increase in pHi was eliminated by (1) specific inhibition of the NHE (EIPA, 5 micromol/L), (2) AT1-receptor blockade (losartan, 10 micromol/L), (3) inhibition of protein kinase C (PKC) (chelerythrine, 5 micromol/L), (4) blockade of endothelin (ET) receptors with a nonselective (PD 142,893, 50 nmol/L) or a selective ETA antagonist (BQ-123, 300 nmol/L). The increase in pHi by exogenous Ang II (500 nmol/L) was also reduced by both ET-receptor antagonists. Our results indicate that after myocardial stretch, pHi increases because of stimulation of NHE activity. This involves an autocrine-paracrine mechanism in which protein kinase C, Ang II, and ET play crucial roles.
Assuntos
Comunicação Autócrina/fisiologia , Concentração de Íons de Hidrogênio , Músculos Papilares/fisiologia , Comunicação Parácrina/fisiologia , Álcalis , Alcaloides , Amilorida/análogos & derivados , Amilorida/farmacologia , Angiotensina II/farmacologia , Animais , Antiarrítmicos/farmacologia , Benzofenantridinas , Gatos , Antagonistas dos Receptores de Endotelina , Endotelinas/fisiologia , Inibidores Enzimáticos/farmacologia , Coração/fisiologia , Losartan/farmacologia , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Fibras Musculares Esqueléticas/química , Fibras Musculares Esqueléticas/enzimologia , Oligopeptídeos/farmacologia , Músculos Papilares/citologia , Peptídeos Cíclicos/farmacologia , Fenantridinas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Trocadores de Sódio-Hidrogênio/fisiologiaRESUMO
In adult rabbit ventricular preparations, action potential duration is significantly increased when stimulation frequency is increased from 0.1 to 1.0 Hz. In neonatal preparations, a similar change in stimulation frequency produced no significant increase in action potential duration. To identify the ionic basis for this difference, we studied different outward currents in single myocytes from papillary muscle and from epicardial tissue of adult and neonatal rabbits. The densities of the outward currents in neonatal cells were about one-half of the current density in adult cells. The density of the voltage-activated transient outward current (I(to1)) was smaller in cells from papillary muscle than in cells from epicardium in adult and newborn rabbits. We found major differences in the kinetic behavior of I(to1) between adult and neonatal cells: 1) the rate of apparent inactivation was faster in neonatal cells, and 2) the recovery from inactivation was significantly faster in neonatal cells, with a time constant of 113 vs. 1,356 ms. We propose that this marked difference in the recovery from inactivation of I(to1) is the basis for the difference in frequency dependence of action potential duration.