Advances in myocardiology最新文献

The effect of ischemia on the concentration of active pyruvate dehydrogenase (PDH) complex has been investigated in glucose-perfused hearts of normal rats fed a normal diet or a high-fat diet or starved for 48 hr and in hearts from alloxan-diabetic rats. Global ischemia induced by low flow (approximately equal to 1 ml/min) lowered the concentration of active complex under most conditions employed. Parallel studies of the effect of anoxia and of potassium arrest of the heart indicated that the effect of low-flow ischemia may result from decreased mechanical activity of the heart as a consequence of tissue hypoxia; the enzymatic mechanism may be activation of PDH kinase by increased reduction of mitochondrial NAD. In hearts of normal rats fed a normal diet, global ischemia induced by zero flow increased the concentration of active complex. Evidence is given that this may result from a combination of anoxia and acidosis. In aerobic perfusions, concentrations of active complex were ranked in the order: normal diet greater than high-fat diet greater than 48-hr starved greater than alloxan-diabetic. This order was maintained when the concentration of active complex was lowered by global ischemia induced by zero flow.

A mathematical model of simple oxygen diffusion into a homogeneous cylindrical muscle is developed. The model incorporates a variable sigmoidal relationship between oxygen consumption and oxygen concentration. For any given consumption-concentration relationship, the simulated mean basal metabolic rate (averaged over the radial extent of the muscle) is computed. This calculation is repeated for a range of muscle diameters, yielding the basal metabolic rate-muscle size relationship. This theoretical relationship, which is specific for the underlying oxygen consumption-concentration relationship, is then compared to observed resting heat production-muscle size data reported in the literature. Simulated results fail to explain observed data unless the underlying oxygen consumption-concentration relationship is of a highly improbable form. It is suggested that agreement between theoretical results, based on realistic oxygen consumption-concentration relationships, and experimental observations might be achieved if the mathematical model were extended to include a contribution by myoglobin-facilitated oxygen diffusion to the total oxygen flux.

Ischemia and hypoxia both cause a rapid loss of potassium from myocardial cells. We have investigated the relationship between the accumulation of potassium in the extracellular fluid and the early loss of contractility. Experiments were performed on the isolated rabbit heart perfused with physiological saline at 36 degrees C, paced at 3 Hz. Tension was recorded from the apex. Extracellular potassium concentration [( K+]o) was recorded with small ion-selective electrodes. After the onset of global ischemia, [K+]o rose within 15 sec and reached 9.5 +/- 1.1 mmoles/liter after 5 min. Developed tension (T) fell to 9 +/- 2% of control over the same period. During substrate-free hypoxia, T declined at a similar rate, and [K+]o rose slowly to 5.5 +/- 0.1 mmoles/liter after 5 min. The relationship between [K]o and T during normal perfusion and oxygenation was investigated by incrementally increasing the perfusate [K+]. T dropped to 78.6 +/- 4.5% of control at a [K+]o of 9 mmoles/liter. Comparison of the relationship between [K+]o and T during high-potassium perfusion, ischemia, and hypoxia shows that extracellular potassium accumulation per se makes almost no contribution to the decline of contractile function in ischemia or hypoxia. (Values are means +/- S.E., N = 5.)

Our previous studies revealed that sympathetic-nerve stimulation (SNSt) plays an important role in the precipitation and the augmentation of myocardial ischemia in dogs with coronary constriction. To clarify the underlying mechanism of the detrimental effect of free fatty acids (FFA) at a high plasma concentration and the beneficial effect of L-carnitine on myocardial ischemia, ischemic changes following SNSt were compared among three groups of dogs with mild or moderate coronary constriction: a saline control group, an intralipid [(IL) 0.1 ml/kg per min + heparin 5 mg/kg] group, and an IL + L-carnitine (200 mg/kg) group. High plasma concentration of FFA aggravated the ischemic changes induced by SNSt in dogs with coronary constriction, in which no signs of increase in myocardial oxygen consumption were seen. L-Carnitine clearly alleviated the mechanical dysfunction, acceleration of anaerobic metabolism, depletion of myocardial contents of high-energy phosphates, myocardial accumulation of lactate, and ECG ischemic changes that were augmented by high plasma FFA in the coronary-constricted dogs with SNSt. From these findings, it was suggested that an increased plasma FFA might aggravate myocardial ischemia, at least, produced by SNSt in dogs with mild or moderate coronary constriction and that L-carnitine might improve the ischemia augmented by FFA, presumably by reducing myocardial accumulation of FFA intermediates.

This chapter describes the basic properties of integral membrane channels from both cardiac sarcoplasmic reticulum and sarcolemma. Channels are studied, under voltage-clamp conditions, following their incorporation into planar phospholipid bilayers by fusion of isolated native membrane vesicles with preformed membranes. The rate of fusion of vesicles may be influenced by a number of factors including divalent cations and negatively charged phospholipids in the preformed bilayer. Mammalian cardiac sarcoplasmic reticulum contains a monovalent cation selective channel with a single-channel conductance of approximately 150 pico-Siemens in the presence of symmetrical solutions of 500 mM K+ at holding potentials ranging from -60 to +60 mV. The probability of the channel being in the open state is high at positive holding potentials and low at negative holding potentials. Mammalian cardiac sarcolemma contains at least three K+-selective channels and one Cl(-)-selective channel.

We have studied the effect of leukotriene D4 (LTD4) on rabbit and rat myocardial contractility and on rabbit coronary arteries. A concentration of 2 X 10(-7) M caused only a small reduction of myocardial contractility, but caused a contraction of smooth muscle in coronary arteries similar to that obtained with potassium (30 mmoles/liter). LTD4 (2 X 10(-7) M) added to the perfusate 10 min before or at the time of reoxygenation after a period of 30 min of hypoxia did not alter contractility or resting tension. LTD4 is unlikely to be a contributing factor in the initiation of cell necrosis on reoxygenation of hypoxic myocardium.

The structure and function of heart muscle were studied in rats with chronic hemolytic anemia induced by phenylhydrazine. Contractural lesions, myocytolysis, fatty dystrophy, and small-focal necrosis were found in the myocardium along with hypertrophy. The disturbances were accompanied by a compensatory increase in the coronary flow by 2.5-fold during myocardial contractions. When the coronary flow of isolated hearts was experimentally decreased to the control level, a great depression of the contractile function developed. Administration of the antioxidant ionol, an inhibitor of lipid peroxidation, simultaneously with phenylhydrazine did not prevent the development of the hemolytic anemia, but decreased by 2 times the degree of hypertrophy and the amount of the lesion foci in the heart muscle. It also significantly inhibited the compensatory increase of coronary flow and completely eliminated depression of the heart contractile function during the normalization of coronary flow. The data allow a suggestion that hemolytic anemia is accompanied by activated lipid peroxidation, this process playing a role in the myocardial damage of anemia. Antioxidants can prevent such damage.

The course of recovery of heart activity [assessed by heart rate, atrioventricular (AV) conduction time, monophasic action potentials, contractile force, and perfusion rate] from hypothermic ischemic arrest was studied on isolated perfused rat hearts. The effect of control ischemic arrest was compared with various cardioplegic protective formulations based on high K+ content. During control hypothermic ischemia (20 degrees C), the heart activity extinguished only gradually, action potentials were biphasic, AV conduction was extremely prolonged, and contractions were slow and relatively strong. On reperfusion (37 degrees C), the recovery of electrical activity was almost instantaneous and normalized within 2 min, whereas the contractile force remained substantially depressed. In contrast, K+-containing cardioplegic solutions stopped the heart within several cycles. Postarrest recovery was delayed and transitorily associated with severe arrhythmias (AV block, repetitive afterdepolarizations and oscillations during elevated plateau, and ventricular fibrillation). Nevertheless, the action potentials as well as the contractile force virtually normalized in 10-15 min. Procaine-containing cardioplegic solutions were ineffective in preventing the onset of postarrest reperfusion arrhythmias, whereas addition of nifedipine to the K+-containing cardioplegic solutions largely prevented these arrhythmias, and contractile force was further improved by high concentrations of glucose. The data indicate that postarrest electrical and mechanical recovery do not recover in parallel. Furthermore, high concentrations of calcium antagonist and glucose preserve the electrical and mechanical properties of the cardiac muscle during periods of cardiac arrest.

The U.S. Pharmacopoeia defines acceptable limits of particle contamination for intravenous solutions. Used conventionally, these solutions are filtered by the lungs, and there are few reports of particle-induced tissue injury to the systemic circulation. We have used an isolated rat heart model to assess whether unfiltered direct intraarterial administration of cardioplegic solutions, as in open-heart surgery, can be damaging to the myocardium. An intravenous solution of U.S. commercial manufacture was selected for evaluation. Particle-counting revealed this solution to be well within the U.S.P. limits. Direct intracoronary infusion of this solution at 20 degrees C and at constant pressure led to an approximate 75% reduction in coronary flow over 20 min. Filtration through a membrane of 0.8-micron porosity largely prevented this reduction of coronary flow. In studies with multidose cardioplegia (3-min infusions every 30 min), hearts given filtered solution recovered almost 90% of their preischemic functional capacity after 3 hr of hypothermic (20 degrees C) ischemic arrest. Hearts given an identical unfiltered solution essentially failed to recover despite the particle counts having conformed to the U.S.P. limit. This functional result was supported by measurement of creatine kinase leakage, which was significantly higher in the unfiltered group. These studies provide an argument for revision of U.S.P. particle limits when applied to intraarterially administered solutions; in particular, we believe that equipment for cardioplegic infusion into coronary arteries should incorporate a 0.8-micron in-line filter.

Restoration of flow to hearts made ischemic for 60 min is known to produce accelerated tissue injury. In these studies, reperfusion produced an enhanced enzyme [creatine phosphokinase (CPK) and lactate dehydrogenase] efflux, development of contracture, and reduced mitochondrial oxidative phosphorylation. These effects were associated with prostaglandin (PG) production as measured by 6-keto-PGF1 alpha efflux from the heart. Three nonsteroidal antiinflammatory agents--indomethacin, aspirin, and mefenamic acid--that inhibit the cyclooxygenase-dependent conversion of arachidonic acid to PGs reduced most aspects of dysfunction associated with reperfusion. In addition, three glucocorticoids--cortisol, dexamethasone, and methylprednisolone--that prevent substrate availability for cyclooxygenase also significantly decreased CPK efflux, but had variable effects on other parameters. These studies suggest that endogenous PGs produced in the heart may contribute to the dysfunction associated with reperfusion of the ischemic myocardium.