Creatine kinase release, potassium-42 content, and mechanical performance in anoxic rabbit myocardium.

We studied whether creatine kinase appearance in venous effluent was specific for, and quantitatively proportional to, the amount of loss of functioning myocardium. Cell viability was determined by simultaneously monitoring tissue (42)K content and mechanical performance during anoxia and reoxygenation in isolated, arterially perfused, interventricular rabbit septa. The septa were paced at 42 beats/min and perfused at 1.8 ml/min per g tissue with a modified Tyrode solution at 28 degrees C. Net total creatine kinase losses of 5.3+/-2.7, 20.6+/-7.2, 55.3+/-7.6, and 110.7+/-27.1 IU/g dry wt (mean+/-SEM) were observed after 20, 30, 40, and 60 min of anoxia, respectively. Maximum (42)K losses during the same intervals of anoxia were 16.8+/-3.4, 38.3+/-2.9, 47.0+/-1.4, and 84.3+/-14.8 mmol K(+)/kg dry wt and correlated with creatine kinase losses, r = 0.97. Upon reoxygenation, (42)K content returned to a new plateau which was expressed as a percentage of decrease from control content. These unrecovered (42)K losses were -2.7+/-0.9, 0.7+/-2.9, 6.6+/-1.9, and 14.0+/-6.5% after 20, 30, 40, and 60 min of anoxia, respectively, and correlated with the creatine kinase loss, r = 0.97. Net loss of developed tension after reoxygenation was 9.0+/-2.3, 26.7+/-17.9, 31.7+/-1.1, and 60.7+/-8.8% of control after these anoxic intervals and correlated with creatine kinase loss, r = 0.92. The small enzyme loss that occurred after 20 min anoxia without evidence for irreversible loss of cell function was congruent with0.1% of total tissue enzyme content. The significant correlation of enzyme loss with the irreversible losses of potassium content and contractile performance supported the hypothesis that creatine kinase appearance in the venous effluent was the result of cell death.

Nitrogen-13 flux from L-[13N]glutamate in the isolated rabbit heart: effect of substrates and transaminase inhibition.

Kinetic and biochemical parameters of nitrogen-13 flux from L-[13N]glutamate in myocardium were examined. Tissue radioactivity kinetics and chemical analyses were determined after bolus injection of L-[13N]glutamate into isolated arterially perfused interventricular septa under various metabolic states, which included addition of lactate, pyruvate, aminooxyacetate (a transaminase inhibitor), or a combination of aminooxyacetate and pyruvate to the standard perfusate containing insulin and glucose. Chemical analysis of tissue and effluent at 6 min allowed determination of the composition of the slow third kinetic component of the time-activity curves. 13N-labeled aspartate, alanine and glutamate accounted for more than 80% of the tissue nitrogen-13 under the experimental conditions used. Specific activities for these amino acids were constant, but not identical to each other, from 6 through 15 min after administration of L-[13N]glutamate. Little labeled ammonia (1.9%) and glutamine (4.7%) were produced, indicating limited accessibility of exogenous glutamate to catabolic mitochondrial glutamate dehydrogenase and glutamine synthetase, under control conditions. Lactate and pyruvate additions did not affect tissue amino acid specific activities. Aminooxyacetate suppressed formation of 13N-labeled alanine and aspartate and increased production of L-[13N]glutamine and [13N]ammonia. Formation of [13N]ammonia was, however, substantially decreased when aminooxyacetate was used in the presence of exogenous pyruvate. The data support a model for glutamate compartmentation in myocardium not affected by increasing the velocity of enzymatic reactions through increased substrate (i.e., lactate or pyruvate) concentrations but which can be altered by competitive inhibition of transaminases (via aminooxyacetate) making exogenous glutamate more available to other compartments.

A critique on complementary and alternative medicine.

Modern medicine regularly uses the products of science to improve health. Until recently, however, medicine itself has not been practiced in a scientific manner. The growth of evidence-based medicine is predicated upon the concept that insofar as possible, all aspects of medical care ought to be examined with regard to the evidence. All forms of treatments and preventive strategies should be subjected to assessments of efficacy and effectiveness. Efficacy is demonstrated in the day-to-day practice of medicine. An evaluation of effectiveness may lead to one or more randomized clinical trials, where the results of these randomized clinical trials may be necessary to maximize effectiveness. From a health care perspective, safety must be assessed, not only with regard to adverse effects of the particular intervention, but also in the context of a comparison to alternative treatments. If evidence demonstrates the efficacy and/or effectiveness of a particular intervention, it may be unsafe to select a treatment for which evidence of efficacy or effectiveness is lacking. Certainly patients should be fully informed of the evidence that is available for making rational choices. Alternative and complementary modes of medicine should be subject to these principles. The history of digitalis glycosides provides an interesting example of an important treatment arising from herbal medicine, by which many of these elements can be exemplified.

Myocardial ischemia: ionic events in ischemia and anoxia.

The early stages of anoxemia and ischemia are associated with highly selective, reversible defects in sarcolemmal ionic exchange of potassium not necessarily the result of impaired sodium pump function. At a later stage structural defects in the membrane led to irreversible loss of intracellular potassium and creatine kinase. Similar stages can be demonstrated in the sarcolemmal selectivity for divalent cations. The degree of sarcolemmal injury from ischemia can be significantly influenced by the conditions of reperfusion. Reduced calcium content of blood reperfused for only 5 minutes can improve the mechanical recovery of ischemic rabbit ventricle. The influx of calcium during reperfusion impairs those processes required for restoration of sarcolemmal integrity.

Low-cost technologies and public policy.

The evaluation of low-cost technologies is complicated by the difficulty of understanding what is meant by "low" cost. Low unit costs may lead to the widespread use of a technology that results in high aggregate costs. It is often more useful to consider the value than the cost of a technology, recognizing that this value may change, depending upon the group to whom it is applied as well as the factors that are measured. Public policy should attempt not only to control costs but also to obtain the greatest value for expenditures in health care by supporting the development of methodologies to define value, reimbursement strategies that emphasize cost-effectiveness, and clinical guidelines that can reduce variation in practice.

Challenges facing academic health centers and major teaching hospitals.

To understand the unique and complex challenges facing healthcare providers, the author discusses present and projected changes occurring in the healthcare system. Reflecting on their impact on clinical care, education and research, he discusses some ways in which academic health centers around the country are responding to these changes. He concludes by discussing strategies to address some of the issues facing us.

Effects of heart rate on extracellular [K+] accumulation during myocardial ischemia.

The effect of heart rate on extracellular [K+] ([K+]o) accumulation during total global ischemia was investigated in the isolated arterially perfused (37 degrees C) rabbit interventricular septum using intramyocardial K+-sensitive electrodes (tip diameter, 0.3 mm) and intracellular microelectrodes. The heart rates tested were 0, 25, 75, 125, and 150 beats/min in aqueous-perfused septa and 25, 75, and 125 beats/min in blood-perfused septa. In the lower range of heart rates (0-75 beats/min) the rate and magnitude of [K+]o accumulation during 10 min of ischemia were markedly rate dependent, but in the higher range of rates (75-150 beats/min) the rate dependence was markedly attenuated in both aqueous and blood-perfused preparations. The latter finding could be largely attributed to the more rapid shortening of the action potential duration during ischemia at the higher rates and demonstrates that the amount of time the myocardium spends in the depolarized state is an important determinant of the rate of cellular K+ loss during ischemia. Progressive shortening of the action potential duration during ischemia is also a major factor determining the onset of the plateau phase of [K+]o accumulation. The findings help to resolve previous conflicting reports on the effects of heart rate on [K+]o accumulation during ischemia.