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Biomedical subjects

K Wildenthal

Publications and source records attributed to K Wildenthal.

At least 73 records · Page 4Linked to original sources
PubMed1976

Relationships between resting tension and mechanical properties of papillary muscle.

The influence on mechanical properties of changes in resting tension over a range from 0.5 to 4.5 g was investigated in 12 isolated cat papillary muscles. At each resting tension, the muscles contracted isometrically with the exception of an externally applied sinusoidal stretch of 0.5% Lmax (deltaL) and 20 Hz. Stiffness (deltaT/deltaL) was determined from deltaL and the peak amplitudes (deltaT) of the individual cycles from the sinusoidal component of tension. Assuming that the muscle and experimental apparatus behaved as a linear second-order mechanical system, it was possible to divide stiffness into its elastic and viscous components. During rest, total stiffness and its components were linearly related to tension. During contraction, stiffness and its elastic component were linearly related to tension. Furthermore, increasing resting tension increased the intercept and decreased the slope of this linear stiffness-tension relationship. The relationship between viscous stiffness and tension during contraction is more complex in that it is a direct relationship at low resting tensions, but an inverse one at high resting tensions.

Animals↗
PubMed1976

Hormonal and nutritional substrate control of cardiac lysosomal enzyme activities.

Prolonged starvation is known to induce significant alterations in several cardiac lysosomal enzymes, particularly the acid proteinase cathepsin D. To determine what specific factors might mediate these changes, fetal mouse hearts in organ culture were maintained in media designed to simulate selected hormonal or nutritional substrate changes that accompany starvation. Reduced concentrations of glucose caused an increase in the activity of beta-acetylglucosaminidase but had no effect on cathepsin D or acid phosphatase activites (i.e., effects opposite from those of starvation). Also, high concentrations of free fatty acid, acetoacetate, and beta-OH-butyrate induced an increase in cathepsin D (+18%) and a simultaneous decrease in glucosaminidase (-19%), with little change in acid phosphatase. Furthermore, glucagon had no effect on any of the enzymes, whereas growth hormone caused a small (6%) increase in cathepsin D activity. In addition, insulin deprivation caused significant increases (7-25%) in the activities of all three enzymes. Insulin deprivation and excess ketones, but not the other interventions, increased the proportion of enzyme activity which was nonsedimentable. These results suggest the possibility that lysosomal alterations during starvation may be related in part to prolonged insulin deficiency and exposure to high concentrations of ketones and free fatty acids.

Acetylglucosaminidase↗
PubMed1976

Responsiveness to glucagon in fetal hearts. Species variability and apparent disparities between changes in beating, adenylate cyclase activation, and cyclic AMP concentration.

Previous studies of the ability of the immature heart to respond to glucagon have yielded conflicting results. To test the possibility that the apparent discrepancies might be explained in part by species variability, isolated hearts of fetal mice and rats (13-22 days' gestational age) were studied under identical conditions in vitro. Changes in atrial rate and ventricular contractility were measured in spontaneously beating hearts exposed to glucagon, and activation of adenylate cyclase was assayed in cardiac homogenates. In mice of 16 days' gestational age or less, there was no change in heart rate in response to glucagon; at 17-18 days, minimal responsiveness was present; and after 19 days, 10muM glucagon caused an increase in spontaneous atrial rate of 30 +/- 4% (SEM) (P less than 0.001). Measurement of the extent and speed of volume displacement of the isotonically contracting hearts with a specially constructed capacitance transducer revealed that ventricular inotropic responsiveness also appeared after 17-19 days. Cardiac stores of glycogen were reduced in older hearts exposed to glucagon, but not in those aged less than 16 days. In contrast, glucagon failed to activate adenylate cyclase in homogenates of hearts of fetal mice at any age. Furthermore, glucagon failed to elicit an increase in the concentration of cyclic AMP in spontaneously beating hearts that developed tachycardia. Responses in hearts of fetal rats were distinctly different from those in mouse hearts: at no age was there any change in heart rate, strength of contraction, glycogen content, or adenylate cyclase activation. Thus, there are major species differences in cardiac pharmacological maturation. Although the mouse heart develops the ability to increase its rate and strength of contraction and to undergo glycogenolysis in response to glucagon well before birth, the rat heart does not. In addition, there is an apparent disparity in late fetal mouse hearts between the ability of glucagon to induce functional responses and its ability to stimulate adenylate cyclase and increase cyclic AMP levels. It is impossible, of course, to rule out absolutely the possibility that localized increases in a critical cyclic AMP pool were present but too small to measure in the entire tissue. Nevertheless, the most obvious interpretation of our results is that they are compatible with the hypothesis that glucagon may exert some of its hemodynamic effects independently from the adenylate cyclase-cyclic AMP system in the late-fetal mouse heart.

Adenylyl Cyclases↗
PubMed1976

Hormonal control of cardiac protein and amino acid balance.

Isolated hearts of fetal mice in organ culture maintain active protein synthesis and protein degradation. Rates of degradation exceed rates of synthesis and as a result, the hearts are in state of negative protein balance as evidenced by net loss of protein and release of amino acids. Several hormones can alter amino acid metabolism and protein balance by altering synthesis or degradation, or both. In cultured fetal mouse hearts, insulin, the most extensively studies of the hormones increases the rate of protein synthesis by 13 +/- 3.7% and decreases the rate of protein degradation by 22 +/- 4.1% (p less than 0.01 for both). Together, these changes account for a 30-40% reduction in the loss of cardiac protein and in the release of phenylalanine from the heart. These changes are accompanied by a decrease of 21 +/- 2.7% in the total activity of the lysosomal proteinase cathepsin D. and by a reduction in the proportion of the enzyme that is present in the nonsedimentable fraction of the issue homogenate. This suggests that the possibility that insulin may function in part by altering lysosomal enzyme activity or availability, or both. The effects of insulin on protein degradation, amion acid release, and cathepsin D activity persist even when protein synthesis has been inhibited by cycloheximide. These results suggest that insulin plays an important role in the control of cardiac protein synthesis and degradation.

Amino Acids↗
PubMed1975

The diving reflex used to treat paroxysmal atrial tachycardia.

Induction of the diving reflex, by immersion of the face in cold water (2 degrees C) while the breath was held, converted paroxysmal atrial tachycardia to sinus rhythm within 15-35 seconds in seven patients (aged 22-66). Four had histories of heart attacks that had previously required vasopressor therapy, and two had been digitalised; three had no history of prior paroxysmal atrial tachycardia or heart-disease. The reported procedure, which is convenient, non-invasive, and can be self administered by the patient after brief instruction, may offer a useful adjunct to carotid-sinus massage and intravenous infusion of vasopressors for the treatment of paroxysmal atrial tachycardia.

Adult↗
PubMed1975

Fetal mouse hearts: a model for studying ischemia.

A new experimental model for the study of two important aspects of ischemia, namely, oxygen and substrate deprivation, is proposed: the intact, beating fetal mouse heart in organ culture. This model offers long-term stability, ease and reproducibility of preparation, and the ability to manipulate experimental conditions. Hearts deprived of oxygen and glucose ceased beating immediately. After 3-4 hr of deprivation, biochemical and ultrastructural changes consistent with ischemic injury were evident. These include depletion of ATP and glycogen levels, loss of cytoplasmic enzymes, and extensive swelling and disruption of mitochondrial structure. Glucose and insulin partially protected against ATP depletion. Upon resupply of oxygen and glucose , beating resumed immediately, ATP levels rapidly increased to control levels and, consistent with this, mitochondrial structure returned toward normal. During the recovery phase autophagic vacuoles containing damaged mitochondria and myofibrils were seen, indicating that repair mechanisms were activated. Consistent with this, the proportion of lysosomal enzymes that were present in the nonsedimentable fraction of the tissue homogenate increased. We conclude that the cultured fetal mouse heart is a model useful for studying myocardial responses to anoxia and/or substrate deprivation and for assessing interventions designed to limit damage or to stimulate repair after ischemic injury.

Acetylglucosaminidase↗
PubMed1975

Negative inotropic influence of hyperosmotic solutions on cardiac muscle.

In cardiac muscle, moderate degrees of hyperosmolality of the type encountered physiologically or clinically (i.e., less than 200 mosM above control) characteristically exert a positive inotropic effect, which presumably is mediated by increased Ca2+ availability for binding to troponin. In contrast, skeletal muscle displays significant contractile depression on exposure to hyperosmotic solutions, even at mild degrees of hypertonicity. To determine whether a similar potential for hyperosmolarity-induced depression also exists in cardiac muscle, right ventricular papillary muscles from cats were exposed to hypertonic solutions of mannitol or sucrose under circumstances in which positive inotropic effects were precluded by prior exposure to a bathing solution of 4.0 mM Ca2+ and paired electrical stimulation to maximize intracellular Ca2+ before addition of the hyperosmotic substances. In contrast to their usual positive inotropic effects, hypertonic solutions under these conditions caused cardiac depression at all osmolarities tested. Developed tension and its maximal rate of development (dT/dt) decreased by 18% at 50 mosM above control, by 30% at 100 mosM, by 36% at 150 mosM, and by 42% at 200 mosM (P less than 0.01 for all). Time to peak tension and resting tension were not changed significantly. When the muscles were returned to control solutions, tension development also returned toward normal. The data are compatible with the hypothesis that, within the range tested, all degrees of hyperosmolarity exert a significant negative inotropic influence on cardiac muscle, as is true in skeletal muscle; manifestation of this effect of increased tonicity normally would be obscured at low degrees of hyperosmolality, however, by an overriding positive influence that is absent in skeletal muscle.

Animals↗
PubMed1975

Influence of acute myocardial depression on left ventricular stiffness and its elastic and viscous components.

The influence of acute myocardial depression on ventricular stiffness and on its elastic and viscous components was studied in 19 dogs. After the animals were placed on cardiopulmonary bypass, stiffness was measured by sinusoidally injecting volume changes of 0.5 ml (deltaV) at 22 Hz into paced, isovolumically (deltaP) of the sinusoidal pressure response. Stiffness was linearly related to pressure (P) throughout the cardiac cycle, so that deltaP/delta V = alpha P + beta, where alpha and beta are constants. Myocardial depression was induced in one of three different ways: by coronary artery ligation, by administration of propranolol (Inderal), or by administration of pentobarbital. All three interventions caused significant increases in the slope, alpha, of the stiffness-pressure relationship, while the intercept, beta, remained unchanged. Release of the coronary occlusion or administration of acetylstrophantidin partially reversed depression and the change in alpha; Approximation of the mechanical nature of the left ventricle in terms of a linear second-order mechanical system permitted the division of stiffness into its elastic and viscous components. Like total stiffness, both the elastic and the viscous components were linearly related to ventricular pressure. Elastic stiffness was not changed, but the slope of the line relating viscous stiffness to pressure was significantly increased during ischemic depression, indicating that a change in viscosity was primarily responsible for the increase in total ventricular stiffness.

Animals↗
PubMed1975

Importance of calcium in the inotropic effect of hyperosomotic agents, norepinephrine, paired electrical stimulation, and treppe.

The data obtained from these studies demonstrate that the inotropic effect of hyperosmolar mannitol and sucrose and of paired electrical stimulation is critically influenced by extracellular calcium concentration. The inotropic effect of norepinephrine is not prevented by maximal functional extracellular calcium concentrations. Inhibition of systolic calcium flux at the cell membrane by D600 does not prevent the inotropic effect of hyperosmolar mannitol or of paired electrical stimulation but it does prevent the inotropic effect of hyperosmolar intropic effect of treppe. Thus, intracellular calcium regulation appears to be of major importance in the inotropic effect in isolated cardiac muscle of mannitol and paired pacing while systolic calcium flux at the cell membrane appears to be of major importance in the inotropic effect of treppe.

Animals↗
PubMed1975

Dietary control of cardiac lysosomal enzyme activities.

Prolonged starvation in rats is accompanied by consistent increases in the total cardiac activity and the nonsedimentable activity of cathepsin D, the major detectable lysosomal acid proteinase in the heart. Fluorescent staining of rabbit hearts with specific anticathepsin D antiserum reveals that the increase occured predominantly in myocytes, but increased formation of autophagic vacuoles cannot be demonstrated in the myocardial cells by electron microscopy. No changes in cathepsin D occur in animals fed pure carbohydrate or pure fat diets for similar periods, indicating that it is caloric deficiency and not dietary protein deficiency that alters catheptic activity. At the same time that cardiac cathepsin D activity increases markedly, acid phosphatase increases slightly, and the activity of beta-acetyl-glucosaminidase is significantly lower than in hearts of fed rats. The data are compatible with the hypothesis that increased activity of lysosomal acid proteinase may contribute to the net protein catabolism and cardiac atrophy that accompany starvation, especially late in the period of food deprivation. A generalized activation of all lysosomal enzymes does not occur with starvation, however, and the activities of some lysosomal enzymes in the heart decrease.

Animals↗
PubMed1975

Creatine: a possible stimulus skeletal cardiac muscle hypertrophy.

These experiments test whether creatine, a product of muscular contraction, stimulates myofibrillar protein synthesis. It was found that skeletal muscle cells formed both in vitro and in vivo and cardiac muscle cells formed in vivo synthesize myofibrillar proteins faster when supplied creatine in vitro. The rates of synthesis and/or accumulation of three myofibrillar proteins-myosin heavy chain actin, and creatine kinase-were stimulated by creatine. In contrast, the rates of synthesis of total protein and of deoxyribonucleic acid (DNA) and the activities of several nonmyofibrillar enzymes were not altered by creatine. These include lactic dehydrogenase, cathepsin D, acid phosphatase, and beta-acetylglucosaminidase. It is concluded that creatine selectively stimulated the rate of synthesis of contractile proteins in skeletal and cardiac muscle in vitro and may play a role in muscle hypertrophy.

Actins↗
PubMed1974

Influence of calcium on the inotropic actions of hyperosmotic agents, norepinephrine, paired electrical stimulation, and treppe.

To analyze the interaction of calcium ion concentration with hypertonic agents and with other inotropic interventions, isolated right ventricular cat papillary muscles were studied under isometric conditions in Krebs-Ringer bicarbonate solution. Extracellular calcium concentrations were varied between 2.5 and 11.0 mM. Maximal inotropic effects occurred between 5 and 8.0 mM calcium and further elevation to 11.0 mM was without additional influence. The effect of hyperosmotic sucrose and mannitol on papillary muscle performance was compared with that of 10(-6) M norepinephrine at calcium concentrations of 2.5 and 10.0 mM and with paired electrical stimulation in 10.0 mM calcium. Both norepinephrine and the hyperosmotic agents produced significant increases in developed tension and in the maximal rate of tension rise (dT/dt) in Krebs-Ringer in 2.5 and 4.0 mM calcium. In 10 mM calcium norepinephrine increased developed tension and dT/dt, but sucrose and mannitol caused no change or small reductions in both. Paired electrical stimulation, like hyperosmolality, caused no increase in dT/dt in 10 mM calcium. The presence of a potent pharmacological inhibitor of systolic calcium transfer across the cell membrane (D600, 10(-6) M) reduced developed tension and dT/dt by 76+/-2.7 and 74+/-2.0%, respectively, and prevented and in fact reversed the expected increase in dT/dt associated with an increase in rate of stimulation (treppe). However, hypertonic mannitol and paired pacing persisted in causing marked increases in developed tension and dT/dt even in the presence of D600, suggesting that their inotropic effects are not dependent on increased intracellular transfer of calcium during systole through cell membrane channels in which D600 acts as a competitive inhibitor. The results of these studies suggest that apparent functional saturation of intracellular calcium receptor sites eliminates any additional inotropic effect of hyperosmolality or paired pacing. The data are compatible with the hypothesis that the inotropic effects of hyperosmolality and of paired pacing result from an increase in calcium concentration at the myofilaments during contraction. The increase induced by hyperosmolality might occur because of an increase in the total amount of calcium released into the cytosol with each action potential and/or as a passive consequence of cellular dehydration. Norepinephrine has the capacity to increase contractility even when intracellular calcium receptor sites appear to be functionally saturated, suggesting that it may act at least in part by a mechanism that is independent of changes in net intracellular calcium concentration.

Animals↗