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Left ventricular (LV) contractile function and pump function were depressed in isolated working hearts from rats treated with either guanidinopropionic acid (GPA), an inhibitor of creatine influx, or the anthracycline antibiotic, adriamycin, for 6 and 10 weeks, respectively. In both groups of treated animals myocardial phosphocreatine content was lower than in control hearts, while ATP content was unchanged. Hearts of treated animals exhibited only a minor depression of cardiac output with a submaximal pressure load or during volume overload. However, at maximal pressure load GPA- and adriamycin-treated hearts performed 43% and 37% less pressure-volume work than control hearts. These changes were due both to decreased LV pressure development and diminished cardiac output. LV diastolic stiffness was significantly higher at the submaximal pressure load and the LV filling pressure area, which reflected LV filling, was lower in hearts of both treated groups. The differences in both indices were exaggerated when the maximal pressure load was applied. Limited LV filling due to incomplete myocardial relaxation appeared to represent the underlying cause of cardiac failure when afterload was increased. These results may be explained if adaptation of cardiac contractile function in some chronic cardiac diseases arises from a limited energy supply to the myofibrils.
J Mol Cell Cardiol 1989 Feb
PMID:Adaptation of cardiac contractile function to conditions of chronic energy deficiency. 273 32

Using data derived from clinical and experimental observations, we examine the role of the myocardial beta-adrenergic receptor system in pathophysiologic processes involved in heart muscle disease and heart failure. The available data suggest that the sympathetic nervous system exerts important influences on myocardial structure and function. As such the beta-adrenergic pathways represents an obvious locus for therapeutic intervention in evolving cardiomyopathic states.
J Mol Cell Cardiol 1985 Jul
PMID:Beta-adrenergic function in heart muscle disease and heart failure. 286 87

The sequence of myocardial changes in the mouse induced by doxorubicin (Dx) treatment (10 mg/kg i.v.) has been investigated by electron microscopy with the help of the zinc iodide-osmium tetroxide (ZIO) technique. Accumulation of ZIO-reactive material, possibly oxidized glutathione and other disulfides, in the sarcoplasmic reticulum (S.R.) is among the earliest (1 h after Dx injection), more prominent and persistent findings (up to 100 days). It may have a pathogenic relationship with a number of functional and morphologic changes occurring in myocardial cells, including impairment of calcium transport and contractility, S.R. dilation up to extensive vacuolization, as well as inhibition of DNA, RNA and protein synthesis leading to atrophy and disruption of sarcomeres. The latter finding, first appearing in a few cells 4 to 7 days after Dx and progressively increasing in severity and extension during the next 3 months, may represent a key factor in the evolution of chronic cardiomyopathy to cardiac insufficiency. In most cells, only a minority of mitochondria showed obvious ultrastructural lesions, which were first observed 24 h after treatment and disappeared by the end of the first month, when no more mitochondrial damage was found outside degenerating cells. The myocardium of mice receiving multiple Dx injections (4 mg/Kg, 10 times, or 9 mg/Kg, 5 times) showed the same changes observed in animals treated with a single dose, though they were more severe and extensive.
Virchows Arch B Cell Pathol Incl Mol Pathol 1985
PMID:Early and late sarcoplasmic reticulum changes in doxorubicin cardiomyopathy. An ultrastructural investigation with the zinc iodide-osmium tetroxide (ZIO) technique. 286 24

Alpha-adrenoceptor (alpha-AR) mechanisms may contribute to systolic and diastolic dysfunction of the left ventricle. Centrally acting alpha 2-AR agonist drugs, including methyldopa, clonidine, and guanabenz, activate brainstem alpha 2-AR and this activation results in a decrease in overall sympathetic tone and an increase in parasympathetic tone. Peripherally acting alpha 1-AR antagonists, such as prazosin, inhibit the actions of catecholamines at post-synaptic receptor sites. Heart failure is characterized by hyperactivity of sympathetic pathways and parasympathetic withdrawal. In this situation, alpha 2-agonists reduce sympathetic activity and improve hemodynamic parameters of cardiac function; both acute and chronic administration of alpha 2-AR have been demonstrated to reduce serum catecholamine levels, heart rate, and arterial blood pressure, and to improve exercise performance. Diastolic dysfunction of the left ventricle is characterized by a marked decrease in ventricular compliance, often a result of hypertension and left ventricular hypertrophy; the end result is an increase in left ventricular filling pressure and pulmonary venous pressure. Treatment with alpha 2-AR, by decreasing sympathetic tone and blood pressure, and alpha 1-AR antagonists, by reducing blood pressure and by directly inhibiting the actions of catecholamines at alpha 1-AR, may produce a reduction in the degree of ventricular hypertrophy and improve diastolic performance of the left ventricle. Thus, therapeutic intervention in heart failure with either alpha 2-AR agonists or alpha 1-AR antagonists may favorably modulate these alterations in sympathetic tone and improve ventricular function.
J Mol Cell Cardiol 1986 Nov
PMID:Alpha-adrenergic mechanisms in the pathophysiology of left ventricular heart failure--an analysis of their role in systolic and diastolic dysfunction. 287 38

beta-Adrenoceptor concentrations have been measured in ventricles of rabbits with adriamycin-induced cardiomyopathy. Despite considerable cardiac hypertrophy (1.6 +/- 0.7 mean +/- S.E.M. g ventricle/kg body wt, n = 6; to 2.2 +/- 0.1) no change in beta-adrenoceptor density was observed (33.8 +/- 2.0 fmol/mg protein in membranes from cardiomyopathic rabbits compared with 36.8 +/- 3.0 for controls). Furthermore, no alteration in the profiles of high affinity agonist binding was observed, and the receptor interaction with the adenylate cyclase stimulatory coupling factor was unimpaired. These results indicate that, despite the marked changes which occur during the development of this model of low-output heart failure, the cardiac beta-adrenoceptor systems are normal.
J Mol Cell Cardiol 1988 Sep
PMID:Ventricular beta-adrenoceptors in adriamycin-induced cardiomyopathy in the rabbit. 290 8

We investigated systolic blood pressure (BP), ventricular myosin isoenzyme (MI) pattern, and myosin P-light chain phosphorylation (MP) of male and female normotensive (WKY) and spontaneously hypertensive rats (SHRSP). BP increased in SHRSP of both sexes during maturation. Male SHRSP reached a significantly higher BP (262 mmHg at week 64) than female SHRSP (217 mmHg at week 64). WKY remained at approximately 114 mmHg throughout the life-span investigated (5 to 64 weeks). MI pattern (expressed as %V1/%V3) shifted age-dependent to the V3 form: In female SHRSP MI pattern was 41/25 at week 18, 34/35 and 40/38 within week 22 to 32, and shifted to 18/53 until week 64. In male SHRSP MI pattern was 25/44 at week 18 and shifted gradually to 13/60 until week 53. MI patterns of WKY of both sexes were 100% V1 within week 5 to 12, shifted gradually to 51/23 and then remained constant until week 64. MP of the ventricle of female WKY and SHRSP was approximately 41% until week 52. At week 64, however, MP of female SHRSP decreased to 18% whereas female WKY remained at approximately 41%. MP of the ventricle of male WKY and SHRSP was approximately 38% until week 38. At week 44, however, MP of male SHRSP decreased to 22% whereas male WKY remained constant. Isometric tension generation of chemically skinned rat ventricular fibres increased after MP by calcium-calmodulin-dependent myosin light chain kinase. Both the shift to the V3 form and the decreased MP level might contribute to the development of cardiac failure in old SHRSP of both sexes.
J Mol Cell Cardiol 1988 Oct
PMID:Chronic hypertension changes myosin isoenzyme pattern and decreases myosin phosphorylation in the rat heart. 297 39

Rats were fed a diet containing beta-guanidinopropionic acid (GP), an inhibitor of creatine transport. After 6 to 8 weeks of feeding the myocardial creatine (Cr) and phosphocreatine (PCr) stores were severely depleted while ATP content was normal. Hearts of GP-treated rats perfused according to Neely's working heart model revealed clear cardiac contractile failure: the maximal work capacity at a stepwise increase in resistance as well as the maximal oxygen consumption were 32 to 40% less in the GP group. The cardiac failure in GP-treated working hearts was associated with a rise in the left ventricular diastolic pressure, which could cause a diminished cardiac output probably due to impaired LV filling. The extent of the contractile failure was found to depend on functional load and on the degree of Cr (PCr) substitution. The energy fluxes through creatine kinase measured by the 31P-NMR saturation transfer technique were diminished by a factor of two after substitution of 90% of creatine, but still exceeded the rate of ATP turnover. The results are compatible with the concept of phosphocreatine pathway for intracellular energy transport and show that PCr is an important high energy phosphate compound for cardiac contractile function.
J Mol Cell Cardiol 1988 Jun
PMID:The cardiac contractile failure induced by chronic creatine and phosphocreatine deficiency. 321 3

The effects of graded hypoxia, graded reoxygenation after anoxic perfusion and of different extracellular K+-concentrations on cardiac energy metabolism and performance were studied in isolated, perfused, electrically paced rat hearts. Graded hypoxia was induced by different oxygen partial pressure (PO2: 736 to 43 mmHg, nine intermediate steps; O2 supply: (AVD*CF): 300 to 21 microliters/g*min) in perfusate for 3 min, thus leading to different levels of relative mechanical steady state. Evaluated free energy change of ATP-hydrolysis (dG/d zeta) decreased largely in parallel with peak systolic pressure (Psyst) and systolic dP/dtmax, whereas diastolic dP/dtmin declined already to lowest values with moderate hypoxia. For regular beats and beats potentiated by paired stimulation the same relationships were found. Complete reoxygenation of hearts perfused anoxically beforehand (10 or 30 min, PO2 less than 6 mmHg), restored Psyst and dG/d zeta completely. Graded reoxygenation from different levels of hypoxia resulted in restitution of dG/d zeta and Psyst to the same levels as in graded hypoxia. The inotropic effect of paired stimulation was moderately reduced. Cytosolic Pi-levels remained increased during partial reoxygenation and exhibited no distinct relationship with mechanical performance. High extracellular K+ (13.5 mM) resulted in increased Psyst and elevated dG/d zeta-levels. Cardiac failure during graded hypoxia and high K+ occurred at comparatively high dG/d zeta levels. Reoxygenation with high K+, led to recovery of dG/d zeta levels but not of Psyst values. According to the results obtained in early hypoxic failure free energy dependence of Na+/K+-ATPase is of minor relevance whereas free energy dependence of sarcoplasmic Ca2+ regulating processes appears to be important.
J Mol Cell Cardiol 1988 Dec
PMID:Myocardial performance and free energy of ATP-hydrolysis in isolated rat hearts during graded hypoxia, reoxygenation and high Ke+-perfusion. 324 7

The effect of therapeutic doses of digitalis in modifying neural activity has been the subject of considerable controversy. In earlier studies we reported an increase both in serotonergic activity in the posterior hypothalamus and pons-medulla and in cardiac sympathetic tone in the failing cardiomyopathic hamster. In this study we examine the effects of doses of digitoxin, known to be therapeutic for hamster heart failure, on monoamine neurotransmitter metabolism in the brain and heart during the cardiomyopathy. Both digitoxin and ASI-222, a polar amino-glycoside which does not cross the blood-brain barrier, given either acutely (6 mg/kg ip) or chronically (2 mg/kg/day ip for 10 days), normalized the failure-induced increase in serotonin turnover in the pons-medulla but had no effect on the changes in the posterior hypothalamus. Digitoxin therapy also reduced cardiac and adrenal sympathetic activity partially restoring cardiac catecholamine stores. In order to more clearly define the pathways involved we measured serotonin (microgram/g protein) in 18 brain nuclei after 10 days of digitoxin or vehicle treatment. Heart failure was associated with an increase in serotonin in five nuclei: the mammillary; bodies, ventromedial, periventricular and paraventricular nuclei of the hypothalamus, and the centralis superior nucleus of the raphe. Digitoxin therapy completely normalized the changes in the centralis superior and ventromedialis nuclei; neither congestive heart failure nor digitoxin affected serotonin levels in other nuclei. We conclude that there is an increase in activity in specific brain serotonergic nuclei in congestive heart failure. Digitalis reduces cardiac sympathetic tone and restores the changes in two of these nuclei: the ventromedial and the centralis superior.+2
J Mol Cell Cardiol 1985 Nov
PMID:Digitoxin therapy partially restores cardiac catecholamine and brain serotonin metabolism in congestive heart failure. 407 5

Concentric left ventricular hypertrophy was produced in puppies by coarctation banding of the aorta at age 7 weeks. Hemodynamic, morphologic and biochemical studies were carried out 18 months after the operation. Systolic blood pressure proximal to the aortic constriction was 216 +/- 16 mmHg in experimental dogs compared with 115 +/- 5 mmHg in littermate control dogs. Ejection fraction of control and experimental dogs were 59 +/- 4 and 64 +/- 7, respectively. The left ventricular end-diastolic pressure was 6.0 +/- 0.4 in control and 8.4 +/- 1.1 in experimental dogs. There was no sign of overt heart failure in the experimental dogs. Anatomical analysis of different regions of the heart indicated that LV mass in the experimental dogs was increased by about 60%. Ultrastructure of mitochondria in situ, as observed under electron microscope, was normal both in control and hypertrophic hearts. Mitochondria isolated from epicardial and endocardial regions of the stable hypertrophic hearts showed normal rates of respiration, phosphorylation, citrate synthase, and cytochrome c oxidase activities compared to those isolated from hearts of littermate control dogs. It was, therefore, concluded that mitochondrial function is adequately preserved to meet the increased demand for energy in this model of stable cardiac hypertrophy of long duration.
J Mol Cell Cardiol 1983 Apr
PMID:Mitochondrial function in canine experimental cardiac hypertrophy. 630 71


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