Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We have previously reported that the heart retains its pumping performance despite loss of contractile mass during tumor disease and malnutrition. This adaptation is associated with increased agonist affinity of the beta-receptor. The present study was undertaken to evaluate if increased beta-receptor agonist affinity has a physiologic counterpart which may contribute to the remained function in hypotrophic hearts. The isolated, perfused, working rat heart was used as a model. Hearts from tumor-bearing rats showed an increased sensitivity and reactivity to graded isoproterenol stimulation compared to freely-fed control animals. Starved and protein-calorie malnourished (PCM) control animals had a similar response of heart rate, left ventricular peak pressure and contractility as the tumor-bearing group. This increased response to beta-adrenergic stimulation thus seems to be a general adaptation to loss of contractile mass and not to a tumor-specific reaction. Tumor-bearing animals had lower myocardial content of norepinephrine and epinephrine compared to starved, PCM and freely-fed control rats. Oxygen consumption was higher in hearts from tumor-bearing animals compared to freely-fed controls during all experimental conditions. Starved and PCM rats, in contrast, had decreased oxygen consumption compared to the freely-fed controls. The heart might thus be one of the organs contributing to the increased energy expenditure seen in malignant tumor disease possibly due to a changed adrenergic regulation in the tumor state compared to uncomplicated undernutrition.
J Mol Cell Cardiol 1987 Jul
PMID:Cardiac sensitivity and responsiveness to beta-adrenergic stimulation in experimental cancer and undernutrition. 282 95

Basal levels of cyclic adenosine monophosphate (cAMP) were measured in embryonic chick hearts at various times during development. Basal cAMP was highest on incubation day 5 and decreased throughout the remaining incubation period. Cyclic AMP could not be stimulated above basal level by intravenous in ovo administration of isoproterenol or tyramine on incubation day 5; however, there was a decrease in cAMP 2 mins after intravenous injection which was identical to the decrease in cAMP in controls injected with saline. Heart rate decreased following intravenous injection of saline on incubation day 5, but a similar decrease was not observed following intravenous isoproterenol injection. Functional sympathetic innervation of the heart does not occur until incubation day 16, and this fact is responsible for the insensitivity to tyramine stimulation on incubation day 5. Although the level of cAMP could not be stimulated above basal level on incubation day 5, beta-antagonists caused a decrease in the level of cAMP, with no decrease in heart rate. These observations indicate that the beta-receptor is coupled to adenylate cyclase on incubation day 5 but it is questionable whether adenylate cyclase is effectively coupled to heart rate. Isoproterenol and tyramine caused a significant elevation in cardiac cAMP and heart rate on incubation day 17 following intravenous in ovo injection. Hearts made sympathetically aneural by removal of premigratory neural crest responded to isoproterenol but not tyramine on incubation day 17 which demonstrates that the morphologically aneural hearts are also functionally aneural.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1986 Aug
PMID:Cyclic AMP in normal and sympathetically aneural chick hearts during development. 287 90

The effects of exogenous glutamate (20 mM) on myocardial energy metabolism and cardiac function during low-flow ischaemia and subsequent reperfusion were studied in isolated working rat hearts. Hearts were made severely ischaemic for 60 min by reducing the perfusion rate to 0.17 ml/min, and then reperfused for 30 min. Low-flow ischaemia resulted in a 50% reduction of myocardial ATP, a 70% reduction of both creatine phosphate (CP) and GTP, and a 250% rise in AMP. After reperfusion, CP was restored to normal levels but ATP and GTP remained significantly low. All hearts failed completely to recover cardiac pump function. The addition of glutamate to the perfusate during low-flow ischaemia had no significant effect on myocardial high-energy phosphates (HEP) but slightly increased succinate production. Subsequent reperfusion without added glutamate resulted in the recovery of 62% of pre-ischaemic aortic flow rate, as well as restoration of myocardial ATP and GTP to 70% of their control values and of creatine phosphate to supranormal levels. Reperfusion with added glutamate did not raise HEP levels any further but did increase recovery of cardiac function to 92% or more of pre-ischaemic values. Thus, by mechanism(s) which are not yet clear but which may include an increase in HEP via anaerobic succinate production, elevated levels of exogenous glutamate exert a highly beneficial effect on the post-ischaemic recovery of cardiac function.
J Mol Cell Cardiol 1988 Nov
PMID:Effects of glutamic acid on cardiac function and energy metabolism of rat heart during ischaemia and reperfusion. 290 55

Energy metabolism was assessed in dilated (congestive) and hypertrophic myopathic hearts from Syrian hamsters after isolated, working heart perfusion with palmitate and/or glucose as substrates. Hearts with these two types of cardiomyopathy were found to be distinctively different from control hearts, and also different from each other. Both cardiomyopathic groups had developed hypertrophy by 3 months but the dilated hearts had a decreased muscle mass by 6 months. In the hypertrophic hearts coronary flow rates per gram of non-collagen protein and, thus, oxygen delivery were markedly increased. With either substrate the hypertrophic hearts maintained more normal levels of adenosine triphosphate in contrast to the dilated hearts whose levels were approximately 50% lower than controls by 6 months of age despite similar heart rates and left ventricular systolic pressure development in all three groups. Lactate to pyruvate ratios in the diseased hearts were comparable to control values. Total coenzyme A levels were statistically lower in the dilated compared to the control group of hearts. Carnitine and its acyl esters, on the other hand, varied markedly with levels of total carnitine decreasing to 50% of control levels in both cardiomyopathic groups by 6 months. In spite of this, the mass action ratios for the carnitine acyl-CoA transferase enzyme complexes were not markedly altered in the control or myopathic hearts regardless of whether palmitate and/or glucose were the perfusate substrates. These results suggest that the decreased carnitine levels are not of sufficient magnitude at this stage in the disease to cause a decrease in cardiac function secondary to restricted energy production. Total carnitine levels were found to be increased in liver and serum of the cardiomyopathic hamsters but unchanged in skeletal muscle. Thus, the deficiency in myocardial carnitine would appear to be due to a specific myocardial problem and not due to a problem of synthesis or supply.
J Mol Cell Cardiol 1986 Mar
PMID:Energy metabolism and mechanical function in perfused hearts of Syrian hamsters with dilated or hypertrophic cardiomyopathy. 293 27

The purpose of this study was to determine whether thyroid hormone could directly affect the phenotypic expression of two isozymic systems [lactate dehydrogenase (LDH) and myosin] and the energy transducing potential of cultured neonatal heart cells. In addition we determined if these biochemical systems developed in culture as they normally do during in vivo post-natal development. Cells were maintained for 14 days in culture medium containing 10% horse serum and Earle's salts. Experimental cultures were supplemented with 10 nmol/l 3,3',5-triiodo-L-thyronine (T3). Hearts used to study in vivo development were excised from rats at the ages of 2 and 14 days post-natal to correspond with the time of isolating and harvesting the cultured heart cells, respectively. Adult hearts were used to represent the final developmental stage. Cultured cardiomyocytes without T3 administered to the culture medium showed no change in the isozymic profiles (myosin and LDH) or in metabolic potential during the 2 week culture period. The T3 treated cultures showed a complete shift to the V1 myosin isozyme. The glycolytic and aerobic metabolic potential [i.e., phosphofructokinase (PFK) and citrate synthase (CS) activities] and the LDH isozyme distribution were unaltered by T3 treatment. During in vivo development a shift toward the V1 myosin and H-LDH isozymes along with an increase in aerobic metabolism occurred in the rat heart. These findings indicate that the development of these selected biochemical systems in cultured cardiac myocytes does not result from an intrinsic myogenetic program and thus must be regulated in vivo by epigenetic factor(s). These results show that T3 has the potential to be the prime determinant of the phenotypic expression of the myosin isoforms, but does not have the potential to be the sole determinant for the expression of the LDH isozymes or the glycolytic (PFK) and aerobic (CS) capacities of cardiac muscle cells.
J Mol Cell Cardiol 1988 Aug
PMID:The effects of triiodothyronine on cultured neonatal rat cardiac myocytes. 297 10

Hearts of genetically myopathic male hamsters (BIO 53 : 58) were studied at 1 month, 2 months, 3 months, 4 to 5 months and 7 months of age. The time course of alterations in the cardiac myofibrillar ATPase activity, the relationship of myofibrillar ATPase activity to free [Ca2+], myosin ATPase activity and the distribution of heavy chain myosin isoenzymes were evaluated. Mg2+-Ca2+ ATPase activity of cardiac myofibrils in myopathics was increased in 4 month and 7 month-old hamsters. Elevated Mg2+ ATPase activity was found as early as in 2-month-old hamster. However, there was no loss in the regulation of the myopathic myofibrillar assembly as measured by the PCa response (10(-7) M to 10(-4) M Ca2+). Scans of SDS electrophoresis slab gels of cardiac myofibrillar proteins from control (C) and myopathic animals (M) did not show any differences at any age group (1, 4 and 7 months). There was a significant decrease in myosin Ca2+ ATPase activity and actin activated Mg2+-ATPase activity at 4 to 5 months and 7 months of age in the myopathic hearts. At all ages in normal and myopathic animals cardiac myosin consisted of three isoenzymes, V1, V2 and V3. At all ages in controls and at 1 to 3 months in myopathics, V1 predominated and the isoenzyme distribution was V1 greater than V2 greater than V3. However, in myopathics at 4 to 5 months, the distribution was V1 = V3 greater than V2 and at 7 months was V3 greater than V2 greater than V1. Our experiments suggest alterations in different components of the contractile protein system that occur at different stages of myopathy.
J Mol Cell Cardiol 1985 Feb
PMID:Multiple cardiac contractile protein abnormalities in myopathic Syrian hamsters (BIO 53 : 58). 315 46

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

Regional variations in the size and shape of isolated myocytes were studied using the two-kidney, one clip (2K1C) renal model of hypertension. Weanling male Sprague-Dawley rats (50 to 75 g) were anesthetized by ketamine (100 mg/kg) during renal artery clipping (0.2 mm internal diameter silver clip) and were then allowed to grow for 6 to 8 weeks, when the blood pressure had stabilized at 180 mmHg. Hearts were removed, weighed and then were perfused with a calcium-free Joklik medium containing collagenase. Isolated myocytes were collected from five regions and fixed in isoosmolar glutaraldehyde: right ventricular free wall (RVFW), right and left halves of the interventricular septum (RIVS, LIVS), and epicardial and endocardial halves of the left ventricular free wall (LEPI, LENDO). Myocyte volume was measured by Coulter Counter. Myocyte length was measured by sonic digitizer. Cross-sectional area was calculated from myocyte volume and length. Tailcuff systolic pressure and heart weight were significantly increased in 2K1C rats as compared to control. Body weights were not different. Cell volume was significantly increased in RIVS, LIVS, LEPI, and LENDO, but not in RVFW. Cell length was not significantly increased in any region. Thus, the 2K1C model showed a predominant left ventricular hypertrophy in which the right half of the septum acted in concert with the left ventricle. The shape of the hypertrophied myocytes, having an increase in volume due to an increase in cross-sectional area but not length, was most consistent with a pressure-induced form of cardiac hypertrophy.
J Mol Cell Cardiol 1988 Nov
PMID:Regional myocyte size in two-kidney, one clip renal hypertension. 323 84

Coenzyme A (CoA) degradation was studied in isolated working hearts from acutely diabetic rats (48 h). Hearts from diabetic rats had elevated levels of total CoA (752 +/- 15 nmol/g dry) compared to control (537 +/- 14 nmol/g dry). When hearts from diabetic animals were perfused for 5 mins with perfusate containing pyruvate, (5 mM) and glucose (11 mM) CoA levels remained unchanged. Addition of palmitate, (1.2 mM) and glucose (11 mM) to the perfusate, however, resulted in a rapid drop in CoA levels to 672 +/- 19 nmol/g dry. Palmitate had no effect on CoA levels in control hearts which did not have elevated levels of CoA. Addition of insulin to the buffer containing glucose and palmitate prevented the decrease in CoA levels in diabetic hearts. The level of long chain acyl CoA in diabetic hearts perfused with pyruvate was 105 +/- 11 nmol/g dry, and did not change when insulin was present in the perfusate. In the presence of palmitate, levels of long chain acyl CoA increased from 76 +/- 16 to 149 +/- 13 nmol/g dry, and, in this case, addition of insulin caused a further increase to 192 +/- 18 nmol/g dry. Thus, the lower rate of CoA degradation in the presence of insulin was associated with a rise in long chain acyl CoA levels. In a separate series of experiments, CoA levels were increased in control hearts in vitro (from 537 +/- 14 to 842 +/- 19 nmol/g dry). Subsequent perfusion of these hearts that contained elevated CoA with palmitate also resulted in a rapid drop of CoA to 655 +/- 17 nmol/g dry.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1987 Mar
PMID:Coenzyme A degradation in the heart: effects of diabetes and insulin. 329 61

In a previous study, we demonstrated a significant release of adenosine, inosine and hypoxanthine during hypoxia and subsequent reoxygenation. The present study was designed to determine whether or not exogenous adenosine, inosine and hypoxanthine are beneficial for the recovery of hypoxia-induced loss of cardiac contractile force. Hearts were perfused for 20 min under hypoxic conditions, followed by 45 min-perfusion under reoxygenated conditions, and changes in contractile force, resting tension and metabolic parameters of the perfused heart were examined. When either adenosine, inosine or hypoxanthine were exogenously infused during hypoxia at the rate of 3 mumol/min, remarkable recovery (61 to 68%) of cardiac contractile force was observed upon reoxygenation. The recovery was accompanied by a significant restoration of myocardial ATP (90 to 100%) and CP contents (80 to 86%), suggesting that exogenous metabolites are utilized for the restoration of myocardial ATP during reoxygenation, which may lead to a beneficial recovery of hypoxia-induced loss of cardiac contractile force upon reoxygenation. Infusion of exogenous metabolites also resulted in an almost complete inhibition of hypoxia- and reoxygenation-induced release of creatine phosphokinase from the perfused heart as well as a significant depression of hypoxia-induced calcium accumulation in the cardiac tissue. Since these phenomena are considered to represent increases in cell membrane permeability, protection of the myocardium against hypoxia- and reoxygenation-induced changes in cell membrane permeability may be an alternative mechanism for the beneficial effect of adenosine, inosine and hypoxanthine on the hypoxic myocardium.
J Mol Cell Cardiol 1988 Mar
PMID:Adenine nucleotide metabolites are beneficial for recovery of cardiac contractile force after hypoxia. 339 53


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