Energy Metabolism In Rat Heart Research Articles

Adaptation to hypoxia alters energy metabolism in rat heart.

The present study characterized metabolic changes in the heart associated with long-term exposure to hypoxia, a potent stimulus for pulmonary hypertension and right ventricular hypertrophy. When anesthetized rats adapted to chronic hypoxia spontaneously respired room air, their mean right intraventricular peak systolic pressure (RVSP) was twice that in normal control animals with the same arterial PO2. RVSP was linearly related to right ventricular mass (r = 0.78). Oxidative capacity (O2 consumption) of homogenates of right and left ventricles from both groups of rats was measured with one of the following substrates: pyruvate, glutamate, acetate, and palmitoyl-L-carnitine. Oxidation of all substrates was significantly greater in the left than in the right ventricle in normal rats but not in hypoxia-adapted animals, where it was the same, within the experimental error. O2 consumption by the left ventricle was greater in control than in experimental rats, but right ventricular O2 consumption was similar in the two groups. Maximal reaction velocity of cytochrome-c oxidase was about the same in the two ventricles, and there were no significant differences between control and hypoxia-adapted animals. HPLC analyses showed significantly higher aspartate levels and aspartate-to glutamate concentration ratios in both ventricles of hypoxic rats than in corresponding tissues from controls, indicative of a decreased flux through the malate-aspartate shuttle under conditions of O2 limitation. Myocardial glutamine levels were lower in hypoxic rats, and glutamine-to-glutamate concentration ratios decreased, although primarily in the pressure-overloaded right ventricle. These findings indicate that normal energy metabolism in the left ventricle differs from that in the right and that the differences, particularly those of amino acid metabolism, are markedly influenced by chronic exposure to hypoxia.

Impact of aging on adenosine levels, A1/A2 responses, arrhythmogenesis, and energy metabolism in rat heart.

Adenosine formation, energy metabolism, A1 and A2 responses, and arrhythmogenesis were examined in hearts from young adult (4-6 mo) and aged rats (18-20 mo). Aging reduced heart rate from 308 +/- 9 to 252 +/- 13 beats/min and myocardial O2 consumption (MVO2) from 127 +/- 5 to 103 +/- 4 microliters O2.min-1.g-1 and increased atrioventricular conduction time from 47 +/- 4 to 61 +/- 8 ms. Differences in intrinsic rate were reduced by A1 antagonism with 10 microM 8-cyclopentyl-1,3-dimethylxanthine. Adenosine efflux and cardiac microdialysate [adenosine] in isovolumically working hearts increased twofold with aging, despite reduced MVO2. Enhanced [adenosine] was not due to altered uptake and catabolism but was associated with twofold higher cytosolic adenosine 5'-monophosphate concentration despite comparable energy state (free energy of ATP hydrolysis = -62.25 +/- 0.38 and -61.78 +/- 0.46 kJ/mol in young adult and aged hearts, respectively). Bradycardia (presumably A1 mediated) was 10-fold more sensitive in aged [-log dose required to produce 50% ectopy (pEC50) = 4.9 +/- 0.1] than in young adult hearts (pEC50 = 3.9 +/- 0.1). Adenosine also became potently arrhythmogenic with aging (-log dose required to produce 20% ectopy = 3.6 +/- 0.3 in young adult and 5.3 +/- 0.2 and aged hearts). Alternatively, vasodilation (presumably A2 mediated) was less sensitive with aging (pEC50 = 6.1 +/- 0.1 in young adult and 4.5 +/- 0.1 in aged hearts; pEC50 = 3.8 +/- 0.1 in young adult and 3.1 +/- 0.1 in aged aortic rings). The data indicate that aging 1) enhances interstitial [adenosine], probably via elevated myocardial adenosine 5'-monophosphate concentration, 2) enhances A1 sensitivity and arrhythmogenesis, and 3) reduces adenosine A2 sensitivity. These changes contribute to altered cardiovascular function in aged hearts.

Effects of glutamic acid on cardiac function and energy metabolism of rat heart during ischaemia and reperfusion

The effects of exogenous glutamate (20 m m) 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 highenergy 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.

Effects of the anti-cancer drug adriamycin on the energy metabolism of rat heart as measured by in vivo 31P-NMR and implications for adriamycin-induced cardiotoxicity

In vivo 31P-NMR was used to measure the effects of the anti-tumor drug adriamycin on the energy metabolism of rat heart. The exclusive acquisition of NMR signal from cardiac muscle was assured by positioning a solenoidal radio-frequency NMR coil around the heart. Appropriate control experiments verified that 31P-NMR spectra solely originated from this organ. Acute effects occurring shortly after adriamycin administration are expressed in 31P spectra as a dose-dependent decline in the cardiac levels of phosphocreatine, after which stabilization at a new steady-state level occurs. These acute effects of a single dose are complete in 30–60 min and no significant further changes take place within 150 min after drug introduction. Longer-term effects of single high doses and of multiple lower doses were measured up to a week after the initiation of treatment. It seemed that at a total dose of 20 mg/kg, drug-induced interference with cardiac energy metabolism was more pronounced than at the same dose in the acute phase. These 31P-NMR data demonstrate that adriamycin treatment is accompanied by a decrease of the cardiac phosphocreatine/ATP ratio which might be an expression of the well-established cardiotoxicity of the drug.

Development of enzymes of energy metabolism in rat heart.

The behavior of several enzymes was studied during rat heart development (4 days before birth to adult stage). Hexokinase has its highest activity during the fetal period; it decreases at birth and remains with low activity in the adult. The alpha-glycerophosphate dehydrogenase and alpha-glycerophosphate oxidase profiles are similar up to the 15th day of development. From there onwards, both profiles diverge, the cytoplasmic activity increasing 3-fold, while the mitochondrial activity remains unchanged. The developmental profiles of the malate dehydrogenases are almost parallel. The development of citrate synthase and succinate dehydrogenase results in a 2- to 4-fold increase in their activities. However, ATPase increases dramatically (20-fold) over the same period. With respect to the enzymes of the adenine nucleotide metabolism, adenylate kinase is fully expressed throughout all ages examined, showing no variation during development. AMP deaminase and creatine kinase increase during development, the cytoplasmic creatine kinase reaching a high level at birth whereas the increases of the mitochondrial enzymes take place gradually during development.

Comparison between developmental and senescent changes in enzyme activities linked to energy metabolism in rat heart

The developmental and senescent patterns of a number of heart enzyme activities linked to energy metabolism have been studied in rats aged between 4 days and 21 months. A morphometric study of mitochondrial volume fractions and numbers has been also carried out. Developmental changes result in a rise of most mitochondrial enzymes (NADP +-isocitrate dehydrogenase, malic enzyme, succinate dehydrogenase, citrate synthase) and mitochondrial volume fractions. Exceptions are NAD +-isocitarte dehydrogenase, which declines from 4 days onwards, and NAD +-malate dehydrogenase, which declines and then rises over the same period. Senescent changes follow two different trends. While pyruvate kinase and those mitochondrial enzymes lying between citrate formation and isocitrate oxidation (citrate synthase, NADP +- and NAD +-isocitrate dehydrogenases) decline to some degree, mitochondrial succinate dehydrogenase and NAD +-malate dehydrogenase activities increase over the same period. This could point towards a partial impairment of Krebs cycle function, and a reduced energy-producing capacity in the aged rat heart.