Jong, J.W. de

Metabolic and genetic regulation of cardiac energy substrate preference (Article)

2006-10-03T00:00:00Z

Proper heart function relies on high efficiency of energy conversion. Mitochondrial oxygen-dependent processes transfer most of the chemical energy from metabolic substrates into ATP. Healthy myocardium uses mainly fatty acids as its major energy source, with little contribution of glucose. However, lactate, ketone bodies, amino acids or even acetate can be oxidized under certain circumstances. A complex interplay exists between various substrates responding to energy needs and substrate availability. The relative substrate concentration is the prime factor defining preference and utilization rate. Allosteric enzyme regulation and protein phosphorylation cascades, partially controlled by hormones such as insulin, modulate the concentration effect; together they provide short-term adjustments of cardiac energy metabolism. The expression of metabolic machinery genes is also dynamically regulated in response to developmental and (patho)physiological conditions, leading to long-term adjustments. Specific nuclear receptor transcription factors and co-activators regulate the expression of these genes. These include peroxisome proliferator-activated receptors and their nuclear receptor co-activator, estrogen-related receptor and hypoxia-inducible transcription factor 1. Increasing glucose and reducing fatty acid oxidation by metabolic regulation is already a target for effective drugs used in ischemic heart disease and heart failure. Interaction with genetic factors that control energy metabolism could provide even more powerful pharmacological tools.

Peripheral blood lymphocyte cell subsets in subjects with chronic obstructive pulmonary disease: association with smoking, IgE and lung function (Article)

1997-01-01T00:00:00Z

In contrast to the numerous studies which show that lymphocytes play an important role in the pathogenesis of asthma, few studies have investigated the role of lymphocytes in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of the present study was to investigate lymphocyte subsets in peripheral venous blood of smoking and non-smoking COPD patients and healthy controls. The interaction of smoking and IgE has also been assessed, and it was investigated whether a lower level of FEV1 was associated with changes in lymphocyte subsets. In the present study, peripheral venous blood lymphocyte subsets were investigated in 42 smoking and non-smoking, non-atopic subjects with a clear diagnosis of COPD (43-74 years) who all used bronchodilator therapy only, and in 24 normal, healthy control subjects (40-72 years). No significant differences in lymphocyte subsets were found when either total groups or smoking subjects of both groups were compared. However, the percentage of CD8+ lymphocytes (suppressor/ cytotoxic T-cells) was significantly higher in the non-smoking COPD subjects compared with the non-smoking, healthy control subjects (P < 0.05). In addition, within the group of non-smoking COPD subjects, a higher CD4:CD8 ratio was associated with a higher FEV1 as a percentage of predicted (% pred.) (r = 0.55, P = 0.01) and a lower total serum IgE (r = -0.45, P = 0.04). Within the group of smoking COPD subjects, a higher FEV1 % pred. was associated with a higher percentage of CD19+ lymphocytes (B-cells) (r = 0.65, P < 0.01). The present study provides further evidence that the changes in the balance of T-cell subsets and IgE synthesis possibly plays a role in the pathogenesis of COPD.

Controversies in preconditioning (Article)

1997-01-01T00:00:00Z

Preconditioning is an effective mean of protecting the heart against prolonged ischemia by pretreating it with a minor insult, and the present paper reviews various controversies in this highly active field of research. In many models, adenosine plays a role by triggering the activation of protein kinase C. It may work in conjunction with other agents, such as bradykinin, but the putative role of noradrenaline is uncertain. Regulation of the enzyme producing adenosine (i.e., 5'-nucleotidase) has been reported during preconditioning but, because its activity does not seem to be associated with infarct size, it is unlikely that the hydrolase plays a pivotal role. Controversial data have been published on the involvement of mitochondrial ATPase, which may be ascribed to the poor time resolution of the experiments described; however, we do not believe that either acidosis or tissue ATP are important factors in triggering preconditioning. The role of glycolysis in the preconditioning effect remains to be firmly established; opposite mechanisms are activated in low-flow and stop-flow protocols. Although species differences regarding preconditioning exist, they seem to be more of a quantitative than a qualitative nature. The phenomenon could be clinically relevant because evidence is accumulating that preconditioning may take place during bypass surgery and coronary angioplasty if longer balloon-occlusion times are used.

Preconditioning in globally ischemic isolated rat hearts: effect on function and metabolic indices of myocardial damage (Article)

1996-01-01T00:00:00Z

We assessed the effects of ischemic preconditioning on heart recovery and metabolic indices of damage following global ischemia and reperfusion, in relationship to post-ischemic lactate release. Three groups of Langendorff rat hearts were studied: (1) A control group of 40 min global ischemia and 45 min reperfusion; (2) preconditioning by 5 min global ischemia and 15 min reperfusion prior to sustained ischemia and reperfusion; (3) Preconditioning by three episodes of brief ischemia-reperfusion prior to sustained ischemia. Repetitive episodes of brief ischemia-reperfusion were associated with increased reactive hyperemia, decreased release of purines and prostaglandin 6-keto F1 alpha, lower tissue glycogen but no change in lactate washout. After 40 min ischemia, release of lactate was 173 +/- 17, 196 +/- 6 and 149 +/- 9 mumol/g in groups 1, 2 and 3, respectively (P < 0.01, group 2 v group 3). Preconditioning had no effect on ischemic arrest but had divergent effects on the development and the magnitude of ischemic contracture: delay and attenuation in group 2 but enhanced onset in group 3. Preconditioning provided a dose-dependent protection from the increase in left ventricular end-diastolic pressure, reduced the reperfusion release of purine metabolites and of creatine kinase, but neither improved systolic function nor prevented arrhythmia. 6-Keto F1 alpha production was 87 +/- 13, 132 +/- 19 and 241 +/- 35 pmol/g in groups 1, 2, 3, respectively (P < 0.01 group 1 v group 3). We conclude that when subjected to prolonged global ischemia, preconditioned isolated rat hearts develop less post-ischemic contracture, lose less purine nucleosides and creatine kinase activity. In addition, preconditioning leads to increased production of prostacyclin. Differences among preconditioning protocols in lactate production seem to be related to the ischemic contracture development, but may not play an ultimate role in attenuation of myocardial damage or improvement of postischemic recovery.

Myocardial malondialdehyde and uric acid release after short-lasting coronary occlusion during coronary angioplasty: potential mechanisms for free radical generation (Article)

1991-01-01T00:00:00Z

Myocardial release of hypoxanthine and lactate during percutaneous transluminal coronary angioplasty (Article)

1989-01-01T00:00:00Z

The response of myocardial lactate and hypoxanthine metabolism during percutaneous transluminal coronary angioplasty was studied in a series of 15 patients undergoing this procedure. A minimum of 4 balloon inflations was performed per patient with an average duration per occlusion of 49 +/- 11 seconds (mean +/- standard deviation) for a total occlusion time of 192 +/- 40 seconds. Thermodilution coronary venous blood flow measured in the great cardiac vein decreased from control values of 72 +/- 4 ml/min (mean +/- standard error of the mean) to 47 +/- 10 ml/min with the fourth coronary occlusion (p less than 0.005). Arteriovenous lactate and hypoxanthine showed peak differences during the reactive hyperemia after the first 2 occlusions which did not increase after subsequent occlusions. Within minutes after the procedure, lactate and hypoxanthine efflux was no longer seen, demonstrating the reversibility of the metabolic disturbances after repeated ischemia. The results of this study indicate that there is no permanent alteration in lactate or hypoxanthine metabolism after percutaneous transluminal coronary angioplasty with 4 coronary occlusions of 40 to 60 seconds' duration, with a total occlusion time of 192 +/- 40 seconds.

Urate production by human heart (Article)

1989-01-01T00:00:00Z

Xanthine oxidoreductase has been demonstrated in the heart of various species. However, its presence in human heart is still debated. In the literature, high to undetectable levels have been reported. We studied the arterial-venous urate difference across the heart of patients undergoing both routine cardiac catheterization and percutaneous transluminal coronary angioplasty. Urate is the end product of the reaction catalysed by xanthine oxidoreductase. In 10 patients, studied before angioplasty, the plasma urate level in the great cardiac vein exceeded the arterial one by 26 +/- 10 nmol/ml (P = 0.028). In a further 13 patients, urate production was maximal immediately after the last of four consecutive occlusions (23 +/- 8 nmol/ml, P = 0.018) and concomitant with increased coronary sinus hypoxanthine levels. We conclude that xanthine oxidoreductase is probably present in the heart of patients, suffering from ischemic heart disease, and responsible for the increase in urate production during transient myocardial ischemia.

Regional cardioprotection by subselective intracoronary nifedipine is not due to enhanced collateral flow during coronary angioplasty (Article)

1987-01-01T00:00:00Z

Twelve patients with proximal stenosis of the left anterior descending artery, normal myocardial wall motion but without angiographically demonstrable collateral circulation, were studied during transluminal occlusion. Prior to the first transluminal occlusion before crossing the lesion with the balloon, patients were randomly given 0.2 mg nifedipine or its solvent in the left mainstem. The same dose was repeated via the balloon catheter, positioned across the lesion, immediately prior to the second transluminal occlusion. In all patients great cardiac venous flow and ST-elevation were monitored during and after each transluminal occlusion. The lactate extraction ratio A-GCV/A (A = arterial, GCV = great cardiac vein) was determined prior to the angioplasty procedure, 10-15 seconds after each transluminal occlusion and 10 minutes after the third transluminal occlusion. Great cardiac venous flow rose significantly to an average of 160% of basal flow when nifedipine was administered into the mainstem before the angioplasty procedure while its solvent had no effect. During each transluminal occlusion, great cardiac venous flow diminished on average by 30% in those who received nifedipine and by 28% in those who received only its solvent. This difference was statistically not significant. After angioplasty great cardiac venous flow was slightly, but not significantly, increased in both groups with respect to basal flow (104% resp. 120% of control). Patients who received nifedipine in the post-stenotic area just before the second transluminal occlusion, had significantly lower lactate production, measured immediately after the transluminal occlusion compared with the patients who received only its solvent (P less than 0.01). The ST-elevation during the second transluminal occlusion was significantly lower in the nifedipine group (0.1 mm in nifedipine group versus 1.4 mm in solvent group; P less than 0.05, unpaired t-test). Nifedipine given intracoronary in the post-stenotic area just before coronary angioplasty reduces lactate release and electrocardiographic signs of myocardial ischemic injury. This regional cardioprotective effect seems not due to an enhanced collateral flow, but to a regional cardioplegic effect, which precedes the ischemic event.

Nifedipine for angina and acute myocardial ischemia (Article)

1983-01-01T00:00:00Z

This paper reviews the mechanisms believed to be responsible for myocardial ischaemia and the mode of action of calcium antagonist drugs. The clinical management of patients with myocardial ischaemia is discussed in the context of current knowledge about patho-physiology and drug action.

Hypoxanthine production by ischemic heart demonstrated by high pressure liquid chromatography of blood purine nucleosides and oxypurines (Article)

1981-01-01T00:00:00Z

An isocratic high pressure liquid chromatographic system was developed for the estimation of purine nucleosides and oxypurines in blood. Use was made of a reversed-phase column. Nucleotides derived from erythrocytes affected the separation; these compounds were removed with A12O3. The recovery of the whole clean-up procedure exceeded 75%, and the lower detection limit of the assay for blood metabolites was 0.1 mumol/l. In 6 healthy volunteers, non-resting, the following blood concentrations (mean values +/- S.D. in mumol/l) were observed: adenosine (less than 0.1), inosine (0.2 +/- 0.1), hypoxanthine (2.2 +/- 1.3) and xanthine (0.2 +/- 0.1). In plasma and serum the total amount of these compounds was 1.9 and 5.4 times higher, respectively, presumably due to nucleotide breakdown during blood processing. The myocardial arterial-venous differences of blood purine nucleosides, oxypurines and lactate were subsequently measured in blood samples from 13 patients with angiographically documented ischemic heart disease, undergoing an atrial pacing stress test. No significant release of adenosine, inosine and xanthine by the heart was detectable in this study. The myocardial arterial-venous difference of lactate changed from 0.01 +/- 0.03 mmol/l (mean +/- SEM) at rest, to -0.10 +/- 0.04 mmol/l during pacing (p less than 0.002). Relatively larger changes were observed for hypoxanthine: pacing increased the arterial-venous difference from -0.01 +/- 0.05 to -0.51 +/- 0.17 mumol/l (p less than 0.02). We conclude that the high pressure liquid chromatographic assay of blood hypoxanthine is a useful tool in the diagnosis of ischemic heart disease.

Palmitate activation : aspects of palmitate metabolism (Doctoral Thesis)

1971-12-08T00:00:00Z