▪ Abstract Immune cell–mediated destruction of pathogens may result in excessive collateral damage to normal tissues, and the failure to control activated immune cells may cause immunopathologies. The search for physiological mechanisms that downregulate activated immune cells has revealed a critical role for extracellular adenosine and for immunosuppressive A2A adenosine receptors in protecting tissue from inflammatory damage. Tissue damage–associated deep hypoxia, hypoxia-inducible factors, and hypoxia-induced accumulation of adenosine may represent one of the most fundamental and immediate tissue-protecting mechanisms, with adenosine A2A receptors triggering “OFF” signals in activated immune cells. In these regulatory mechanisms, oxygen deprivation and extracellular adenosine accumulation serve as “reporters,” while A2A adenosine receptors serve as “sensors” of excessive tissue damage. The A2A receptor–triggered generation of intracellular cAMP then inhibits activated immune cells in a delayed negative...

Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors.

Daniel 1. Sessler, M. D. * ANESTHESIA and surgery commonly cause substantial thermal perturbations. Hypothermia, the typical alteration, results from a combination of anesthetic-induced impairment of thermoregulatory control, a cool operating room environment, and factors unique to surgery that promote excessive heat loss. Available data suggest that inhibition of normal thermoregulatory defenses contributes more to hypothermia than does cold exposure per se. Furthermore, much core hypothermia results from altered distribution of body heat rather than from a systemic imbalance between metabolic heat production and heat loss.

Perioperative Heat Balance

Isothermal titration calorimetry (ITC) is now routinely used to directly characterize the thermodynamics of biopolymer binding interactions and the kinetics of enzyme-catalyzed reactions. This is the result of improvements in ITC instrumentation and data analysis software. Modern ITC instruments make it possible to measure heat effects as small as 0.1 microcal (0.4 microJ), allowing the determination of binding constants, K's, as large as 10(8) - 10(9)M(-1). Modern ITC instruments make it possible to measure heat rates as small as 0.1 microcal/sec, allowing for the precise determination of reaction rates in the range of 10(-12) mol/sec. Values for K(m) and k(cat), in the ranges of 10(-2) - 10(3) microM and 0.05 - 500 sec(-1), respectively, can be determined by ITC. This chapter reviews the planning of an optimal ITC experiment for either a binding or kinetic study, guides the reader through simulated sample experiments, and reviews analysis of the data and the interpretation of the results.

Isothermal Titration Calorimetry: Experimental Design, Data Analysis, and Probing Macromolecule/Ligand Binding and Kinetic Interactions

The thyroid hormones are very hydrophobic and those that exhibit biological activity are 3',5',3,5-L-tetraiodothyronine (T4), 3',5,3-L-triiodothyronine (T3), 3',5',3-L-triiodothyronine (rT3) and 3,5',-L-diiothyronine (3,5-T2). At physiological pH, dissociation of the phenolic -OH group of these iodothyronines is an important determinant of their physical chemistry that impacts on their biological effects. When non-ionized these iodothyronines are strongly amphipathic. It is proposed that iodothyronines are normal constituents of biological membranes in vertebrates. In plasma of adult vertebrates, unbound T4 and T3 are regulated in the picomolar range whilst protein-bound T4 and T3 are maintained in the nanomolar range. The function of thyroid-hormone-binding plasma proteins is to ensure an even distrubtion throughout the body. Various iodothyronines are produced by three types of membrane-bound cellular deiodinase enzyme systems in vertebrates. The distribution of deiodinases varies between tissues and each has a distinct developmental profile. Thyroid hormones. (1) the nuclear receptor mode is especially important in the thyroid hormone axis that controls plasma and cellular levels of these hormones. (2) These hormones are strongly associated with membranes in tissues and normally rigidify these membranes. (3) They also affect the acyl composition of membrane bilayers and it is suggested that this is due to the cells responding to thyroid-hormone-induced membrane rigidificataion. Both their immediate effects on the physical state of membranes and the consequent changes in membrane composition result in several other thyroid hormone effects. Effects on metabolism may be due primarily to membrane acyl changes. There are other actions of thyroid hormones involving membrane receptors and influences on cellular interactions with the extracellulara matrix. The effects of thyroid hormones are reviewed and appear to b combinations of these various modes of action. During development, vertebrates show a surge in T4 and other thyroid hormones, as well as distinctive profiles in the appearance of the deiodinase enzymes and nuclear receptors. Evidence from the use of analogues supports multiple modes of action. Re-examination of data from th early 1960s supports a membrane action. Findings from receptor 'knockout' mice supports an important role for receptors in the development of the thyroid axis. These iodothyronines may be better thought of as 'vitamone'-like molecules than traditional hormonal messengers.

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Thyroid hormones and their effects: a new perspective

OBJECTIVE--To compare the effects of metoprolol and atenolol on carbohydrate and lipid metabolism and on insulin response to an intravenous glucose load. DESIGN--Randomised, double blind, double dummy, controlled crossover trial. SETTING--University Hospital, Uppsala, Sweden. PATIENTS--60 Patients with primary hypertension (diastolic blood pressure when resting supine 95-119 mm Hg on at least two occasions during four to six weeks of treatment with placebo) randomised to receive either metoprolol (n = 30) or atenolol (n = 30) during the first treatment period. INTERVENTIONS--Placebo was given for a run in period of four to six weeks. Metoprolol 100 mg twice daily or atenolol 25 mg twice daily was then given for 16 weeks. The two drugs were then exchanged and treatment continued for a further 16 weeks. END POINT--Evaluation of effects of treatment with metoprolol and atenolol on glucose, insulin, and lipid metabolism and glucose disposal mediated by insulin. MEASUREMENTS AND MAIN RESULTS--Reduction of blood pressure was similar and satisfactory during treatment with both drugs. Glucose uptake mediated by insulin was measured during a euglycaemic hyperinsulinaemic clamp to evaluate patients9 sensitivity to insulin. Glucose uptake decreased from 5.6 to 4.5 mg/kg/min when patients were taking metoprolol and from 5.6 to 4.9 mg/kg/min when they were taking atenolol. Both drugs caused a small increase in fasting plasma insulin and blood glucose concentrations and glycated haemoglobin concentration. Despite decreased sensitivity to insulin the increase in insulin concentration in response to an intravenous glucose tolerance test was small, suggesting inhibition of release of insulin. Very low density lipoprotein and low density lipoprotein triglyceride concentrations were increased with both drugs and high density lipoprotein cholesterol concentration was decreased. Low density lipoprotein cholesterol concentration was not affected. CONCLUSIONS--Long term use of metoprolol and atenolol causes metabolic abnormalities that may be related to the increased incidence of diabetes in patients with hypertension who are treated pharmacologically. These results may help to explain why the two drugs have failed consistently to reduce the incidence of coronary heart disease in several large scale studies.

Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients.

The effects of L-carnitine administration (2 g i. v. three times weekly for 6 weeks) were studied in a double blind trial comprising 2 × 14 patients on regular haemodialysis treatment. The initial plasma carnitine concentrations were normal in the male, but slightly lowered in the female participants and rose more than ten-fold in the patients receiving active treatment. The majority (15/28) of patients had moderate hypertriglyceridaemia, whereas plasma HDL cholesterol levels were normal. Activities of hepatic and lipoprotein lipase were decreased and fat tolerance impaired. The S-triiodothyronine and/or thyroxine levels were subnormal in 11 patients. Four patients had fasting hyperin-sulinemia, and 6 demonstrated abnormal B-glucose patterns after a peroral glucose load. The galactose elimination rate demonstrated moderately impaired hepatocyte function in four patients. No effects of carnitine treatment on any of the variables could be detected.

Plasma lipoproteins, liver function and glucose metabolism in haemodialysis patients: lack of effect of L-carnitine supplementation.

Left ventricular function was non-invasively studied in 28 randomly selected haemodialysis patients before and after administration of L-carnitine, 2 g i.v. three times per week or saline in a double blind designed study over a six-week period. Cardiac function variables showed no relationship to muscle (vastus lateralis) and plasma carnitine concentrations. No apparent deficiency in muscle carnitine was found, whereas total plasma carnitine was lower in female patients than in female controls, p less than 0.002. The echocardiographic left ventricular end-diastolic diameter was initially increased in about one third and the ejection fraction was depressed in about one fifth of the patients. An increased A:H ratio was found in 15%. Systolic time intervals were deranged in 30% of the patients. After carnitine administration, marked increases of muscle and plasma carnitine levels were found, p less than 0.01, but no effects were recorded in any of the cardiac tests. Muscle carnitine increased from 14.6 mmol/kg dry weight to a median of 23.7 mmol/kg. We found no support for the hypothesis that carnitine depletion is responsible for cardiac dysfunction in haemodialysis patients.

Carnitine and left ventricular function in haemodialysis patients

Bandmann, U., Monti M. & Wadso, I. Microcalorimetric Measurements of Heat Production in Whole Blood and Blood Cells of Normal Persons. Scand. J. clin. Lab. Inivest. 35, 121–127, 1975.Microcalorimetric measurements have been made of the heat production in whole blood and its major cell fractions. All measurements were made with samples from normal subjects. The average heat effect value found (±S.D.) for whole blood was 62 ± 7 mW/I. The value obtained for erythrocytes was 82 ± 6 mW per liter of packed cells suspended in phosphate buffer at pH 7.4. For lymphocytes and for polymorphonuclear leukocytes heat effect values were 4.6 ± 1.8 and 1.2 ± 0.4 pW/cell, respectively, for cells suspended in buffer. For plasma suspensions corresponding values were 2.2 ±1.4 and 3.5 ± 1.0 pW/cell, respectively. For thrombocytes suspended in plasma the heat effect value was 59 ± 8 fW/cell. Heat production in cell-free plasma was close to zero. Using heat effect values determined for the different cell fractions, values could ...

Clinical Physiology: Microcalorimetric Measurements of Heat Production in Whole Blood and Blood Cells of Normal Persons

Twenty-eight haemodialysis patients were randomized to L-carnitine, 2 g i.v. three times a week, and saline over a 6-week period. No obvious deficiency of carnitine was found in vastus lateralis with a median value of 12.9 mmol/kg dry weight; range 6.2-21.4. Female patients had lower total plasma carnitine compared to female controls, p less than 0.002, whereas no decrease was found in males. No relationship was found between muscle and total plasma carnitine. After carnitine administration the muscle carnitine level increased about 60%, p less than 0.01, and the total plasma carnitine level more than tenfold, whereas the initially high degree of acylation decreased, p less than 0.02. Maximum dynamic muscular strength was reduced with a mean value of 44% compared with healthy controls. Total metabolic activity of isolated skeletal muscle fibres, measured as heat production with a new technique using a perfusion microcalorimeter, showed a median value of 0.40 mW/g, 25% lower than normal, p less than 0.02. Carnitine administration had no effect on several different tests of muscular function. Neurophysiologically, discrete improvements in the temperature responses were recorded, but no changes in sensory and motor nerve conduction velocities or in vibration thresholds were noted. No symptomatic improvement was observed even in patients with the lowest carnitine levels prior to treatment. Our data do not support the hypothesis that carnitine deficiency contributes to muscle and nerve dysfunction in patients on chronic haemodialysis.

L-Carnitine and haemodialysis: Double blind study on muscle function and metabolism and peripheral nerve function

Heat production in human erythrocytes has been measured by a new microcalorimetric technique. The calorimeter consisted of a twin thermopile heat conduction unit. A 1 ml sample was enclosed in a steel ampoule which was introduced into the measuring zone of the calorimeter through a heat exchange system. Measurements were made on erythrocytes suspended in plasma and in phosphate buffer (pH 7.4) containing glucose. Heat effects produced per liter erythrocytes were 79 ± 11 mW and 79 ± 8 mW, respectively (mean ± S.D.). In various types of anemia significantly higher values were found, mean value 126 ± 29 mW/l erythrocytes.

Mario Monti

Papers

Plasma lipoproteins, liver function and glucose metabolism in haemodialysis patients: lack of effect of L-carnitine supplementation.

Carnitine and left ventricular function in haemodialysis patients

Clinical Physiology: Microcalorimetric Measurements of Heat Production in Whole Blood and Blood Cells of Normal Persons

L-Carnitine and haemodialysis: Double blind study on muscle function and metabolism and peripheral nerve function

Microcalorimetric measurements of heat production in human erythrocytes. I. Normal subjects and anemic patients.