Olav Reikerås

INCREASED PLASMA GLUCOSE LEVELS AFTER HYPNORM ANAESTHESIA, BUT NOT AFTER PENTOBARBITAL ANAESTHESIA IN RATS

The effects of the fentanyl fluanisone combination (Hypnorm®) and pentobarbitone sodium (Pentobarbital®) anaesthesia on blood glucose, insulin and glucagon were tested in rats in the fed and fasted state. Blood glucose was measured before and at 10, 20 and 30 min after injection of the anaesthetic agents. At 30 min the rats were sacrificed, and blood was drawn for measurement of glucagon and insulin. Pre-anaesthetic values for insulin and glucagon were established in separate groups of fasted and fed rats. In fasting rats given Hypnorm®, blood glucose and plasma insulin were unchanged while there was a non-significant increase in plasma glucagon. The fasted rats given Pentobarbital® had unchanged blood glucose and plasma insulin and a non-significant depression of glucagon. The fed rats given Hypnorm® had a significant increase in blood glucose at 10 min and nearly a doubling of glucose values at 20 and 30 min (P<0.001). Glucagon increased far less than in the fasted group, whereas insulin was doubled from preanaesthetic values (P<0.05). The fed rats given Pentobarbital®, had unchanged blood glucose, a slight nonsignificant depression of glucagon and a significant increase in insulin (P<0.01). Thus Hypnorm® induced hyperglycaemia in fed but not in fasted rats, probably because more glucose was available in the fed state. Fed animals are a modification of the standard fasted animal model, and may be preferable when exploring hyperglycaemic or other reactions to anaesthetic agents.

Catecholamine binding and concentrations in acute phase plasma after surgery

The present study was undertaken to decide whether the bound fractions and/or total concentrations of catecholamines were determinative for the variability of biologically active concentrations in human plasma. The binding and concentrations of noradrenaline (NA) and adrenalin (Adr) were determined in acute phase plasma after major hip surgery in five subjects. The bound fractions before surgery were 23.0% and 18.4% for NA and Adr, respectively. The binding of catecholamines increased in the post-operative period. Five days after surgery the binding of NA and Adr was 30.9% and 24.0%, respectively. The surgical trauma induced an acute phase reaction in plasma with a decrease of albumin (HSA) concentrations whereas the concentrations of alpha-1 acid glycoprotein (AAG) increased. The catecholamine concentrations showed a considerable inter- and intraindividual variability. However, the present work shows that the variability of the biologically active catecholamine concentrations is mainly dependent on the total plasma concentrations and not the plasma protein binding.

Increments in glucose, glucagon and insulin after morphine in rats, and naloxone blocking of this effect

In awake rats adapted to experimental conditions and allowed food ad libitum, hyperglycemia was induced by the administration of morphine 10 mg/kg through indwelling catheters in the external jugular vein. High glucose values were measured at 5, 15 and 25 min. Glucagon values were high at 5 and 15 min, and again at basal level at 25 min. Insulin was increased after morphine both at 5, 15 and 25 min, whereas somatostatin levels did not change after morphine. When morphine was administered together with naloxone after an initial 10 min period of naloxone administration, there was no increment in glucose, insulin or somatostatin values; neither at 5, 15 or 25 min. There was a remarkable glucagon decrease after naloxone and morphine remaining from 5 to 25 min. Then, one of the possible mechanisms for the hyperglycemic response after morphine may be an opioid effect on pancreas, stimulating glucagon and thereby causing hepatic glucose output.

Cardiac effects of secretin; an approach to its mechanisms of action as shown by beta-adrenergic blockade and measurement of left ventricular dimensions in dogs.

In previous studies, the peptide secretin has demonstrated the ability to increase cardiac output and peripheral organ flow. In this investigation the mechanisms of the myocardial effects of secretin were studied. The secretin effects on cardiac output, stroke volume and systemic resistance were unaltered after propranolol, whereas the effect on LVdP/dt was reduced and the heart rate effect negligible. Systemic pressure, myocardial blood flow and myocardial oxygen consumption were unchanged by secretin infusion both before and after beta-receptor blockade. Secretin caused reduction of all three end-systolic left ventricular diameters. Thus, an inotropic effect by secretin was confirmed. Beta-receptor blockade reduced the inotropic effect and almost abolished the chronotropic effect, whereas the vasodilating effect was unaltered. The main haemodynamic effect of secretin was caused by activation of receptors other than the beta-adrenergic receptors.

Morphine and morphine/naloxone modification of glucose, glucagon and insulin levels in fasted and fed rats.

In rats weighing 200-250 g catheters were placed in the internal jugular vein and carotid artery. After 1 week of accommodation the training for the experimental situation, morphine (10 mg kg-1) was injected intravenously alone or in combination with naloxone (0.04 mg ml-1, 0.8 ml h-1). Otherwise no form of anaesthesia was used during the experiments. In control fed and fasted rats, there were no significant differences in blood glucose. In fed rats, morphine increased blood glucose as compared to control rats (p < 0.001). This was not seen in the fasted rats. The morphine induced increase in blood glucose in the fed rats was abolished by naloxone (p < 0.001). Glucagon was significantly higher in fasted than in fed control rats (p < 0.01). It was significantly increased after morphine in fed (p < 0.05), but not in fasted rats. The morphine induced increase in glucagon in fed rats was abolished by naloxone (p < 0.01). Insulin was significantly higher in fed than in fasted control rats (p < 0.05). Morphine increased insulin levels significantly in fed and fasted rats (p < 0.001), p < 0.01). The morphine induced increase in insulin in the fed rats was abolished by naloxone treatment. It is concluded that morphine stimulates glucose and glucagon release in fed but not fasted rats, and that these increases are caused by opioid action. Insulin increases after morphine were proved to be opioid-mediated only in the fed state.

Comparison of the modifying effects of somatostatin and propranolol on morphine-induced changes in glucose, glucagon and insulin levels in fed rats

Twenty-eight rats in four different groups were used. Catheters were implanted in the carotid artery and jugular vein one week before the experiments were performed. The rats were trained to the experimental situation daily, and allowed food and water ad libitum. One group of rats was used to establish control values; a second was injected with morphine (10 mg/ml, 1 ml/kg); a third group got morphine injection (10 mg/ml, 1 ml/kg) combined with somatostatin infusion (0.01 mg/ml, 1 ml/h); and the fourth group was injected with morphine (10 mg/ml, 1 ml/kg) combined with propranolol (0.4 ml, 1 mg/ml). Blood samples for venous glucose and arterial insulin and glucagon were drawn 15 min after start of stimulation. Glucose, insulin and glucagon levels were significantly higher in morphine treated than in control rats. When morphine was combined with somatostatin, the increase in glucose, insulin and glucagon was significantly reduced. However, after the morphine and propranolol stimulation the increase in glucose and glucagon was significantly reduced, whereas the insulin levels were as high as when morphine was given alone. The combined reduction of both glucagon and glucose after somatostatin or propranolol treatment in morphine exposed rats, points to glucagon as a potential link between opioid stimulation and hyperglycemia. Beta-receptor stimulation seems to contribute to the glucagon but not to the insulin release after morphine.

Elevated plasma beta-endorphin/beta-lipotropin concentration following a radius fracture.

Plasma beta-endorphin/beta-lipotropin concentration was assessed soon after a fracture. Blood samples from 14 patients with radius fractures were obtained from both arms soon after admission to the hospital (mean 245 min) after the accident. Follow-up samples were taken after healing of the fractures. Higher plasma beta-endorphin/beta-lipotropin concentrations were found in blood samples taken soon after a fracture in both arms compared with the concentrations after healing of the fracture. At admission, mean beta-endorphin/beta-lipotropin concentrations in the fractured and the contralateral arms were 12.7 pmol/L and 13.2 pmol/L, and after recovery 11.1 pmol/L and 11.5 pmol/L (p=0.012 and p=0.041), respectively. The pain decreased according to the visual analogue scale (VAS) (0-10) from 4.64 at admission to 0.58 after healing (p<0.001). In conclusion, this study showed that beta-endorphin/beta-lipotropin concentrations are increased in both arms following a radius fracture compared to the level after the fracture has healed.

Distribution of the increased cardiac output secondary to the vasodilating and inotropic effects of secretin

Infusion of the peptide secretin augments cardiac output due to vasodilating and inotropic properties. The aim of this investigation was to study how the increased cardiac output is distributed in the peripheral circulation. Before, during and after 15 min infusion of secretin 64 CU kg-1 h-1 flow changes in renal, carotid, femoral and the superior mesenteric arteries were measured by means of electromagnetic flowmetry in anaesthetized dogs. Cardiac output and stroke volume increased by 41 and 27%, respectively, whereas the total systemic resistance fell 35%. The LVdP/dt increased by 35%. After 5 min infusion, renal and carotid flows increased by 62 and 50%, respectively, whereas the femoral flow was only slightly elevated and the superior mesenteric flow unchanged. Both the femoral and the superior mesenteric flow gradually augmented and at the end of the infusion flow was substantially elevated in all four arteries. The study demonstrated that the increased cardiac output by secretin was distributed to all the four arteries, although a preponderance of flow to the renal circulation was indicated. This flow profile may be regarded as favourable in the management of low output conditions.

Renal blood flow during acute ischaemic heart failure in dogs: Effects of dopamine and high doses of insulin

The effects of acute ischaemic heart failure on renal blood flow and the influence of dopamine at low dose range and high doses of insulin were examined. Acute left ventricular (LV) failure was induced in dogs by injection of 50-micron plastic microspheres into the left main coronary artery. The dogs showed signs of severely depressed LV function. Cardiac output was decreased to a significantly greater extent than renal blood flow, and while total peripheral resistance was significantly increased, there were no significant changes in renal vascular resistance. The results indicate different sympathetic discharge to the various vascular beds during acute ischaemic heart failure. Dopamine at low dose range and high doses of insulin were found to improve myocardial contractility and to reduce renal vascular resistance and increase renal blood flow.

Morphine effects on the release of glucagon, insulin and somatostatin from the isolated, perfused rat pancreas

The pancreatic glands from six male Wistar rats weighing between 200 and 250 g were isolated and perfused. After 30-min equilibration and 20-min basal periods, perfusion with 0.2 mg/ml of morphine for 20 min resulted in a significant (P<0.05) increase in insulin release, with no changes in release of gucagon or somatostatin. After a recovery period of 20 min, a higher morphine concentration of 2 mg/ml was introduced for another 20-min period. With this morphine dose there were significant increases in release of insulin (P<0.05), glucagon (P<0.01) and somatostatin (P<0.05). This shows that morphine induces the release of insulin, glucagon and somatostatin from pancreas in a dose-dependent way, and that release of insulin and glucagon is not primarily affected by regulation of somatostatin levels.