Effect of anaesthetic agents on bile flow and biliary excretion of 131I-cholylglycyltyrosine in the rat.

We have compared in the rat the effects of i.v. anaesthetic agents on bile flow rate and on the biliary excretion of a novel bile acid, 131I-cholylglycyltyrosine (131I-cholylgly.tyr.). Etomidate 1-mg bolus and 2-mg h-1 infusion, Althesin 3-mg bolus and 14.5-mg h-1 infusion and propofol 3.3-mg bolus and 3.3-mg h-1 were given via a tail vein cannula and pentobarbitone 50 mg kg-1 was given by the intraperitoneal route, to groups of six rats. Each animal received only one anaesthetic agent. One hour after cannulation of the common bile duct, 131I-cholylgly.tyr. 5 microCi was injected into the jugular vein and bile was collected every 1 min for 10 min. The mean (SD) percentage cumulative biliary excretion of 131I-cholylgly.tyr. at the end of 10 min was: propofol group 74.1 (5.2)%; Althesin group 82.3 (2.2)%; etomidate group 69.4 (17.6)%; pentobarbitone group 76.4 (3.2)%. Propofol and Althesin were relatively more choleretic, causing bile flow rates twice that produced by pentobarbitone. Only Althesin caused a significant increase in biliary excretion of 131I-cholylgly.tyr. relative to that in rats that received pentobarbitone. Bile flow rates for the respective anaesthetic techniques (microliter min-1/100 g body weight) (mean (SD)) were: propofol group 14.1 (1.8); Althesin group 12.5 (1.7); etomidate 8.5 (1.4); pentobarbitone group 7.3 (1.0). There was a marked metabolic acidosis in all rats except in the propofol group, in which normal acid-base status and oxygenation were observed.

Orthotopic liver transplantation: postoperative complications and their management.

The Birmingham liver transplant programme started in 1982. Forty-six patients have been transplanted with a follow-up of 3 months or longer. Twenty-seven patients are still alive, of whom sixteen have lived for more than one year. The 30 day hospital mortality was 30.4 per cent and the actuarial predicted one year survival 55.5 per cent. Four patients have been regrafted for chronic rejection and graft failure. Thirteen patients have required surgery in the postoperative period for: bleeding (two), removal of abdominal packs (four), biliary leaks and obstruction (five), duodenal perforation (one) and small bowel obstruction (one). Acute rejection was common, occurring in 30 patients and progressing to chronic rejection in 4. Ten patients developed renal failure with an 80 per cent mortality and eleven patients developed grand mal fits. Severe bleeding (greater than 70 units) was associated with previous abdominal surgery and a high mortality (88.9 per cent). Opportunistic fungal infection carried a 100 per cent mortality. Although more than half of all transplanted patients will survive for more than one year, the postoperative period is still one of high morbidity and mortality.

Transperitoneal oxygenation with fluorocarbons.

This work investigated the improvement of arterial oxygenation in hypoxic rats during peritoneal perfusion with the oxygen-carrying perfluorocarbon blood substitute FC43. Three groups of six Wistar rats were ventilated with hypoxic gas mixtures to obtain an arterial oxygen tension (PaO2) of approximately 55 mm Hg. Two groups were subjected to peritoneal perfusion at 20 ml/min with oxygenated FC43 or the gelatine solution Haemaccel. A third group was sham operated but not perfused. In both perfused groups PaO2 increased significantly, more so in the FC43 group. Carbon dioxide tensions significantly decreased only in the FC43 group. Significant increases in arterial oxyhemoglobin saturation were seen after 15 min in the FC43 group and after 60 min in the Haemaccel group. More than 15% of oxygen consumption could be delivered by peritoneal perfusion with FC43.

Effect of intrathecal and intracarotid administration of ketamine on blood pressure and heart rate in rats.

Intrathecal and intracarotid effects of ketamine were investigated in anaesthetized rats. Ketamine was administered in the subarachnoid space in doses ranging from 300 to 1500 micrograms X kg-1. In these doses ketamine produced a short-lasting hypotension and bradycardia which may be due to inhibition of sympathetic outflow from thoraco-lumbar region. On the other hand when ketamine (5 mg X kg-1) was injected into the cerebral circulation it produced a rise in blood pressure and heart rate, probably through a cholinergic mechanism.

The effect of ketamine on the peripheral circulation: a possible sympathetic ganglion blocking effect.

The effects of induction of anaesthesia, endotracheal intubation and surgical stimuli on the systemic and peripheral circulations were studied in three groups of patients. In group KA (n = 8) anaesthesia was induced with ketamine (2 mg kg-1) and alcuronium, supplemented by N2O-O2 alone; in group KAH (n = 9) 0.5% halothane was added to the N2O-O2; and in the control group TAH (n = 8) anaesthesia was induced with a sleep dose of thiopentone and alcuronium, supplemented by N2O-O2 and halothane. The circulation in the finger was monitored by photo-electric plethysmography. Induction produced a significant pressor response in both ketamine groups, but not in the TAH group, while the finger plethysmogram demonstrated peripheral vasodilatation in all three groups. Intubation, on the other hand, elicited a significant pressor response in the TAH and in the KAH group but not in the KA group. The finger plethysmogram, however, always showed peripheral vasoconstriction during intubation in the thiopentone group (TAH) but never in either of the ketamine groups. The results suggest that ketamine exerts a peripheral ganglion blocking effect.

Endotoxin protection against oxygen toxicity and its reversal by acetylsalicylic acid.

This study investigated the involvement of substances derived from arachidonic acid in the mechanism of endotoxin's protective action against pulmonary oxygen toxicity. Eighty-three percent of rats treated with a small dose of endotoxin (1 mg/kg) survived exposure to over 95% oxygen for 7 days. In contrast, all control rats exposed to the same oxygen concentration died within 3 days. When the endotoxin-treated rats were also treated with the soluble lysine salt of acetylsalicylic acid (100 mg/kg), 7-day survival decreased to 25%. This suggests that prostaglandin metabolism may play an important role in the protective action of endotoxin during hyperoxia.

Whole body oxygenation using intraperitoneal perfusion of fluorocarbons.

A preliminary study was undertaken to assess the feasibility of increasing the arterial oxygen tension, and decreasing the arterial carbon dioxide tension, in intact animals, by means of peritoneal perfusion with the perfluorocarbon-containing, oxygen-transporting blood substitute, 20% Fluosol-DA. Perfusion was carried out in rabbits using a bubble oxygenator and circulator pump, delivering Fluosol at a rate of 25 ml min-1. Control blood-gas measurements were carried out at various FIO2 between 0.5 and (if the animal was not severely hypoxic) 0.16. The measurements were repeated during the intraperitoneal perfusion of Fluosol. At all values of FIO2, significant increases in PaO2 were seen (P less than 0.05). Significant decreases of PaCO2 (P less than 0.05) were seen if the animals were not hypoxic (PaO2 greater than 10 kPa).

Pharmacokinetics of 4-aminopyridine in human volunteers. A preliminary study using a new GLC method for its estimation.

The concentrations of 4-aminopyridine hydrochloride in the blood and urine from volunteers were measured following a bolus injection i.v. of 0.3 mg kg-1. The drug was assayed by means of a new GLC method which is described. The pharmacokinetics of 4-aminopyridine are complicated by an additional increase in plasma concentration during the elimination phase of the drug.

Antagonism of ketamine-diazepam anaesthesia by 4-aminopyridine in human volunteers.

Five healthy human volunteers were anaesthetized on two separate occasions, 1 week apart, using a standard diazepam-ketamine induction followed by an infusion of ketamine for 1 h. Ten minutes after stopping the infusion, either 4-aminopyridine 0.3 mg kg--1 in saline or the same volume of saline alone was administered i.v. It was concluded that 4-aminopyridine enhanced dramatically the rate of recovery of the subjects to full consciousness and normal motor co-ordination when compared with the saline controls.

A new method for studying the relationship between hepatic uptake of drugs and their pharmacodynamic effects in anaesthetized cats.

1 A new in vivo experimental method is described whereby the liver can be temporarily excluded from the general circulation by means of a portocaval shunt operation. The influence of this manoeuvre upon the effects of pancuronium and Org 6368 was investigated using the tibialis muscle preparation of anaesthetized cats. 2 The procedure also allowed intraportal injections of the drugs to be made so that the effect of first-passage uptake by the liver could be compared with hapatic exclusion in the same animal. 3 Hepatic exclusion greatly increased the duration of action of both drugs. Whereas intraportal injection did not significantly alter the effect of pancuronium on the tibialis muscle, the effect of Org 6368 was greatly diminished when given by this route. 4 The liver appears to tolerate short periods of hepatic exclusion and it is concluded that this technique may become a useful tool for studying the handling of drugs by this organ.

Inhibition of neuronal uptake of noradrenaline in the isolated perfused rat heart by pancuronium and its homologues, Org. 6368, Org. 7268 and NC 45.

The cardiovascular effects of pancuronium may be caused partly by an interaction of this drug with the sympathetic nervous system. We examined one possible mechanism of interaction, the effect on the re-uptake processes for noradrenaline. Pancuronium and its closely related steroidal homologues, Org. 6368, Org. 7268 and NC 45, were studied at a high concentration (500 mumol litre-1) for inhibition of the uptake of tritiated noradrenaline into neuronal sites (Uptake1) and extraneuronal sites (Uptake2) in the isolated perfused rat heart. All drugs tested caused almost total inhibition of Uptake1. The bis-quaternary steroids pancuronium and Org. 6368 were selective for Uptake1 inhibition, the mono-quaternary steriods Org. 7268 and NC45 also produced significant inhibition of Uptake2. Uptake1 inhibition was investigated in detail using lesser concentrations of the compounds. All four steroids were found to cause a concentration-dependent inhibition of Uptake1. It seems likely, therefore, that inhibition of neuronal uptake of noradrenaline plays a significant role in the aetiology of the chronotropic actions of pancuronium in the rat.

Antagonism of the cardiovascular effects of ketamine by diazepam in volunteers.

In healthy volunteers pretreated with atropine (0.5 mg), ketamine given as a bolus i.v. injection (2 mg/kg) followed by an infusion of ketamine (1 mg/kg/hr) for one hour, caused a significant rise in blood pressure and heart rate. This cardiovascular stimulation was rapidly counteracted by diazepam (0.2 mg/kg i.v.) given when the response to ketamine was already maximal.

Inhibition of neuronal and extraneuronal uptake of noradrenaline by ketamine in the isolated perfused rat heart.

The effect of ketamine on the uptake of 3H-noradrenaline in the isolated perfused rat heart was studied. A dose-dependent inhibition of uptake by both neuronal and extraneuronal processes was found. These effects may account for the positive chronotropic and pressor effects of the drug.

Effects of the analeptic drug, 4-aminopyridine, upon post-operative respiratory depression in patients. A preliminary study.

The analeptic agent, 4-aminopyridine, was given to patients who had undergone elective ear, nose and throat surgery and showed severe central respiratory depression due to intra-operative fentanyl administration. The respiratory depression due to fentanyl was found to be partially antagonised by 4-aminopyridine. In view of these preliminary findings it is suggested that the drug might find a use in combatting postoperative fentanyl-induced respiratory depression.

Inhibition of catecholamine uptake in the isolated rat heart by haloalkylamines related to phenoxybenzamine.

1. Twenty-one haloalkylamine derivatives were tested as inhibitors of both the neuronal uptake of (3)H-noradrenaline (NA) by the Uptake(1) mechanism and the extraneuronal uptake of (3)H-NA by the Uptake(2) mechanism in the isolated rat heart.2. At a concentration of 50 muM most of the compounds tested caused a significant inhibition of both uptake processes, although there were wide differences in the relative effects on Uptake(1) and Uptake(2). Some tentative structure activity relationships for uptake inhibition were formulated from these results.3. Phenoxybenzamine was confirmed to be a potent inhibitor of both the Uptake(2) and Uptake(1) mechanisms, with IC50 values for these two systems of 2.8 muM and 0.9 muM respectively.4. The substances N-(9-fluorenyl)-N-methyl-beta-chloroethylamine (SKF 550), N-(3,4-dimethoxyphenylisopropyl)-N-benzyl-beta-chloroethylamin (SKF 625A) and N-(4-methoxyphenoxyisopropyl)-N-benzyl-beta-chloroethylamine (SKF 784A) were significantly more potent than phenoxybenzamine as Uptake(2) inhibitors, and were all less potent than phenoxybenzamine as Uptake(1) inhibitors. The compound SKF 550 is the most potent and selective inhibitor of Uptake(2) so far described. It has an IC50 for Uptake(2) of 0.08 muM, and an IC50 for Uptake(1) of approximately 40.0 muM.5. Comparison of the present results with the known activities of these blocking agents suggests that no correlation exists between adrenoceptor blocking activity and ability of the substances to act as inhibitors of Uptake(2) or Uptake(1).