The analgesic properties of sub-anaesthetic doses of anaesthetics in the mouse

Trichlorethylene in a sub-anaesthetic concentration (0.5% v/v in oxygen) has an analgesic effect on mice, which develops slowly and reaches a maximum roughly equivalent to that produced by 5 mg/kg of methadone hydrochloride given by intraperitoneal injection. Ethyl chloride causes analgesia in sub-anaesthetic concentrations (3%) but is much less potent than trichlorethylene. Halothane (0.75%) produces slight but definite analgesia. Cyclopropane and diethyl ether have no appreciable analgesic effect. Concentrations of nitrous oxide (up to 90%) in oxygen lack any observable analgesic action on the mouse. Trichlorethylene is considerably potentiated by nitrous oxide, its anaesthetic rather than its analgesic action being affected. Nitrous oxide (40%) potentiates the analgesic rather than the anaesthetic action of halothane (0.75%). However, increasing the concentration of nitrous oxide to 60% causes the anaesthetic action of halothane to predominate.     

Alfentanil potentiates anaesthetic and electroencephalographic responses to ketamine in the rat

The interactions between mu-opioid and N-methyl-D-aspartate (NMDA) receptors have important implications for clinical pain management. We recently examined the pharmacokinetics of ketamine in rats following i.v. infusion of ketamine (racemate, 50 mg/kg/5 min) and found increased central nervous system distribution of ketamine in the presence of low constant plasma alfentanil concentrations (approximately 50 ng/ml). We now report on the effects of low plasma alfentanil concentrations on the duration of anaesthetic and electroencephalographic (EEG) responses to i.v. infusion of ketamine. Compared to ketamine alone, alfentanil significantly increased both the duration of anaesthesia (by 130%, P=0.00022) and the processed EEG power (microV(2)/s) (by 48%, P=0.0040). The plasma ketamine concentration producing half-maximal EEG effect was significantly reduced (by 60%, P<0.0001) in the presence of alfentanil. The results indicate that low plasma alfentanil concentrations potentiate the anaesthetic and EEG effects produced by ketamine.     

Cardioprotective effects of nicorandil in rabbits anaesthetized with halothane: potentiation of ischaemic preconditioning via KATP channels

1. The roles of ATP-sensitive K+ channels (KATP channels) in ischaemic or pharmacological preconditioning in the rabbit heart remain unclear. Infarct limitation by ischaemic preconditioning was abolished by the KATP channel blocker glibenclamide under ketamine/xylazine anaesthesia, but not under anaesthesia induced by pentobarbital. Infarct limitation by the KATP channel opener pinacidil was detected under ketamine/xylazine anaesthesia, but not under pentobarbital anaesthesia. Thus, these effects appear to be anaesthetic dependent. 2. In the present study, we examined whether nicorandil (a KATP channel opener nitrate) exhibits cardioprotective actions under halothane anaesthesia, another commonly used volatile anaesthetic. Control animals were subjected to 40 min coronary occlusion and 120 min reperfusion. Before 40 min ischaemia, the nicorandil group received nicorandil (100 microg/kg per min, i.v., for 10 min), the 5' preconditioning (PC) group received 5 min ischaemia/20 min reperfusion, the 2.5'PC group received 2.5 min preconditioning ischaemia/20 min reperfusion, the nicorandil +2.5'PC group received both nicorandil and 2.5 min ischaemia/20 min reperfusion, the nicorandil +2.5'PC + 5-hydroxydecanoate (5HD) group received both nicorandil and 2.5 min ischaemia/20 min reperfusion in the presence of 5-hydroxydecanoate (5HD; a KATP blocker) and the 5HD group received 5 mg/kg, i.v., 5HD alone. Myocardial infarct size in control (n = 7), nicorandil (n = 5), 5'PC (n = 8), 2.5'PC (n = 5), nicorandil + 2.5'PC (n = 5), nicorandil + 2.5'PC + 5HD (n = 5) and 5HD (n = 4) groups averaged 44.4 +/- 3.6, 41.7 +/- 5.7, 17.8 +/- 3.2,* 34.1 +/- 4.8, 21.3 +/- 4.2,* 39.1 +/- 5.6 and 38.9 +/- 5.0% of the area at risk, respectively (*P <0.05 vs control). 3. Thus, nicorandil alone did not have an infarct size-limiting effect in halothane-anaesthetized rabbits. However, the results suggest that even when nicorandil alone does not demonstrate a direct cardioprotective effect, it may enhance ischaemic preconditioning via KATP channels. Key words: ATP-sensitive K+ (KATP) channel, ischaemic preconditioning, myocardial infarction, nicorandil, rabbit.     

Some cardiovascular and respiratory effects of four non-barbiturate anaesthetic induction agents

Summary Some cardiovascular and respiratory effects of four non-barbiturate anaesthetic agents were studied in the induction of anaesthesia in cardiac surgical patients in an attempt to achieve cardiovascular stability. The four agents, diazepam, ketamine, nitrous oxide and propanidid were given to four groups of patients with 20 in each group. Ketamine caused a rise in blood pressure while the other three agents caused a fall similar to thiopentone, most marked with propanidid and least with nitrous oxide. Ketamine caused a progressive tachycardia during the period of the study, propanidid caused a tachycardia similar to thiopentone while diazepam and nitrous oxide caused little change in heart rate. With the three intravenous agents there was a fall in PaO₂. Arterial carbon dioxide tension fell with propanidid, rose with ketamine and was unchanged with diazepam and nitrous oxide. The quality of narcosis, frequency of ventricular arrythmias and ease of intubation were compared.     

The effect of anaesthetic agents on cerebral cortical responses in the rat.

1. In rats, surgically anaesthetized with Urethane, an increase in the depth of anaesthesia upon administration of ethyl carbamate (Urethane), pentobarbitone sodium (Nembutal), thiopentone sodium (Intraval), althesin, ketamine, trichloroethylene, halothane, methoxyflurane, diethyl ether, ethyl-vinyl ether, cyclopropane, enflurane or chloroform resulted in a dose-dependent increase in the latency, the decrease in the amplitudes of the initial positive and negative components of the short latency cortical response to electrical stimuli applied to the forepaw. 2. The same changes were seen when starting from initially unanaesthetized rats and anaesthetizing them with Urethane. 3. With all the inhalational agents used these changes lasted for as long as the administration except with nitrous oxide where the changes in the cortical response were transient. 4. The tranquilizing agents diazepam, chlordiazepoxide, and haloperidol showed no such action. Chloral hydrate and chlorpromazine, on the other hand, produced moderate changes in the evoked cortical response similar to those seen with the other anaesthetic agents used.     

Pharmacodynamic and pharmacokinetic interactions between ketamine and diazepam

Anaesthesia with continuous i.v. ketamine and 65% nitrous oxide in oxygen was given to a total of 49 patients undergoing major abdominal surgery. A control group was premedicated with atropine and other groups received in addition rectal diazepam or clorazepate i.v. For further patients had been on oral diazepam or barbiturates for 1-14 years; as premedication they received atropine alone. The anaesthetic technique gave good operative conditions in the 4 groups of patients. The haemodynamic stimulation of ketamine was significantly reduced in patients premedicated with diazepam. Psychotomimetic side effects were not prominent in any of the groups. Patients premedicated with diazepam required a lower rate of ketamine infusion as compared to controls during the initial 30 min of anaesthesia. The patients in the other groups did not differ from the control group in this respect. There were large differences in metabolic pattern between the groups. As compared to the controls, the patients on long-term diazepam or barbiturates had high concentrations of hydroxylated metabolites, with levels higher than that of norketamine. The patients pretreated with diazepam had very low plasma levels of hydroxylated metabolites. Clorazepate premedication did not significantly affect the metabolism of ketamine. The biological half-life of ketamine was significantly increased in the diazepam-treated group, and it was shortened in those on long term treatment with barbiturates or diazepam.     

General anesthetics inhibit the nitrous-oxide-induced activation of corticotropin releasing factor containing neurons in rats

The activation of intracerebral corticotropin releasing factor (CRF) system is involved in nitrous oxide analgesia. We evaluated the effect of general anesthetics on nitrous-oxide-induced CRF activation and antinociception. Male Sprague-Dawley rats inhaled isoflurane (0%, 0.6%, 1.0% and 1.5%) or were administered with intravenous propofol (0, 0.1 and 0.2 mg/kg/min), with or without 75% nitrous oxide inhalation, for 90 min. The brain was fixed with fixative, and brain sections, including the paraventricular nucleus of the hypothalamus, were double immunostained with c-Fos and CRF antibodies to assess the activation of CRF-containing neurons. In other groups of rats, the effect of propofol on nitrous oxide antinociception was evaluated with tail flick latency tests. Both inhaled isoflurane and intravenous propofol inhibited nitrous-oxide-induced activation of CRF neurons, suggesting that these general anesthetics may inhibit one of the analgesic mechanisms of nitrous oxide. Indeed, propofol inhibited the antinociceptive action of nitrous oxide, as evaluated with tail flick latencies (TFL).     

Propofol. A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic

Propofol is an intravenous anaesthetic which is chemically unrelated to other anaesthetics. Induction of anaesthesia with propofol is rapid, and maintenance can be achieved by either continuous infusion or intermittent bolus injections, with either nitrous oxide or opioids used to provide analgesia. Comparative studies have shown propofol to be at least as effective as thiopentone, methohexitone or etomidate for anaesthesia during general surgery. The incidence of excitatory effects is lower with propofol than with methohexitone, but apnoea on induction occurs more frequently with propofol than with other anaesthetics. Additionally, a small number of studies of induction and maintenance of anaesthesia have found propofol to be a suitable alternative to induction with thiopentone and maintenance with halothane, isoflurane or enflurane. Propofol is particularly suitable for outpatient surgery since it provides superior operating conditions to methohexitone (particularly less movement), and rapid recovery in the postoperative period associated with a low incidence of nausea and vomiting. When used in combination with fentanyl or alfentanil, propofol is suitable for the provision of total intravenous anaesthesia, and comparative studies found it to be superior to methohexitone or etomidate in this setting. Infusions of subanaesthetic doses of propofol have been used to sedate patients for surgery under regional anaesthesia, and also to provide sedation of patients in intensive care. In the latter situation it is particularly encouraging that propofol did not suppress adrenal responsiveness during short term studies. If this is confirmed during longer term administration this would offer an important advantage over etomidate. Thus, propofol is clearly an effective addition to the limited range of intravenous anaesthetics. While certain areas of its use need further study, as would be expected at this stage of its development, propofol should find a useful role in anaesthetic practice.     

Responses of striatal neurons to anesthetics and analgesics in freely moving rats

The effects of anaesthetics and analgesics on striatal neurons were examined in freely moving rats by recording extracellular action potentials of neurons in the striatum. Spontaneous multiple unit activity was reduced to less than 20% of control firing rates following either pentobarbital 35 mg/kg i.p., halothane 3%, chloral hydrate 400 mg/kg i.p., or urethane 1.5 g/kg i.p. Morphine 15 mg/kg i.p., decreased striatal neuronal firing whereas ketamine, 50 mg/kg i.p., excited striatal neurons. The only analgesic agent tested that did not significantly affect striatal neuronal firing was nitrous oxide (70% N2O/30% O2). These findings demonstrate that nitrous oxide is a suitable analgesic which can be used to alleviate stress and pain associated with immobilization procedures without appreciably altering spontaneous striatal discharge rates.     

Der Einfluß von Stickoxydul und Chloralose-Urethan auf den Kreislauf und die präganglionäre Sympathicusaktivität der Katze

Summary Arterial pressure, heart rate, preganglionic discharges of the cervical sympathetic nerve and action potentials of the phrenic nerve were recorded in 10 cats under four different conditions: fully conscious (artificial respiration with air, relaxation with suxamethonium), in analgesia (artificial respiration with 66.6% nitrous oxide in oxygen) and in chloralose-urethan anaesthesia (40 mg/kg and 200 mg/kg i.v., respectively) alone or in combination with nitrous oxide. In 10 control experiments cats received nitrous oxide in oxygen during a period of 160 min. In addition, 11 experiments were performed to compare the effects of 66.6% with those of 75% nitrous oxide. The above parameters were recorded both during rest and during acoustic stimulation or asphyxia.In the first series of experiments the effects of analgesia and anaesthesia were expressed as per cent change from the values recorded during the waking state. Inhalation of 66.6% nitrous oxide only slightly depressed the sympathetic activity and the heart rate at rest. The arterial blood pressure remained constant. During acoustic stimulation and asphyxia the sympathetic activity was depressed by 22.9 and 37.5%, respectively. In contrast to nitrous oxide, chloralose-urethan caused a pronounced inhibition of the sympathetic activity by 65.7% at rest; heart rate was decreased by 17.1% while blood pressure was unaltered. During acoustic stimulation and asphyxia the sympathetic activity was depressed by 70.2 and 73.4% respectively.In the second series the effects of 66.6% nitrous oxide observed during the initial inhalation period of 20 min remained unchanged throughout the following 140 min of the experiment. In the third group the administration of 75% nitrous oxide for a period of 20 min did not produce effects differing from those after 66.6% nitrous oxide.Nitrous oxide analgesia combined with suxamethonium appears to be more suitable for neuropharmacological research than chloralose-urethan anaesthesia because of the lesser depression of the sympathetic centers observed.

     

Dexmedetomidine and haemodynamic responses to acute central hypovolaemia in conscious rabbits

1. Effects of the alpha2-adrenoceptor agonist dexmedetomidine on vasoconstrictor and heart rate (HR) responses to acute central hypovolaemia were studied in eight chronically instrumented rabbits. We compared intravenous (i.v.) and fourth ventricular (V4) dexmedetomidine (0.1-10 microg/kg) and the reversal of effects by the alpha2-adrenoceptor antagonist idazoxan and the opioid agonist alfentanil. 2. Gradual inflation of an inferior vena cava (IVC) cuff reduced cardiac index (CI) by 8%/min, with progressive vasoconstriction and increased HR. In control rabbits, at approximately 40% baseline CI, there was sudden decompensation with failure of vasoconstriction and a fall in mean arterial pressure (MAP). 3. Dexmedetomidine (i.v. and V4) reduced resting MAP and HR and caused an earlier decompensation during central hypovolaemia. Intravenous dexmedetomidine (3 and 10 microg/kg) also reduced the slope of the initial vasoconstrictor response and the maximum HR. 4. The effects of dexmedetomidine were reversed by the antagonist idazoxan, which prevented the decompensation phase. Intravenous alfentanil was also effective in restoring the vasoconstrictor response and delaying decompensation with hypovolaemia after dexmedetomidine. Combining dexmedetomidine with an opioid, such as alfentanil, may provide the benefit of reduced sympathetic tone without increased risk of cardiovascular collapse.     

Assessment of general anaesthetic cytotoxicity in murine cortical neurones in dissociated culture

General anaesthetics are proposed to cause unconsciousness by modulating neuronal excitability in the mammalian brain through mechanisms that include enhancement of inhibitory GABA_A receptor currents and suppression of excitatory glutamate receptor responses. Both intravenous and volatile agents may produce neurotoxic effects during early postnatal rodent brain development through similar mechanisms. In the following study, we investigated anaesthetic cytotoxicity in primary cortical neurones and glia from postnatal day 2-8 mice. Cultures at 4-20 days in vitro were exposed to combinations of ketamine (100 μM to 3 mM), nitrous oxide (75%, v/v) and/or isoflurane (1.5-5%, v/v) for 6-12 h. Neuronal survival and cell death were measured via microtubule associated protein 2 immunoassay and lactate dehydrogenase release assays, respectively.Clinically relevant anaesthetic concentrations of ketamine, nitrous oxide and isoflurane had no significant neurotoxic effects individually or when given as anaesthetic cocktails, even with up to 12 h exposure. This lack of neurotoxicity was observed regardless of whether cultures were prepared from postnatal day 0-2 or day 8 mice, and was also unaffected by number of days in vitro (DIV 4-20). Significant neurotoxic effects were only observed at supraclinical concentrations (e.g. 1-3 mM ketamine).Our study suggests that neurotoxicity previously reported in vivo is not due to direct cytotoxicity of anaesthetic agents, but results from other impacts of the anaesthetised state during early brain development.     

The effect of eltanolone on pulmonary vascular resistance in landrace swine.

This paper reports on the haemodynamic effects of eltanolone observed in Landrace swine during the investigation of the drug with respect to safety in malignant hyperthermia-susceptible individuals. Pigs were sedated with intramuscular ketamine, followed by induction of anaesthesia employing thiopentone administered via an ear-vein. After intubation, anaesthesia was maintained using nitrous oxide in oxygen. A total of eight pigs were then further anaesthetised on two separate occasions using one of two dose schedules. A bolus of 1.5 mg kg(-1) of eltanolone was administered, followed by a continuous infusion at either 2 or 10 mg kg(-1) h(-1). There were no significant changes in heart rate, mean arterial pressure, cardiac output or systemic vascular resistance following eltanolone. In all cases eltanolone induced marked rises in pulmonary artery pressure and pulmonary vascular resistance (P<0.01) at all measuring points and in right ventricular stroke work at 6-10 min after drug exposure. We conclude that the selective influence of eltanolone on the pulmonary vasculature is probably species-specific, but may have clinical significance in patients with pulmonary hypertension.     

The cardiovascular effects of cyclopropane in the intact, decerebrate and pithed rabbit preparations.

1 The anaesthetic cyclopropane was given to intact, decerebrate and pithed unanaesthetized rabbit preparations to determine the relative importance in vivo of its central and peripheral cardiovascular effects. 2 Cyclopropane elevated both the heart rate and the mean arterial pressure in the intact rabbit. 3 In the decerebrate rabbit, cyclopropane elevated the heart rate and efferent cervical preganglionic nerve activity and diminished the magnitude of these components of the aortic baroreceptor reflex, the mean arterial pressure being unaffected. 4 Apart from slight myocardial depression, cyclopropane was largely without effect in the pithed rabbit. 5 It is concluded that cyclopropane produces its cardiovascular effects by supra-collicular activation eliciting an elevation of mean arterial pressure, a central sub-collicular activation producing an increase in heart rate, and that in vivo the peripheral effects of cyclopropane are of minimal importance in comparison to these central effects.     

Effects of mu-opioid receptor agonists on circulatory responses to simulated haemorrhage in conscious rabbits.

1. Cardiac output, arterial pressure, heart rate, systemic vascular conductance, respiratory rate and arterial blood PO2 and PCO2 were measured in unanaesthetized rabbits. Haemorrhage was simulated by inflating a cuff placed around the inferior vena cava so that cardiac output fell at a constant rate of about 8% of its resting value per min. 2. The effects of drug treatments on resting haemodynamic and respiratory variables, and on the haemodynamic response to simulated haemorrhage, were tested. The treatments were; 4th ventricular (-)-naloxone HCl (10-100 nmol), 4th ventricular H-Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH (DAMGO; 30-300 pmol), and i.v. morphine sulphate (0.5-5.0 mumol kg-1). The interactions of graded 4th ventricular doses of naloxone (3-100 nmol) with the actions of DAMGO (100-300 pmol) on these responses were also assessed. 3. After sham treatments, the circulatory response to simulated haemorrhage had two phases. During the first compensatory phase, systemic vascular conductance fell, heart rate rose, and mean arterial pressure fell by only about 7 mmHg. A second decompensatory phase supervened when cardiac output had fallen by about 50%. At this point systemic vascular conductance rose abruptly and arterial pressure fell to less than or equal to 40 mmHg. 4. Low 4th ventricular doses of naloxone (10-30 nmol) and DAMGO (30-100 pmol) had no discernible effect on the circulatory response to simulated haemorrhage. Higher doses of naloxone (30-100 nmol) and DAMGO (100-300 pmol) prevented the decompensatory phase. These high doses of naloxone and DAMGO lowered resting heart rate without affecting the other haemodynamic or respiratory variables.(ABSTRACT TRUNCATED AT 250 WORDS)     

SIMULATION OF ACUTE HAEMORRHAGE IN UNANAESTHETIZED RABBITS

1. We have shown that it is feasible to match the linear rate of fall of cardiac output that occurs during haemorrhage at 2.7 ml/kg per min in unanaesthetized rabbits by constricting the thoracic inferior vena cava so as to decrease venous return. 2. The changes in systemic vascular resistance, arterial pressure and heart rate that occurred during haemorrhage were mimicked by simulated haemorrhage. They were reproducible when simulated haemorrhage was performed three times at 90 min intervals, and when it was repeated four times over 12 days. 3. Simulated haemorrhage caused rises in plasma renin activity (PRA) and plasma arginine vasopressin concentration (AVP) that were similar to those reported after haemorrhage. The response of PRA was unaffected by repeated simulated haemorrhage, but the response of AVP was less on the third occasion. 4. When the shed blood was re-infused after haemorrhage, cardiac output tended to remain low and systemic vascular resistance high. After simulated haemorrhage, all haemodynamic variables returned to normal within 2 min of releasing the caval cuff. 5. Haematocrit fell during haemorrhage, and remained low for at least 5 days after replacement of the shed blood. Haematocrit was unaffected by simulated haemorrhage. 6. Venous pressure below the inflatable cuff rose by 6 mmHg in the course of simulated haemorrhage. 7. We conclude that the central haemodynamic effects of haemorrhage can be closely and repeatedly simulated by inflating a cuff on the inferior vena cava. This provides a useful technique for repeatedly studying the effects of acute reduction of central blood volume in conscious animals.     

Spectral frequency index monitoring during propofol-remifentanil and propofol-alfentanil total intravenous anaesthesia

BACKGROUND: The aim of this study was to evaluate the usefulness of spectral frequency index (SFx) monitoring to assess the depth of anaesthesia during propofol-opioid total intravenous anaesthesia (TIVA). METHODS: Thirty-three patients scheduled for laparoscopic cholecystectomy under propofol TIVA were prospectively and randomly allocated to receive either remifentanil (bolus of 1.0 microg/kg, followed by continuous infusion from 0.25 to 0.05 microg/kg/min) [n = 18] or alfentanil (bolus of 10 microg/kg, followed by continuous infusion from 2.0 to 0.5 microg/kg/min) [n = 15]. EEG activity was monitored to achieve the desired depth of anaesthesia, and intravenous propofol was titrated to keep the SFx at 70-80%. The remifentanil and alfentanil groups were compared in relation to the plasma propofol concentration required for an adequate level of hypnosis during maintenance of anaesthesia, Pearson correlation coefficient for the relationship between the plasma propofol concentration and SFx values, recovery parameters, and recall of events during anaesthesia. RESULTS: The study groups were comparable with regard to demographic characteristics, type and duration of surgery, and time to resumption of spontaneous ventilation. No evidence of explicit recall was noted. The mean plasma propofol concentration required for an adequate level of hypnosis during maintenance of anaesthesia was significantly higher in the alfentanil group (3.20 microg/mL) compared with the remifentanil group (2.17 microg/L) [p < 0.05]. In both groups, the Pearson correlation coefficient test showed a linear correlation between SFx values and propofol concentration in the studied propofol concentration range. The mean time to orientation for name and place was significantly shorter (p < 0.05), the mean propofol concentration at orientation for name and place and at the resumption of spontaneous ventilation timepoints was significantly lower (both p < 0.01), and the mean SFx value at resumption of spontaneous ventilation timepoint was significantly higher (p < 0.01) in the remifentanil group. CONCLUSIONS: As SFx is linearly related to plasma propofol concentration, this index may be used to measure anaesthetic effect during propofol anaesthesia. The results of this clinical trial are consistent with a previous computer-simulated opioid-propofol model with regard to intraoperative and recovery variables, although the recovery occurred at different propofol concentration and SFx values.     

Opiate-like analgesic activity in general anaesthetics

1 The interaction of naloxone with various anaesthetics was studied both in vivo and in vitro.2 Naloxone (10 mg/kg) did not significantly alter the anaesthetic duration of halothane, diethylether, ketamine, pentobarbitone or Althesin.3 Naloxone (10 mg/kg) reduced the analgesic activity of nitrous oxide, ketamine and morphine in the rat tail-flick test. With the exception of pentobarbitone and Althesin, the other anaesthetic agents also induced analgesia but were not antagonized by naloxone.4 Specific [(3)H]-dihydromorphine binding was displaced by the opiates naloxone (IC(50) = 7.6 nm), methionine-enkephalin (Met-enkephalin, IC(50) = 40 nm) and morphine (IC(50) = 54 nm). Similarly, displacement was observed with xylazine (IC(50) = 9 mum), ketamine (IC(50) = 130 mum) and Althesin (IC(50) = 150 mum); other anaesthetics agents tested were inactive in mm concentrations.5 Ketamine (IC(50) = 200 mum) and xylazine (IC(50) = 9.5 mum) were also capable of displacing specific [(3)H]-D-Ala(2)-enkephalin (D-Leu) binding, as were morphine (IC(50) = 95 nm) and Met-enkephalin (IC(50) = 40 nm).6 On the stimulated guinea-pig ileum, Met-enkephalin and morphine inhibited the contractions, the IC(50) values were 30 nm and 50 nm respectively. The anaesthetics ketamine (IC(50) = 10 mum) and Althesin (IC(50) = 8 mum) were active. Xylazine (IC(50) = 12 nm) exhibited considerable potency in inhibiting the contractions on this preparation. Naloxone 0.5 mum produced a 1000 fold shift in the opiate dose-response curve but the anaesthetic responses showed only slight sensitivity to antagonism by naloxone.7 The activity of Althesin was found to be due to the vehicle in which this anaesthetic is solubilised.8 Whilst several anaesthetic agents showed analgesic activity, specific dihydromorphine binding displacement or guinea pig ileum inhibiting activity, these effects showed variable sensitivity to naloxone.     

Effects of the intravenously administered anaesthetics ketamine,propofol, and thiamylal on the cortical renal blood flow in rats

Intravenous anaesthetics such as ketamine, propofol, and thiamylal are widely used, although the direct effects of these anaesthetics on the renal blood flow (RBF) have not been well elucidated. In this study, we examined the effects of bolus and continuous administrations of ketamine, propofol, and thiamylal on cortical RBF and the effects of noradrenaline (NA) on RBF under continuous administration of these anaesthetics. We used laser Doppler flowmetry to measure the effects of bolus injection and continuous infusion of ketamine, propofol, and thiamylal on cortical RBF in male Wistar rats. We also examined the effects of the anaesthetics on mean arterial blood pressure (MAP) and heart rate (HR). Bolus injections of ketamine, propofol, or thiamylal (1-8 mg/kg each, n = 10) at clinically relevant concentrations did not affect MAP, HR, or RBF. Continuous administration of ketamine, propofol, or thiamylal (1-8 mg/kg/h each, n = 10) did not affect MAP, HR or RBF. Exogenous NA (2 microg/kg) caused an increase in MAP and a decrease in RBF and HR. In experiments with continuous infusions of propofol or thiamylal (1-8 mg/kg/h each, n = 10), similar results were observed without infusion of any anaesthetics. However, bolus injection of NA did not result in a decrease in RBF during continuous ketamine infusion (98.8 +/- 6.7% of control, n = 6, p < 0.05), while ketamine did not affect the NA-induced increase in MAP. In conclusion, bolus and continuous administrations of ketamine, propofol, and thiamylal did not affect the RBF. From our present findings, ketamine would be useful for maintaining the RBF.     

INHIBITION OF NITRIC OXIDE SYNTHASE SPECIFICALLY ENHANCES ADRENERGIC VASOCONSTRICTION IN RABBITS

1. The effect of inhibition of nitric oxide biosynthesis using N-nitro-L-arginine (NOLA) was examined in conscious rabbits and rabbit isolated aortae. 2. In autonomically blocked conscious rabbits intravenous infusion of NOLA (15 mg/kg) significantly increased arterial pressure and hindlimb vascular resistance but did not affect heart rate. Depressor and hindlimb vasodilator responses to acetylcholine (3-12 micrograms/kg per min) were significantly attenuated in the presence of NOLA. In contrast, NOLA significantly enhanced responses to intravenous infusion of glyceryl trinitrate (10-40 micrograms/kg per min) in vivo. 3. Infusion of noradrenaline (1-4 micrograms/kg per min) or the release of neuronal noradrenaline in response to the infusion of tyramine (80-320 micrograms/kg per min) increased arterial pressure and hindlimb vascular resistance in autonomically blocked conscious rabbits. After the administration of NOLA, the vasoconstrictor responses to both noradrenaline and tyramine were significantly enhanced. 4. In isolated rabbit aortae, NOLA (10 mumol/L) significantly impaired relaxant responses to acetylcholine but did not affect responses to glyceryl trinitrate. NOLA enhanced contractile responses to the adrenoceptor agonists noradrenaline and phenylephrine but did not affect the contractile responses to the thromboxane-mimetic U46619. 5. These data indicate that in autonomically blocked conscious rabbits, NOLA causes systemic vasoconstriction, impairs dilator responses to acetylcholine and enhances dilator responses to glyceryl trinitrate. In addition, NOLA enhances constrictor responses to both exogenous and neuronally-released noradrenaline. These results suggest that nitric oxide is important in the regulation of normal vascular tone and in the modulation of vascular responses to vasodilator and vasoconstrictor agents.