Interaction of i.v. anaesthetic agents with 5-HT3 receptors

Using N1E-115 neuroblastoma cells as an experimental model, we have examined if four commonly used i.v. anaesthetic induction agents interact with 5-HT3 receptors. Specifically, we tested the hypothesis that the antiemetic effects of propofol may result from 5-HT3 receptor antagonism. Binding of tropisetron (a 5-HT3 selective reference compound), etomidate, ketamine, thiopentone and propofol to 5-HT3 receptors was assessed by measuring the displacement of [3H]BRL 43694 from whole N1E-115 cells. The rank order potency (Ki) was tropisetron (1.7 (SEM 0.2) nmol litre-1) > etomidate (83.(4) mumol litre-1) > or = ketamine (97 (4) mumol litre-1) > thiopentone (177 (9) mumol litre-1) > propofol (819 (171) mumol litre-1). With the exception of thiopentone these effects were outside the clinical range and suggest that anaesthetic agents are unlikely to interact directly with 5-HT3 receptors, and that other mechanism(s) must underlie the antiemetic effects of propofol.     

Hyporeactivity of rat diaphragmatic arterioles after exposure to hypoxia in vivo. Role of the endothelium

The effect of prior in vivo hypoxia on the in vitro responses to changes in transmural pressure, alpha-adrenoceptor activation, and depolarization with KCl were evaluated in first-order diaphragmatic arterioles. Rats (n = 14 per group) were exposed to normoxia (controls) or to hypoxia (inspired O2 concentration = 10%) for 12 or 48 h. The arteriolar pressure-diameter relationships were recorded over a pressure range from 10 to 200 mm Hg. In separate groups of arterioles (n = 12 per group), the diaphragmatic arteriolar responses to phenylephrine (10(-8) to 10(-5 M) or KCl (10 to 100 mM) were determined after exposure to either room air or hypoxia for 48 h. In half of the arterioles studied, the endothelium was removed. After 12 h of hypoxia, the pressure-diameter relationship was normal in endothelialized arterioles but was shifted upward in de-endothelialized vessels (p < 0.05). After 48 h of hypoxia, the constrictor response to increasing transmural pressure was severely suppressed in all arterioles. The intraluminal diameters during activation with phenylephrine and KCl were larger in arterioles from rats exposed to hypoxia (103 +/- 8 and 81 +/- 7 microns, respectively) than in control arterioles (41 +/- 5 and 54 +/- 6 microns, respectively; p < 0.05 for differences). During maximum phenylephrine- and KCl-induced constriction in de-endothelialized arterioles, diameters averaged 125 +/- 8 and 105 +/- 8 microns, respectively, for arterioles from hypoxic rats and 32 +/- 6 and 40 +/- 5 microns, respectively, for arterioles from control vessels. Exposure to hypoxia results in impairment of diaphragmatic arteriolar smooth muscle reactivity and reversal of the normal inhibitory influence of the endothelium on diaphragmatic arteriolar tone.     

Genetic maps of eight linkage groups of Aspergillus niger based on mitotic mapping

The effects of etomidate on corticosteroid synthesis were compared with those of methohexitone. We studied 40 neonates, 22 delivered by elective and 18 by emergency Caesarean section. Apgar scores, blood sugar and plasma concentrations of cortisol and etomidate were evaluated at birth and 2 and 6 h postpartum. There was no difference in Apgar scores attributable to the induction agent. The median cortisol concentrations in cord blood were small (136 nmol litre-1; range 47-478 nmol litre-1, and 259 nmol litre-1; range 58-1504 nmol litre-1 after elective and emergency sections, respectively). During the study, cortisol concentrations increased in the infants in the methohexitone groups and decreased in those in the etomidate groups; this effect was most evident 2 h after delivery (methohexitone groups 245 nmol litre-1, range 70-959 nmol litre-1; etomidate groups 121 nmol litre-1, range 56-320 nmol litre-1). There was no difference at 6 h postpartum (methohexitone groups 183 nmol litre-1, range 25-756 nmol litre-1; etomidate groups 190 nmol litre-1, range 33-628 nmol litre-1). The concentration changes during the study period differed significantly (P < 0.005) with respect to the induction agent. Blood glucose concentrations were small (mean (SD) in all 40 neonates 2 h postpartum was 2.64 (0.77) mmol litre-1), and did not differ between the groups. There were 17 cases of moderate to severe hypoglycaemia (blood glucose concentrations less than 2.5 mmol litre-1): nine in the etomidate group and eight in the methohexitone group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thiopental or etomidate for rapid sequence induction with rocuronium

We have assessed the effect of the choice of i.v. induction agent on intubation conditions, 60 s after administration of rocuronium 0.6 mg kg-1. We studied 60 adult patients, allocated randomly to one of two groups. Anaesthesia was induced with alfentanil 10 micrograms kg-1 followed by thiopental 5 mg kg-1 (AT-R group; n = 30) or etomidate 0.3 mg kg-1 (AE-R group; n = 30). Both groups received rocuronium 0.6 mg kg-1. Laryngoscopy was started 60 s later and intubation conditions were evaluated according to a standard score, which considered ease of laryngoscopy, condition of the vocal cords and reaction to intubation. In the AT-R group, overall intubation conditions were scored as excellent in 20 patients, good in nine and fair in the remaining patient. In the AE-R group, overall intubating conditions were excellent in 24 and good in six patients. The difference between the two groups was not significant. Of the three components of the intubation score assessed, response to intubation stimulus was significantly less pronounced in group AE-R compared with group AT-R (P < 0.05): group AE-R, no reaction in 24 patients, slight diaphragmatic movement in five and mild coughing in one patient; group AT-R, no reaction in 13, slight diaphragmatic movement in 14, mild coughing in two and severe coughing in one patient. We conclude that etomidate as part of an induction regimen containing alfentanil and rocuronium attenuated the reaction to intubation to a greater extent than thiopental.     

A comparison of the cerebral protective effects of etomidate, thiopental, and isoflurane in a model of forebrain ischemia in the rat

We evaluated the effect of etomidate, thiopental, and isoflurane on ischemic neuronal injury in rats. Control group animals received 1.2% isoflurane. The animals in the etomidate and thiopental groups received an infusion of either etomidate or thiopental until electroencephalographic (EEG) burst-suppression was attained. In the fourth group, the isoflurane concentration was increased to 3% (sufficient to produce EEG burst-suppression). Forebrain ischemia was induced by bilateral carotid artery occlusion with simultaneous hypotension for 10 min. Three days after ischemia, two blinded observers evaluated neuronal injury in coronal brain sections stained with hematoxylin and eosin. Injury to the ventral CA1 of the hippocampus was less in the etomidate group than in the control group. Injury to the entorhinal cortex was less in the thiopental group than in the control group. Histopathologic outcome in animals anesthetized with 1.2% isoflurane and 3% isoflurane was not different. Although these data indicate that etomidate and thiopental might reduce ischemic injury in some structures, the magnitude of the protective effects observed was small.     

Right ventricular diastolic disfunction and its relation to left ventricular performance in patients with hypertension

The potential effects of propofol emulsion (Diprivan) on the neuromuscular transmission and muscular contraction were studied using in vitro and in vivo nerve-muscle preparations of rats. The contractions of the isolated rat diaphragm elicited by either indirect or direct electrical stimulation were inhibited by propofol emulsion at threshold concentrations of 42 and 112 mumol l-1, respectively. Similarly, the gastrocnemius muscle contractions induced by either indirect or direct electrical stimulation in vivo were inhibited by propofol emulsion administration as a bolus injection of 2.5 mg kg-1 intravenously, followed by intravenous infusion of 150 micrograms kg-1 min-1 for 1 h into rats. The inhibitory effects of propofol in both preparations were greater with indirect rather than direct stimulation. Propofol emulsion was found to be capable of enhancing the paralysis of the indirectly stimulated rat diaphragm in vitro and gastrocnemius muscle in vivo induced by either pipecuronium or succinylcholine. The combination of propofol and pipecuronium led to a synergistic inhibition of the neuromuscular transmission, while the combination of propofol and succinylcholine led to additive inhibition. Pretreatment with propofol emulsion at these threshold concentrations markedly inhibited the stimulant effects of aminophylline and digoxin on the indirectly and directly induced diaphragmatic contractions. Also, the enhancement effects of aminophylline on the indirectly and directly and of digoxin on indirectly induced rat gastrocnemius muscle contractions were markedly inhibited by propofol emulsion administration to rats. Pretreatment with propofol emulsion at the threshold concentrations enhanced the inhibitory effects of verapamil on diaphragmatic contractions elicited either indirectly or directly and enhanced the inhibitory effect of adenosine on the contractions elicited indirectly. Similarly, the inhibitory effects of verapamil on the indirectly and directly and of adenosine on indirectly induced rat gastrocnemius muscle contractions were markedly potentiated by propofol emulsion administration to rats. In addition, doubling the concentration of calcium in the bathing fluid produced no change in the inhibitory effects of propofol emulsion on either indirectly or directly elicited diaphragmatic contractions, while doubling the concentration of external magnesium potentiated the propofol effects. Pretreatment with 4-aminopyridine suppressed the inhibitory effects of propofol emulsion on diaphragmatic contractions elicited either indirectly or directly. These results suggest that propofol acts presynaptically to inhibit the neuromuscular transmission and acts at the muscle membrane to inhibit the muscular contraction.     

Inhibition by anaesthetics of 14C-guanidinium flux through the voltage-gated sodium channel and the cation channel of the 5-HT3 receptor of N1E-115 neuroblastoma cells

The influence of local and general anaesthetics on cation influx through the fast, voltage-dependent sodium channel and the 5-HT3 receptor cation channel was studied in N1E-115 mouse neuroblastoma cells by measuring 2-min influx of the organic cation 14C-guanidinium induced by either veratridine (1 mmol/l) or 5-HT (100 mumol/l). The veratridine-induced influx of 14C-guanidinium was potentiated by scorpion toxin and inhibited by tetrodotoxin. The 5-HT-induced 14C-guanidinium influx was not affected by tetrodotoxin but it was inhibited by nanomolar concentrations of the selective 5-HT3 receptor antagonists ondansetron and ICS 205-930; at high micromolar concentrations these compounds also inhibited the veratridine-induced influx of 14C-guanidinium. The 14C-guanidinium influx through both channels was inhibited by local and general anaesthetics. The rank order of potency for inhibition of veratridine-induced influx by local anaesthetics was tetracaine > bupivacaine > cocaine > lidocaine > procaine and that for inhibition of the 5-HT3 receptor channel was tetracaine > bupivacaine > cocaine > procaine > lidocaine. With the exception of procaine and cocaine, which were equipotent at both channels, the local anaesthetics were 4.4-fold (lidocaine) to 25-fold (tetracaine) more potent at the fast sodium channel than at the 5-HT3 receptor channel. The rank order of potency for general anaesthetics was propofol > etomidate = alfaxalone = ketamine > thiopental = methohexital at the fast sodium channel, and propofol > or = etomidate > alfaxalone = methohexital > thiopental > ketamine at the 5-HT3 receptor channel.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of propofol and thiopentone on free radical mediated oxidative stress of the erythrocyte

Propofol has free radical scavenging properties similar to those of recognized phenol-based antioxidants. We have examined these properties in an in vitro model of radical-induced cellular injury, comparing its activity with that of thiopentone (which has also been shown to have radical scavenging activity). Haemolysis of human erythrocytes was induced using the azo compound 2,2'-azo-bis(2-amidinopropane) dihydrochloride (ABAP). This was achieved by incubating a 10% suspension of erythrocytes with ABAP 100 mmol litre-1 at 37 degrees C. For propofol, at concentrations of 12.5, 25 and 50 mumol litre-1, the times to achieve 50% haemolysis were mean 126 (SEM 7) min (95% confidence interval 108-144 min), 150 (8) (129-170) min and 182 (12) (160-180) min, respectively (Intralipid control 107 (7) (90-125) min, ANOVA P < 0.0001). For thiopentone, at concentrations of 62.5, 125 and 250 mumol litre-1, the values were 117 (2) (112-121) min, 126 (3) (119-133) min and 138 (2) (132-144) min, respectively (saline control 109 (2) (104-113) min, ANOVA P < 0.0001). Spectroscopic analysis in the visible and ultraviolet spectra demonstrated a steady increase in the proportion of methaemoglobin during haemolysis, with the highest concentrations in the propofol-containing flasks. The formation of methaemoglobin was preceded by the generation of ferrylhaemoglobin (a Fe4+ haemoglobin species). Further experiments examining oxidation of purified methaemoglobin to ferrylhaemoglobin by hydrogen peroxide suggested that propofol, but not Intralipid or thiopentone, reduced ferrylhaemoglobin back to the met- state, and thereby explained the higher concentrations of methaemoglobin in the propofol-containing erythrocyte suspensions. We conclude that propofol is a more potent free radical scavenger in this model of oxidant stress than thiopentone, and that reduction of high oxidation states of haemoglobin may contribute to such activity.     

A clinico-radiological correlation of breast diseases during lactation and the significance of unilateral failure of lactation

OBJECTIVES: The Ishikawa endometrial cancer cell line is hormonally responsive, expressing estrogen and progesterone receptors (ER, PR) when grown in traditional monolayer culture. The purpose of this paper is to demonstrate a three-dimensional spheroid culture system for cancer cells. We used this system to determine the response of the Ishikawa cell line to estradiol-17 beta (E), tamoxifen (T), megestrol acetate (MA), and progesterone (P). METHODS: Ishikawa cells were incubated in polyurethane culture bags using phenol red-free media containing ethanol (0.1%, controls), E (1 mumol, or 1 nmol), T (1 mumol, or 10 nmol), MA (1 mumol, or 10 nmol), or P (1 mumol). Cellular morphology was assessed by hematoxylin and eosin staining, and expression of estrogen and progesterone receptors was determined immunohistochemically using an immunoperoxidase technique. RESULTS: Cells in control cultures demonstrated minimal organization and lacked hormone receptors. In contrast, cells exposed to either E or T displayed significant glandular formation, with multicellular, microvilli-rich, columnar epithelia exhibiting polarized nuclear arrangements. Within 4 weeks, E- and T-treated cultures showed upregulated nuclear staining for PR, with little ER present. Cells treated with MA or P showed less glandular organization but expressed ER with PR downregulation. CONCLUSIONS: These data support the use of this novel three-dimensional culture system to study the modulation of tumor cell biologic activity in response to hormonal agents. Future applications of this model include examining in vitro responsiveness of cancer cell lines to additional biologic agents and chemotherapeutic regimens.     

Phosphatidylcholines as mediators of adaptive cytoprotection of the rat duodenum

BACKGROUND/AIMS: Surfactant phospholipids impede diffusion of acid through the gastric mucus, but their relevance in the defense of the duodenum against luminal acid is not known. METHODS: Duodenal resistance to acid was tested in anesthetized rats by instillation of HCl using a tube implanted in the proximal duodenum. The effects of a detergent (Brij 35; Sigma, St. Louis, MO) and a lipid mixture flushed through the luminal surface on duodenal resistance to acid were studied. The lipid content in the mucus and the effects of acid, prostaglandins, and indomethacin on the lipid layer were also analyzed. RESULTS: Instillation of 100 mumol HCl or 5 micrograms/kg 16,16-dimethyl prostaglandin E2 increased resistance to acid, preventing duodenal lesions induced by 500 mumol HCl. However, 100 mumol HCl or 16,16-dimethyl prostaglandin E2 did not prevent lesions induced by 500 mumol HCl in rats undergoing perfusions with 5% Brij 35. Indomethacin suppressed acid-induced protection. A mixture of tripalmitin and dipalmitoyl-phosphatidylcholine protected against 500 mumol HCl, and the effect was also observed in rats receiving indomethacin. Finally, 100 mumol HCl increased the phosphatidylcholine content in the duodenal mucus but not in rats receiving 5% Brij 35 or indomethacin. CONCLUSIONS: Surface-active phospholipids are critical for adaptive cytoprotection to acid in the rat duodenum.     

Modulation of arteriolar sympathetic constriction by local nitric oxide: onset during rapid juvenile growth

The goal of this study was to determine if the endogenous activity of nitric oxide (NO) and/or prostanoids can limit arteriolar responses to increased sympathetic nerve activity in striated muscle, and to explore possible changes in these influences during rapid juvenile growth. Using intravital microscopy, arteriolar responses to 2-16 Hz sympathetic nerve stimulation were studied in the superfused spinotrapezius muscle of weanling (4-5 weeks old) and juvenile (7-8 weeks old) rats. Nerve stimulation elicited frequency-dependent arteriolar constrictions that were abolished in both age groups by the fast Na+-channel blocker tetrodotoxin or the alpha-antagonist phentolamine. Diameter and flow responses to 2-8 Hz stimulation were greater in juvenile rats than in weanling rats. In juvenile rats but not in weanling rats, the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) reduced arteriolar diameters and blood flow at rest and enhanced the arteriolar diameter and flow responses to sympathetic nerve stimulation. The cyclooxygenase inhibitor meclofenamate reduced resting arteriolar diameters in both age groups, but had no effect on responses to sympathetic nerve stimulation in either group. These results suggest that juvenile growth is accompanied by an overall increase in arteriolar responsiveness to sympathetic nerve activity, and by the onset of local NO activity that limits this increased responsiveness.     

Propofol and etomidate-Lipuro for induction of general anesthesia. Hemodynamics, vascular compatibility, subjective findings and postoperative nausea

Etomidate has become an important induction agent in high-risk patients because of its cardiovascular stability. Its unwanted side-effects such as pain on injection and thrombophlebitis could be significantly reduced by a new (medium chain triglyceride and soya bean) emulsion formulation. Propofol is solved in a mixture of long chain triglyceride and soya bean emulsion. In this double-blind, randomized study we compared the haemodynamic effects, the patients' sensations, signs of thrombophlebitis and postoperative nausea and vomiting (PONV) following injection of both drugs. METHODS: Following premedication with 2 mg Lormetazepam p.o. in 50 patients per group, anaesthesia was induced with either 0.51 mg etomidate in lipid emulsion or 3.04 mg propofol per kg bw. No opioid or benzdiazepine was given i.v. before induction. After injection of the tested drug, the cannula was removed. Changes in blood pressure and heart rate were recorded as well as signs of discomfort during and after injection (pain, burning, tension, cold). Venous sequelae were assessed for 5 days after injection to register signs of thrombophlebitis. RESULTS: Demographic data showed no difference between the two groups. After propofol more often a fall in blood pressure was seen. Pain (25 vs 1 pt), burning 19 vs 1), tension 15 vs 3), cold (35 vs 17) after injection was registered significantly more often in the propofol group, whereas myocloni predominated in the etomidate group (13 vs 6) P < 0.05, chi-squared-test). No difference was seen in PONV in either groups. CONCLUSION: Etomidate formulated in a medium chain lipid emulsion causes significant less discomfort for the patients than propofol, which is solved in a long chain formulation. Myocloni, however, occur significantly more frequently after etomidate than after propofol.     

ST segment changes in the ECG. Anesthesia induction with propofol, etomidate or midazolam in patients with coronary heart disease

Induction of anaesthesia with propofol and fentanyl can lead to marked reductions in mean arterial pressure (MAP) and heart rate (HR). Thus, the application of propofol in patients with severely reduced coronary artery perfusion is controversial. METHODS. The study group consisted of 60 patients undergoing coronary artery bypass grafting (CABG). Anaesthesia was induced over 30 s with propofol (P 1.5 mg/kg), etomidate (E 0.3 mg/kg), or midazolam (M 0.15 mg/kg) following a bolus dose of fentanyl (5 micrograms/kg). Vecuronium was used as a muscle relaxant. During induction we continuously measured MAP and HR and recorded the occurrence of myocardial ischaemia using an automatic ST-segment analyser (Marquette 7010). ST-segment deviations of more than 1 mm in leads II and V5 were interpreted as significant signs of myocardial ischaemia. RESULTS. All groups showed reductions in MAP and HR on induction that were marked in the P group. Intubation caused elevation of MAP and HR to pre-induction levels (HR: all groups) or slightly above (MAP: E, M). Four patients in the P group and 3 in each other group showed significant ST-segment deviation prior to induction. In the P group these deviations disappeared in 2 patients after injection while they remained unchanged in the M group. In the E group injection had no effect on the ischaemic ECG changes but produced another case of significant ST-segment deviation. Laryngoscopy and intubation produced no further significant ST-segment deviation in either group. DISCUSSION. Induction is a critical phase of anaesthesia, especially in patients with limited coronary reserve. Induction agents should alleviate the stress response while causing minimal haemodynamic changes. Despite marked reductions in MAP in the P group, the number of patients with ischaemic ECG changes was cut by half. Their number was unchanged or even raised in the other groups. After application of P, with an alleged reduction of coronary perfusion, a compensational reduction in myocardial oxygen consumption may occur.     

Effect of subarachnoid bupivacaine block on anesthetic requirements for thiopental in rats

BACKGROUND: Subarachnoid bupivacaine blockade has been reported to reduce thiopental and midazolam hypnotic requirements in patients. The purpose of this study was to examine if local anesthetically induced lumbar intrathecal blockade would reduce thiopental requirements for blockade of motor responses to noxious and nonnoxious stimuli in rats. METHODS: After intrathecal and external jugular catheter placement, rats were assigned randomly to two groups in a crossover design study, with each rat to receive either 10 microl of 0.75% bupivacaine or 10 microl of normal saline intrathecally. The doses of intravenously administered thiopental required to ablate the eyelid reflex, to block the withdrawal reflex of a front limb digit, and to block the corneal reflex were compared. In two separate groups of animals, hemodynamic parameters and concentrations of thiopental in the brain were compared between intrathecally administered bupivacaine and saline. RESULTS: The thiopental dose required to block the described responses was decreased with intrathecally administered bupivacaine versus intrathecally administered saline from (mean +/- SD) 40 +/- 5 to 24 +/- 4 mg/kg (P < 0.001) for the eyelid reflex, from 51 +/- 6 to 29 +/- 6 mg/kg (P < 0.005) for front limb withdrawal, and from 67 +/- 8 to 46 +/- 8 mg/kg (P < 0.01) for the corneal reflex. The concentration of thiopental in the brain at the time of corneal reflex blockade for the group given bupivacaine was significantly lower than in the group given saline (24.1 vs. 35.8 microg/g, P = 0.02). CONCLUSION: This study demonstrates that lumbar intrathecally administered local anesthetic blockade decreases anesthetic requirements for thiopental for a spectrum of end points tested. This effect is due neither to altered pharmacokinetics nor to a direct action of the local anesthetic on the brain; rather, it is most likely due to decreased afferent input.     

Effect of propofol as an agent for anesthetic induction on pituitary-adrenocortical function during anesthesia and surgery

Effect of propofol as an agent for anesthetic induction on plasma levels of cortisol, beta-endorphin-like immunoreactivity (beta-ELI), growth hormone (GH) and prolactin were evaluated in 20 non-abdominal surgical patients ranged in ages from 19 to 64 years. Anesthesia was induced with either intravenous propofol 2-2.5 mg in ten patients or intravenous thiopental 4-5 mg in the remaining 10 patients as the control group, and succinylcholine was administered intravenously to facilitate tracheal intubation. Enflurane-nitrous oxide-oxygen was then given to maintain anesthesia in all the patients of both groups. Plasma cortisol levels decreased slightly with anesthesia in the propofol group, but they increased slightly after anesthetic induction in the control group. Therefore they were significantly lower in the propofol group than those in the control group. They tended to increase gradually during surgery and reached the peak value after the emergence from anesthesia in both groups. Plasma beta-ELI levels were unchanged with anesthesia alone in the patients of both groups. They tended to increase gradually during surgery and reached the peak value after the emergence from anesthesia in both groups. Plasma GH levels were not affected with anesthesia, but they increased slightly during surgery in both groups. Plasma prolactin levels increased significantly during anesthesia and surgery in both groups, and they decreased after the emergence from anesthesia but were still significantly higher than the preanesthetic values in both groups. The authors' findings suggest that effects of propofol as an agent for anesthetic induction on pituitary-adrenocortical function during anesthesia and surgery are comparable to those of thiopental, and that propofol does not exert inhibitory effect on pituitary-adrenocortical function during anesthesia and surgery.     

Molecular cloning and characterization of the mouse Kin17 gene coding for a Zn-finger protein that preferentially recognizes bent DNA

We have investigated the effects of ketamine on nitric oxide produced by activated macrophages using a murine macrophage-like cell line, J774. Cells were incubated for 18 h under stimulation with lipopolysaccharide and interferon-gamma or lipoteichoic acid and interferon-gamma, with various concentrations of ketamine (6-600 mumol litre-1). Nitric oxide production was assessed by measuring nitrite, a stable by-product of nitric oxide breakdown, in the medium. Other N-methyl-D-aspartate receptor antagonists, MK-801 (150 mumol litre-1) and dextromethorphan (150 mumol litre-1) were also tested. In addition, we studied the effects of ketamine on production of tumour necrosis factor-alpha by activated macrophages. Ketamine inhibited nitrite production dose-dependently with both lipopolysaccharide- and lipoteichoic acid-activated macrophages by up to approximately 65% at the highest ketamine concentration (600 mumol litre-1). Neither MK-801 nor dextromethorphan had an inhibitory effect. Ketamine also suppressed production of tumour necrosis factor-alpha. The data show that ketamine inhibited nitric oxide production by activated macrophages probably, in part, via inhibition of production of tumour necrosis factor-alpha, an autocrine stimulatory factor for nitric oxide production, but not via the NMDA receptor pathway, which is involved in neuronal nitric oxide production.     

Alpha-adrenergic reactivity of the microcirculation in conscious spontaneously hypertensive rats

The goal of this study was to determine the functional distribution of alpha 1- and alpha 2-adrenoceptors in the striated muscle microcirculation. Experiments were performed in intact conscious spontaneously hypertensive rats (SHR) that were provided with a dorsal microcirculatory chamber to allow microvascular diameter measurements. Administration of selective alpha 1- and alpha 2-agonists, phenylephrine and azepexole, respectively, induced different patterns of microvascular constriction. alpha 1-Adrenoceptor stimulation showed a preferential constriction of large arteries and venules. The entire arteriolar microvasculature was sensitive to alpha 2-adrenoceptor stimulation, whereas the venular vessels did not respond to azepexole. The selective alpha 1- and alpha 2-antagonists prazosin and yohimbine showed patterns of vasodilator activity comparable to those of the corresponding agonists. The specificity of the drug-induced effects was verified by comparing their effects with those of graded hemorrhage, a non-pharmacological method for blood pressure lowering. In the range of blood pressure decreases comparable to that obtained by alpha-adrenoceptor antagonists, graded hemorrhage did not influence microvascular diameters. These results show a differential functional distribution of alpha 1- and alpha 2-adrenoceptors along the microvascular tree in striated muscle of conscious SHR.     

Propofol, but not thiopentone or etomidate, enhances isoflurane-induced coronary vasodilatation in dogs

PURPOSE: To test the hypothesis that thiopentone, propofol, and etomidate alter the coronary vascular effects of abruptly administered isoflurane. METHODS: Dogs (n = 6) received inspired isoflurane 5% in the presence of thiopentone (20 mg.kg-1 induction dose and 20 mg.kg-1.hr-1 infusion), propofol (5 mg.kg-1 induction dose and 40 mg.kg-1.hr-1 infusion), etomidate (2 mg.kg-1 induction dose and 5 mg.kg-1.hr-1 infusion), or isoflurane (1.0 MAC) anaesthesia in a random fashion. Haemodynamics were assessed in the conscious state, during baseline anaesthesia, and at 30 sec intervals for five minutes after beginning isoflurane 5%. RESULTS: Rapidly administered isoflurane caused greater (P < 0.05) reductions in coronary vascular resistance in thiopentone- or propofol--than in isoflurane-anaesthetized dogs. Isoflurane produced greater (P < 0.05) increases in the ratio of coronary blood flow velocity to pressure-work index (an index of myocardial oxygen consumption; +109 +/- 19% during isoflurane alone vs +182 +/- 27% change from baseline during propofol and isoflurane) consistent with relatively greater direct coronary vasodilatation during baseline propofol than during baseline isoflurane anaesthesia. Isoflurane caused larger increases in coronary blood flow velocity in dogs anaesthetized with etomidate concomitant with higher coronary perfusion pressure and pressure-work index than in those anaesthetized with isoflurane alone. CONCLUSIONS: The results suggest that thiopentone, propofol, and etomidate each uniquely modify the coronary vascular responses to abrupt administration of high inspired concentrations of isoflurane in chronically instrumented dogs.     

Hepatocellular integrity during and after isoflurane and halothane anaesthesia in surgical patients

Subclinical disturbance in hepatocellular integrity, indicated by glutathione transferase Alpha (GSTA), has been associated with halothane, sevoflurane and propofol, but not with isoflurane anaesthesia. We anaesthetized 82 patients with isoflurane or halothane at 1 MAC for superficial surgery. GSTA concentration were measured with a sensitive time-resolved immunofluorometric assay in serum samples. GSTA concentrations increased from a baseline value of geometric mean 1.8 micrograms litre-1 (95% confidence intervals 1.4-2.2 micrograms litre-1) to a peak of 4.3 (3.3-5.7) micrograms litre-1 in the isoflurane group and from 2.1 (1.6-2.9) micrograms litre-1 to 6.2 (4.1-9.5) micrograms litre-1 in the halothane group. The change in GSTA was significant within groups but the difference between groups was not significant. Two patients exhibited an unexpectedly large increase in GSTA (peaks 370 and 620 micrograms litre-1) and a mild increase in alanine aminotransferase after halothane anaesthesia. We conclude that hepatocellular integrity was mildly disturbed after isoflurane and halothane anaesthesia but there was no difference between anaesthetics. Halothane anaesthesia may be associated with more advanced hepatocellular disturbance in some cases.     

Endogenous deficiency of nitric oxide as an aggravating factor in retinal vein occlusion

PURPOSE: Following retinal branch vein occlusion (b.v.o.), the arteriole crossing the occluded territories is often constricted. This constriction persists up to several weeks and is correlated with the development of extended territories of non-perfused capillaries. We present here results of an investigation supporting the hypothesis that decrease in the production of nitric oxide (NO) accounts for the observed arteriolar constriction. METHODS: Preretinal [NO] was measured using an NO microprobe in the anesthethized miniature pigs, before and within the first 4 hours following experimental b.v.o. Modifications of arteriolar diameter were correlated to preretinal [NO] changes. The retinal arteriolar sensitivity to constitutive NO was checked by performing preretinal puff injections of nitro-1-arginine (L-NA) after both systemic hypoxia and b.v.o. RESULTS: Two hours after b.v.o. there was 73.7 +/- 4% decrease in preretinal [NO] and a simultaneous 25.4 +/- 3.4% decrease in the diameter of the arteriole in the affected territory. Both persisted for at least 4 hours after b.v.o. Puffing L-NA over an arteriole previously dilated by systemic hypoxia induced a vasoconstriction. However no arteriolar constriction was observed when puffing was performed on an arteriole after b.v.o. CONCLUSIONS: These results show that experimental b.v.o. induced in the affected retina an impairment in the release of constitutive NO and an arteriolar constriction, which in turn, contribute to the development of tissue hypoxia and neuronal swelling and death in the inner retina.