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.     

Pre- and postsynaptic volatile anaesthetic actions on glycinergic transmission to spinal cord motor neurons

1. A common anaesthetic endpoint, prevention of withdrawal from a noxious stimulus, is determined primarily in spinal cord, where glycine is an important inhibitory transmitter. To define pre- and postsynaptic anaesthetic actions at glycinergic synapses, the effects of volatile anaesthetic agents on spontaneous and evoked glycinergic currents in spinal cord motor neurons from 6 - 14-day old rats was investigated. 2. The volatile anaesthetic agents enflurane, isoflurane and halothane significantly increased the frequency of glycinergic mIPSCs, enflurane to 190.4% of control+/-22.0 (mean+/-s.e.m., n=7, P<0.01), isoflurane to 199.0%+/-28.8 (n=7, P<0.05) and halothane to 198.2%+/-19.5 (n=7, P<0.01). However without TTX, isoflurane and halothane had no significant effect and enflurane decreased sIPSC frequency to 42.5% of control+/-12.4 (n=6, P<0.01). All the anaesthetics prolonged the decay time constant (tau) of both spontaneous and glycine-evoked currents without increasing amplitude. With TTX total charge transfer was increased; without TTX charge transfer was unchanged (isoflurane and halothane) or decreased (enflurane). 3. Enflurane-induced mIPSC frequency increases were not significantly affected by Cd(2+) (50 microM), thapsigargin (1 - 5 microM), or KB-R7943 (5 microM). KB-R7943 and thapsigargin together abolished the enflurane-induced increase in mIPSC frequency. 4. There are opposing facilitatory and inhibitory actions of volatile anaesthetics on glycine release dependent on calcium homeostatic mechanisms and sodium channels respectively. Under normal conditions (no TTX) the absolute amount of glycinergic inhibition does not increase. The contribution of glycinergic inhibition to anaesthesia may depend on its duration rather than its absolute magnitude.     

Additive and non-additive effects of mixtures of short-acting intravenous anaesthetic agents and their significance for theories of anaesthesia

1 The potency of a series of short-acting anaesthetics was established by measuring the duration of the loss of righting reflex following a single bolus injection into the tail vein of male Wistar rats. The agents were, in order of potency, etomidate, alphaxalone, methohexitone, alphadalone acetate and propanidid.2 The potency of binary mixtures of these agents was also assessed to see whether the anaesthetic effects of different agents were additive as classical theories of anaesthesia suggest. Mixtures of alphaxalone and alphadalone acetate, alphaxalone and propanidid and methohexitone and propanidid all showed simple additive effects. Mixtures of alphaxalone and etomidate and of alphaxalone and methohexitone showed a greater potency than would be expected if their effects were simply additive. Mixtures of etomidate and methohexitone were not examined.3 Mixtures of alphaxalone and either methohexitone or pentobarbitone produced a greater depression of synaptic transmission in in vitro preparations of guinea-pig olfactory cortex than would have been expected from the sum of the activities of the individual anaesthetics. Other combinations of anaesthetics did not show similar effects although the interaction between alphaxalone and etomidate was not examined.4 Neither alphaxalone nor pentobarbitone affected the membrane: buffer partition coefficient of the other for a model membrane system.5 These results are interpreted as evidence against the classical unitary hypotheses of anaesthetic action based on correlations of anaesthetic potency with lipid solubility and as supporting the view that different anaesthetics act on different structures in the neuronal membranes to produce anaesthesia.     

Effect of ether,chloroform and carbon dioxide on monoamine inactivation

To determine if anaesthetic agents alter monoamine inactivation, we exposed tissue homogenates (liver, kidney and brain) from mice and rabbits to ether and chloroform vapors and carbon dioxide gas. These anaesthetic agents inhibited monoamine oxidase (MAO) activity against tryptamine and serotonin. Concentrations of anaesthetic agents that are achieved in the plasma of man during general anaesthesia caused a 27% (ether) and 49% (chloroform) reduction in mouse liver MAO; higher concentrations caused a 95% inhibition mouse or rabbit liver MAO. Kinetic analysis with tryptamine as substrate indicate that ether and chloroform are noncompetitive, reversible MAO inhibitors that preferentially inhibit Type B MAO. Ether and chloroform cause noncompetitive inhibition of serotonin oxidation by mouse liver MAO and competitive inhibition of serotonin oxidation by mouse brain and kidney MAO. Ether or chloroform did not alter catechol-O-methyltransferase activity from tissues of mice. Isolated blood platelets (rabbit and human) were used as a model system for neuronal uptake. Ether caused an irreversible inhibition of serotonin uptake by platelets.     

The action of volatile anaesthetics on stimulus-secretion coupling in bovine adrenal chromaffin cells.

1. The action of four volatile anaesthetics, ethrane, halothane, isoflurane and methoxyflurane on stimulus-secretion coupling has been studied in isolated bovine adrenal medullary cells. All four agents inhibited the secretion of adrenaline and noradrenaline evoked by 500 microM carbachol at concentrations within the anaesthetic range. Total catecholamine secretion induced by stimulation with 77 mM potassium was also inhibited but at higher concentrations. All four agents inhibited the 45Ca influx evoked by stimulation with 500 microM carbachol and the 45Ca influx in response to K+-depolarization. 2. When total catecholamine secretion in response to potassium or carbachol was modulated by varying extracellular calcium or by adding halothane or methoxyflurane to the incubation medium, the amount of catecholamine secretion for a given Ca2+ entry was the same. 3. The action of methoxyflurane on the relationship between intracellular free Ca and exocytosis was examined using electropermeabilised cells, which were suspended in solutions containing a range of concentrations of ionised calcium between 10(-8) and 10(-4)M. The anaesthetic had no effect on the activation of exocytosis by intracellular free calcium. 4. Halothane and methoxyflurane inhibited the carbachol-induced secretion of catecholamines in a non-competitive manner. 5. Halothane and methoxyflurane inhibited the increase in 22Na influx evoked by carbachol. For halothane and methoxyflurane this inhibition of Na influx appears to be sufficient to account for the inhibition of the evoked catecholamine secretion. 6. We conclude that the volatile anaesthetics ethrane, halothane, isoflurane and methoxyflurane inhibit the secretion of adrenaline and noradrenaline induced by carbachol at concentrations that lie within the range encountered during general anaesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic degradation of propanidid by various tissues. Short communication.

The very short anaesthetic action of 3-methoxy-4-(N,N-diethylcarbamoyl-methoxy)-phenylacetic acid propylester (propanidid, Epantol) is due to its rapid hydrolysis in vivo. In this study, the rates of degradation of this drug under the influence of various isolated tissues have been established. The drug was hydrolysed much more rapidly by liver homogenate than by whole blood or serum. It is concluded that inactivation of propanidid in vivo occurs mainly by the liver, whereas blood esterases play an insignificant part in hydrolyzing the ester. Moreover, it was demonstrated that cardiac tissue is able to hydrolyze the drug as well. It is postulated that the inactivation of propanidid by heart muscle might partly compensate for the severe cardiodepressive action of the anaesthetic agent. A gaschromatographic determination of propanidid has been developed.     

Lack of inhibition of glycolytic enzymes by the neurotoxic organophosphorus compounds Mipafox and Methamidofos

Preincubation with Mipafox and Methamidofos as well as Paraoxon (used as control) did not cause inhibition of hexokinase, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase and lactate dehydrogenase. This is in contrast with the inhibition of glycolysis by other neurotoxic compounds (hexacarbons, acrylamide, carbon disulfide).This work was supported by Fondo de Investigaciones Sanitarias de la Seguridad Social (FISSS, Spain)     

Effects of halothane on the incorporation of [14C]-serine into phospholipid in the guinea-pig ileum

1 The effects of halothane on the incorporation of L-[3-14C]-serine into phospholipid were studied in the resting, innervated longitudinal muscle preparation of the guinea-pig ileum. 2 The anaesthetic, at clinical concentrations, caused a dose-dependent, partial inhibition of incorporation. The effect was rapid and reversible, and did not show characteristics of competitive inhibition. 3 The incorporation was reduced by a decrease in the Ca2+ concentration of the Krebs incubation buffer. Part of the activity persisted in the absence of added Ca2+ and this was most susceptible to inhibition by halothane. Sensitivity to external Ca2+ was not influenced at the halothane concentrations studied. 4 Evidence in support of the 14C-incorporation being due to L-[3-14C]-serine-phospholipid base-exchange activity included: (a) the rapid appearance of radioactivity in phosphatidylserine; (b) the kinetics of this incorporation in relation to that in phosphatidylethanolamine; (c) its dependence on Ca2+, and (d) its sensitivity to 2,4-dinitrophenol and its sensitivity to temperature. 5 It is concluded that this preparation makes it possible for a membrane-bound lipid-dependent activity (L-serine-phospholipid base-exchange) to be studied in conditions of cellular integrity under which the normal functional effects of lipophilic drugs can be simultaneously tested. 6 A rapid gas-chromatographic assay for halothane from an aqueous medium is also described.     

Effects of several inhalation anaesthetics on the kinetics of postsynaptic conductance changes in mouse diaphragm.

1 Miniature endplate currents were recorded with extracellular electrodes in mouse diaphragms in order to measure the kinetics of the conductance change produced by acetylcholine. Miniature endplate potentials (m.e.p.ps) were recorded intracellularly in the same fibres in which the currents were being recoreded. 2 The general anaesthetics, ether, halothane, chloroform and enflurane at low (anaesthetic) concentrations increased the rate of decay of miniature endplate currents (m.e.p.cs) and reduced the amplitude of m.e.p.ps in this way. 3 At high concentrations the anaesthetics caused a reduction in the amplitude of both m.e.p.cs and m.e.p.ps, and a decrease in the rate of decay of the currents. With halothane and enflurane the decay of some currents became biphasic, with a prolonged tail. 4 It was proposed that the increased rate of decay of the conductance caused by the four agents at anaesthetic concentrations is due to an increase in the fluidity of the subsynaptic membrane. Prolongation of the currents at higher concentrations may be caused by an increase in membrane dielectric constant. 5 The effectiveness of the four anaesthetics in producing a 30% decrease in the time constant of decay of m.e.p.cs was shown to be related to their oil/water partition coefficients and followed closely the relationship between anaesthetic potency and oil/water partition coefficient. It is suggested therefore that the four anaesthetics may produce anaesthesia by changing the kinetics of postsynaptic conductance changes at synapses, perphaps by increasing membrane fluidity.     

Effect of general anaesthetics and organic solvents on alpha 1-adrenoceptors in the myometrium

The alpha 1 selective radioligand 3H-prazosin was used to assay alpha 1 receptors in membranes prepared from the rabbit myometrium. 3H-Prazosin was found to bind to a single high affinity site in these membranes which was the presumed alpha 1 receptor. A series of general anaesthetics and organic solvents were tested for their ability to inhibit 3H-prazosin binding. The order of potency of the tested agents to inhibit the binding was: chloroform=halothane=trichloroethylene greater than carbon tetrachloride greater than dichloromethane. The depression of 3H-prazosin binding seemed to be induced on the alpha 1 receptor since non-specific radioligand binding was not affected as revealed by a saturation experiment with 3H-prazosin where halothane was used as inhibiting agent. Computer analysis of the latter experiment also showed that halothane depressed mainly the affinity of 3H-prazosin for the alpha 1 receptor. The ability of the general anaesthetics and organic solvents to inhibit contractions elicited by alpha 1 stimulation with phenylephrine in the rabbit uterus was also investigated. In these tests the order of potency for the inhibition of the contractile response was: carbon tetrachloride greater than or equal to halothane=chloroform greater than trichloroethylene greater than dichloromethane. The mechanism of action for alpha 1 receptor and myometrial depression is discussed.     

In Vivo and In Vitro Sevoflurane-Induced Lipid Peroxidation in Guinea-pig Liver Microsomes

Abstract: Sevoflurane is a recently introduced volatile inhalation anaesthetic and is already used commonly in Japan. We investigated the potential of sevoflurane to cause lipid peroxidation in vivo and in vitro. For the in vitro study, pentane formation in a mixture of guinea pig liver microsomes and sevoflurane in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) was analyzed by gas chromatography. Under anaerobic conditions, pentane formed without sevoflurane, but sevoflurane potentiated this anaerobic pentane formation. Two antioxidant agents, vitamine E and glutathione, reduced the pentane formation induced by sevoflurane. In the in vivo study, 18 guinea pigs were exposed to air (control), 0.5% halothane, or 1.2% sevoflurane. The extent of lipid peroxidation and liver damage was investigated by measuring the level of thiobarbituric acid reactive products and serum transaminase (alanine-aminotransferase: ALAT and aspartate-aminotransferase: ASAT) activity 12 hr after exposure. Both halothane and sevoflurane significantly increased thiobarbituric acid-reactive products. The increase in thiobarbituric acid-reactive products seen with sevoflurane administration was half that seen with halothane. Sevoflurane increased the ALAT activity to the same extent as did halothane but did not increase the ASAT activity. We conclude that sevoflurane potentiates lipid peroxidation in guinea pig liver microsomes in vivo and in vitro. However, because the degree of liver damage as measured by transaminase activity was minimal and the mechanism of sevoflurane-induced lipid peroxidation is still unknown, we must be cautious in applying these results to humans.     

The effects of temperature on the interactions between volatile general anaesthetics and a neuronal nicotinic acetylcholine receptor.

1. Completely isolated identified neurones from the right parietal ganglion of the pond snail Lymnaea stagnalis were investigated under two-electrode voltage clamp. Neuronal nicotinic acetylcholine receptor (AChR) currents were studied at low acetylcholine concentrations (< or = 200 nM). 2. Inhibition of the ACh-induced currents by three volatile general anaesthetics (halothane, isoflurane and methoxyflurane) and the specific inhibitor (+)-tubocurarine was studied as a function of temperature (over the range 4-25 degrees C). 3. The inhibition by the volatile anaesthetics increased (inhibition constants decreased) with decreasing temperature while the inhibition by (+)-tubocurarine did not change significantly near room temperature, but decreased at lower temperatures. The (+)-tubocurarine inhibition appeared to be competitive in nature and showed no significant voltage-dependence. 4. The van't Hoff plots (logarithms of the dissociation constants against reciprocal absolute temperature) were linear for the anaesthetics, but markedly non-linear for (+)-tubocurarine. From these plots, values for the changes in the standard Gibbs free energy delta G degrees water-->AChR, enthalpy delta H degree water-->AChR, entropy delta S degree water-->AChR and heat capacity delta Cp degree water-->AChR were determined. Tubocurarine was found to bind very much tighter to the receptor than the volatile anaesthetics due, entirely, to a favourable increase in entropy on binding. 5. A comparison between the temperature-dependence of the anaesthetic inhibition of the ACh receptor and that of general anaesthetic potencies in animals indicates that the temperature-dependence of animal potencies might be simply accounted for in terms of changes in anaesthetic/receptor binding.     

Adverse effects of general anaesthetics.

This review deals with the adverse reactions associated with general anaesthetic agents in current use. These reactions fall into 2 categories; those which are more common, predictable and often closely related, and those which are rare, unpredictable and carry a high mortality. Both inhalational and intravenous anaesthetic agents affect the central nervous and cardio-respiratory systems in a dose-related manner. Neuronal inhibition results in decreasing levels of consciousness and depression of the medullary vital centres which can lead to cardiorespiratory failure. Both groups of agents have some depressant effect on the myocardium and vascular smooth muscle leading to a fall in cardiac output and hypotension. Centrally-mediated respiratory depression is common to both groups and the inhalational agents have a direct effect on lung physiology. The most important idiosyncratic reactions to the volatile agents are malignant hyperpyrexia and 'halothane hepatitis'. Malignant hyperpyrexia has an incidence of 1:12,000 with a mortality of about 24%. It is triggered most often by halothane together with suxamethonium. Post halothane hepatic necrosis is rare. Evidence points to 2 distinct syndromes; direct toxicity from the products of reductive metabolism, and a more serious illness, immunologically mediated via haptens formed by liver proteins and the products of oxidative metabolism. Prolonged nitrous oxide exposure can cause bone marrow depression and life-threatening pressure effects by expansion of air-filled spaces within the body. The idiosyncratic reactions to the intravenous agents include anaphylactoid reactions (which are rare) and triggering of acute porphyria. Etomidate is immunologically 'clean', but it inhibits cortisol synthesis.     

Clinical pharmacokinetics of the inhalational anaesthetics

At present, the most widely used inhalational anaesthetics are the halogenated, inflammable vapours halothane, enflurane, isoflurane and the gas nitrous oxide. The anaesthetic effect of these agents is related to their tension or partial pressure in the brain, represented at equilibrium by the alveolar concentration. The minimum alveolar concentration for a specific agent is remarkably constant between individuals. The uptake and distribution of inhalational anaesthetics depends on inhaled concentration, pulmonary ventilation, solubility in blood, cardiac output and tissue uptake. Inhalational anaesthetics are mainly eliminated by pulmonary exhalation, but significant amounts of halothane are removed by hepatic metabolism. Inhalational agents currently in use have acceptable pharmacokinetic characteristics, and clinical acceptance depends on their potential for adverse effects. Induction of anaesthesia with halothane is rapid and relatively pleasant and it is the agent of choice for paediatric anaesthesia. Between 20 and 50% is metabolised, and the parent drug is a potent inhibitor of drug metabolism. Post-operatively enzyme induction may follow. The major disadvantages of halothane are myocardial depression, propensity to evoke cardiac arrhythmias and the rare but serious halothane hepatitis. Induction and recovery from enflurane anaesthesia is rapid. Metabolism accounts for 5 to 9% of the elimination. The metabolic product inorganic fluoride may in rare cases cause renal toxicity. Enflurane is a weak inhibitor of drug metabolism at anaesthetic concentrations. Enflurane depresses circulation more than halothane by reducing both myocardial contractility and systemic vascular resistance, but cardiac rhythm is stable. Enflurane anaesthesia may, unlike the other agents, induce epileptic activity. Enflurane is widely used as replacement for halothane in adults. Despite its low blood-gas solubility, the airway irritability of isoflurane precludes a faster induction of anaesthesia than with halothane. Isoflurane is almost resistant to biodegradation. Myocardial contractility is maintained during isoflurane anaesthesia and cardiac rhythm is stable except for the occurrence of tachycardia in some patients. Isoflurane is the inhalational agent of choice for neurosurgical operations. Sevoflurane is an experimental ether vapour: induction and recovery is fast and pleasant. It is metabolised to the same extent as enflurane and subnephrotoxic concentrations of inorganic fluoride may result. Sevoflurane has fewer respiratory and cardiovascular depressant effects than halothane and may be a future alternative for paediatric anaesthesia.(ABSTRACT TRUNCATED AT 400 WORDS)     

Reduced inhibition of cortical glutamate and GABA release by halothane in mice lacking the K+ channel, TREK-1

BACKGROUND AND PURPOSE: Deletion of TREK-1, a two-pore domain K(+) channel (K(2P)) activated by volatile anaesthetics, reduces volatile anaesthetic potency in mice, consistent with a role for TREK-1 as an anaesthetic target. We used TREK-1 knockout mice to examine the presynaptic function of TREK-1 in transmitter release and its role in the selective inhibition of glutamate vs GABA release by volatile anaesthetics. EXPERIMENTAL APPROACH: The effects of halothane on 4-aminopyridine-evoked and basal [(3)H]glutamate and [(14)C]GABA release from cerebrocortical nerve terminals isolated from TREK-1 knockout (KO) and littermate wild-type (WT) mice were compared. TREK-1 was quantified by immunoblotting of nerve terminal preparations. KEY RESULTS: Deletion of TREK-1 significantly reduced the potency of halothane inhibition of 4-aminopyridine-evoked release of both glutamate and GABA without affecting control evoked release or the selective inhibition of glutamate vs GABA release. TREK-1 deletion also reduced halothane inhibition of basal glutamate release, but did not affect basal GABA release. CONCLUSIONS AND IMPLICATIONS: The reduced sensitivity of glutamate and GABA release to inhibition by halothane in TREK-1 KO nerve terminals correlates with the reduced anaesthetic potency of halothane in TREK-1 KO mice observed in vivo. A presynaptic role for TREK-1 was supported by the enrichment of TREK-1 in isolated nerve terminals determined by immunoblotting. This study represents the first evidence for a link between an anaesthetic-sensitive 2-pore domain K(+) channel and presynaptic function, and provides further support for presynaptic mechanisms in determining volatile anaesthetic action.     

Inhibition by polyhalogenated hydrocarbons (PHHC) of ATPases in plasma membranes of parenchymal liver cells

Summary Suspensions of freshly prepared plasma membranes from rat livers were equilibrated with defined mixtures of air with polyhalogenated hydrocarbons (PHHC) at 37°C. During the exposition enzymatic degradation of ATP was inhibited by carbon tetrachloride, chloroform and halothane in a dose-dependent manner. On a molar basis carbon tetrachloride was 5 times more effective than chloroform and halothane. The inhibition was partially reversible.Diethyldithiocarbamate, an agent protecting animals against carbon tetrachloride, was ineffective in this assay.This work was supported by the Deutsche Forschungsgemeinschaft.     

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.     

The negative inotropic action of propanidid. influence on calcium movements in atrial tissue.

Propanidid (Epontol), a general anaesthetic agent with a particularly short action in vivo significantly depressed the contraction amplitude of guinea pig isolated atria. A steep concentration-response curve could be established. Contractile force of electrically driven atria (180/min) was reduced by approximately 50% at a propanidid concentration of 3.5 x 10-4 M in the medium. The negative inotropic effect developed rapidly (less than 10 min). At concentrations of 4.5 x 10-4 M and less propanidid hardly reduced the frequency of spontaneously beating atria. The uptake of extracellular 45 Ca by spontaneously beating atria occurred significantly more slowly in presence of propanidid (4.5 x 10-4 M ), whereas the exchangeable calcium fraction remained unchanged. Accordingly, propanidid reduced the rate of exchange of calcium so that less ionized calcium was available for excitation-contraction coupling. Propanidid (4.5 x 10-4 M) accelerated the uptake of 45Ca by isolated plasma membranes, obtained from guinea pig ventricular muscle. Moreover, the binding capacity for calcium by isolated membranes was increased in presence of propanidid. These observations imply that less ionized calcium is available for activation of the contractile system. It is concluded that the negative inotropic action of propanidid is probably due to the drug's influence on membrane function, thus bringing about an important change in cellular calcium metabolism.     

Effect of the general anaesthetic,propanidid on oxidative phosphorylation and calcium transport in rat liver mitochondria

The general anaesthetic, propanidid was found to have two major sites of action on mitochondrial oxidative phosphorylation. At low concentrations (<100 μM) the compound was an inhibitor of NAD⁺-linked oxidations, acting at, or near, the rotenone-sensitive site on the NADH dehydrogenase enzyme system. High concentrations of propanidid (1–5 mM) stimulated both succinate oxidation and the mitochondrial ATPase: it was concluded that these effects were due to an uncoupling action. Mitochondrial Ca²⁺ transport was inhibited by propanidid when glutamate plus malate were used as substrate, but not when succinate replaced the NAD⁺-linked substrates.     

Cardiac depression by haloalkane propellants,solvents, and inhalation anesthetics in rabbits

A total of 40 closed chested, pentobarbital-anesthetized, and spontaneously breathing rabbits were given 1.5-min inhalation exposures to 5 % concentrations of halothane, 1,1,1-trichloroethane, fluorocarbon 11 (trichlorofluoromethane), fluorocarbon 12 (dichlorodifluoromethane), chloroform, or dichloromethane. Peak left ventricular (LV) $\text{dP}\text{dt}$, LV systolic pressure, and cardiac output were depressed by exposure to each compound and were not accompanied by significant changes in heart rate or LV end-diastolic pressure. Fluorocarbon 11, halothane, and 1,1,1-trichloroethane inhalation also depressed mean arterial pressure. A ranking of the magnitude of these effects showed that fluorocarbon 12 and dichloromethane generally had less effect on cardiac output and LV function than other compounds studied. As cardiac depressants, fluorocarbon 11 and 1,1,1-trichloroethane appeared to be as potent as halothane.