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Background Halogenated anesthetics potentiate the positive inotropic effects of alpha- and beta-adrenoceptor stimulations. Although diabetes mellitus induces significant myocardial abnormalities, the interaction of halogenated anesthetics and adrenoceptor stimulation in diabetic myocardium remains unknown. Methods Left ventricular papillary muscles were provided from healthy and streptozotocin-induced diabetic rats. Effects of 1 minimum alveolar concentration halothane, isoflurane, and sevoflurane on the inotropic and lusitropic responses of alpha (phenylephrine)- and beta (isoproterenol)-adrenoceptor stimulations were studied at 29 degrees C with 12 pulses/min. Data shown are mean percentage of baseline active force +/- SD. Results Phenylephrine induced comparable positive inotropic effects in healthy and diabetic rats (143 +/- 8 vs. 136 +/- 18%; not significant), but the potentiation by halogenated anesthetics was abolished in the diabetic rats (121 +/- 20, 130 +/- 20, and 123 +/- 20% for halothane, isoflurane, and sevoflurane, respectively; not significant). In diabetic rats, the positive inotropic effect of isoproterenol was markedly diminished (109 +/- 9 vs. 190 +/- 18%; P < 0.05), but its potentiation was preserved with isoflurane (148 +/- 21%; P < 0.05) and sevoflurane (161 +/- 40%; P < 0.05) but not with halothane (126 +/- 16%; not significant). Halothane induced a deleterious effect on the sarcoplasmic reticulum, as shown by its impairment in the lusitropic effect of isoproterenol, compared with isoflurane and sevoflurane. Conclusion Potentiation of the positive inotropic effect of alpha-adrenoceptor stimulation by halogenated anesthetics is abolished in diabetic rats. In contrast, potentiation of beta-adrenoceptor stimulation is preserved with isoflurane and sevoflurane but not with halothane, probably because of its deleterious effects on sarcoplasmic reticulum.

Background Direct myocardial effects of volatile anesthetics have been studied in various animal species in vitro. This study evaluated the effects of equianesthetic concentrations of desflurane, sevoflurane, isoflurane, and halothane on contractile parameters of isolated human atria in vitro. Methods Human right atrial trabeculae, obtained from patients undergoing coronary bypass surgery, were studied in an oxygenated (95% O2-5% CO2) Tyrode's modified solution ([Ca2+]o = 2.0 mM, 30 degrees C, stimulation frequency 0.5 Hz). The effects of equianesthetic concentrations (0.5, 1, 1.5, 2, and 2.5 minimum alveolar concentration [MAC]) of desflurane, sevoflurane, isoflurane, and halothane on inotropic and lusitropic parameters of isometric twitches were measured. Results Isoflurane, sevoflurane, and desflurane induced a moderate concentration-dependent decrease in active isometric force, which was significantly lower than that induced by halothane. In the presence of adrenoceptor blockade, the desflurane-induced decrease in peak of the positive force derivative and time to peak force became comparable to those induced by isoflurane. Halothane induced a concentration-dependent decrease in time to half-relaxation and a contraction-relaxation coupling parameter significantly greater than those induced by isoflurane, sevoflurane and desflurane. Conclusions In isolated human atrial myocardium, desflurane, sevoflurane, and isoflurane induced a moderate concentration-dependent negative inotropic effect. The effect of desflurane on time to peak force and peak of the positive force derivative could be related to intramyocardial catecholamine release. At clinically relevant concentrations, desflurane, sevoflurane, and isoflurane did not modify isometric relaxation.

Synaptosomes, or nerve-ending particles, were isolated from the cerebral cortices of young rats by homogenization, differential centrifugation, and density-gradient centrifugation. The sodium-potassium-activated adenosine triphosphatase enzyme system [(Na+ plus K+)-ATPase] of these particles is believed to represent in vitro the sodium-potassium pump of the nerve terminal. Suspensions of synpatosomes were equilibrated with air containing various concentrations of halothane and enflurane, as determined by gas chromatography. Clinical concentrations of the anesthetics had no effect on (Na+ plus K+)-ATPase activity. Fourteen per cent halothane and 14.8 per cent enflurane in the gas phase resulted in 12 and 10 per cent inhibition, respectively, of (Na+ plus K+)-ATPase activity. These data confirm that interference with active cation transport by inhibition of neuronal (Na+ plus K+)-ATPase is not related to the mechanism of halothane or enflurane anesthesia. (Key words: Anesthetics, volatile, halothane; Anesthetics, volatile, enflurane; Metabolism, enzymes, ATPase; Nerve, synaptosomal ATPase; Theories of anesthesia, ATPase.).

Radiocarbon-labeled trichlorofluoromethane (FC-11; 14CC13F) and dichlorodifluormethane (FC-12; 14CC12F2) were separately inhaled by a female subject and a male subject. A predetermined volume of fluorocarbon (1000 ppm; 100 muCi) in air was delivered through a nonrebreating system and a tight-fitting face mask for 7-17 minutes. Total expired gases were collected during fluorocarbon exposure and afterward until no radioactivity was detectable. Expired 14CO2 and 14C-fluorocarbon were assayed. Urine was collected for 72 hours and assayed for nonvolatile radioactivity. Total recoveries of FC-11 were 99.5 and 79.4 per cent in the woman and the man, respectively. Total recoveries of FC-12 were 95.4 and 103.2 per cent. Traces of radioactivity were found in urine (FC-11, 0.07 and 0.09 per cent; FC-12, 0.02 and 0.03 per cent) and in exhaled carbon dioxide (FC-11, 0.13 and 0.10 per cent; FC-12, 0.08 per cent in both subjects). Total metabolites were equal to or less than 0.2 per cent of the administered dose. The amount of radioactivity in urine was insufficient to permit identification of possible fluorocarbon metabolites. The trace of metabolites could be products of radiolabeled impurities. (Key words: Gases, non-anesthetic, dichlorodifluoromethane (Freon 12); Gases, non-anesthetic, trichlorofluoromethane (Freon 11); Pharmacology, fluorocarbons.)

We determined the minimum alveolar concentration (MAC) of four structural isomers having the empirical formula C3H2F5CIO in dogs. MAC for three of the four isomers (including isoflurane and enflurane) ranged from 1.41 to 2.67 (volumes per cent at one atmosphere pressure). The olive oil/gas partition coefficients at 37 degrees C for these isomers ranged from 90.8 to 96.6. In contrast, MAC for the fourth isomer, compound 485, was 12.53 per cent atm. However, the oil/gas partition coefficient for that compound was 25.8. These results suggest that isomer 485, despite its high MAC, does not deviate strikingly from the established correlation between anesthetic potency and lipid solubility.

The addition of halothane, methoxyflurane, or enflurane to hepatic microsomes caused the appearance of a trough at 420 mμ and simultaneous appearance of an absorption band at 385 mμ (type I), indicative of an interaction between cytochrome P-450 and the anesthetics. Diethyl ether had no effect Halot

The relationship between the reductive metabolism of halothane and hepatotoxicity was examined in three rat strains (Fischer 344, Sprague-Dawley, and black hooded Wistar) to determine if there were genetic differences in 1) the reductive metabolism of halothane under identical exposure conditions, and 2) the susceptibility to the hepatotoxic effects of halothane. Halothane hepatotoxic was produced in all rat strains by exposing phenobarbital-pretreated rats to 1 per cent halothane under mild hypoxia (14 per cent oxygen, inspired) for 2 h. Generally the levels of both 2-chloro-1,1,1-trifluoroethane (CTF) and 2-chloro-1,1-difluoroethylene (CDF), two volatile metabolites of halothane, increased from the onset of anesthetic exposure and reached a plateau after approximately 60 min. The exception to this trend were phenobarbital-pretreated Wistar rats (exposed to 1 per cent halothane with 14 per cent oxygen) where the levels of either CDF or CTF were high initially (10-min sample) and decreased in subsequent samples to reach a plateau after 80 min. The plateau levels of both CDF (approximately 6 ppm) and CTF (approximately 20 ppm) were not significantly different among the three rat strains exposed to halothane (1 per cent) and hypoxia with prior enzyme induction. There were, however, significant differences in both biochemical and pathological changes among the three strains exposed under the above identical conditions when the rats were killed 24 h after anesthetic exposure. For example, serum alanine aminotransferase (ALT) was increased fourfold in the Fischer strain but only doubled for the other two strains. Moreover, while all three strains had various amounts of hepatocyte damage in the vicinity of the central veins when the rats were exposed to halothane, hypoxia, and enzyme induction, only the Fischer strain showed hepatocyte damage under the exposure conditions of halothane (1 per cent) and normoxia (21 per cent oxygen, inspired) with prior enzyme induction. The results support the role of reductive metabolism of halothane in the etiology of halothane hepatotoxicity. Furthermore, they suggest that genetic variations in the susceptibility of the liver to the reactive intermediates or metabolites formed during reductive metabolism of halothane may be a significant factor in halothane hepatotoxicity.

The presence of two volatile halothane metabolites, 2-chloro-1,1,1-trifluoroethane (CF3CH2Cl) and 2-chloro-1,1-difluoroethylene (CF2CHCl), and a metabolite-decomposition product, 2-bromo-2-chloro-1,1-difluoroethylene (CF2CBrCl), were identified by gas chromatography-mass spectrometry in exhaled gases of 16 patients anesthetized with halothane in nonrebreathing, semiclosed and totally closed anesthesia circuits. No significant differences in concentrations of CF3CH2Cl and CF2CHCl were found relative to the anesthesia circuits used. CF2CBrCl could not be identified in the expired gases of patients anesthetized with a nonrebreathing circuit (Bain), but was present in gases recovered from both semiclosed and totally closed circuits. Under totally closed-circuit rebreathing conditions, the concentration of CF2CBrCl increased to 4-5 ppm, indicating significant breakdown of halothane by the soda lime. Possible pathways for formation of the two metabolites and the metabolite-decomposition product are presented, as well as clinical implications of these findings.

Since CF3CH2Cl and CF2CHCl are probably the products of reactive intermediates formed during the reductive metabolism of halothane (CF3CHClBr), factors affecting their in vitro and in vivo formation were investigated. In vitro studies with rat hepatic microsomes showed that CF3CH2Cl and CF2CHCl are produced by cytochrome P-450 mediated reductive pathways which were inhibited by the presence of CO. Under conditions of exposure known to promote halothane hepatotoxicity in phenobarbital treated rats (1 per cent halothane, 14 per cent oxygen), the hepatic and blood concentrations of the volatile metabolites were enhanced. Central venous levels of the volatile metabolites were much higher than he concentration in peripheral vessels. The CF3CH2Cl/CF2CHCl ratio in blood was approximately three, whereas the ratio in vitro was almost unity. Liver levels of the two volatile metabolites greatly exceeded the blood levels, but interestingly they were present in equivalent concentrations. The differences in the ratio of CF3CH2Cl to CF2CHCl may be explained by the fact that CF2CHCl is further degraded under oxidative conditions, whereas CF3CH2Cl appears relatively stable. Measurement of these metabolic products in patients undergoing halothane anesthesia may permit rapid detection of an unusually high level of halothane biotransformation along its hepatotoxic pathway.

The mutagenicities of two volatile metabolites of halothane, 2-chloro-1,1,1-trifluoroethane (CF3CH2Cl) and 2-chloro-1,1-difluoro-ethylene (CF2CHCl), and a presumed halothane metabolite, 2-bromo-2-chloro-1,1-difluoroethylene (CF2CBrCl), were investigated in the bacterial assay system developed by Ames and co-workers. Both gas-phase and liquid culture tests were made. In addition, mutagenicity of CF2CBrCl was studied in a modified Ames test system using rapidly growing cells in enriched liquid medium. The purity of tested compounds was verified by combined gas chromatography and mass spectrometry. In the standard Ames test, CF3CH2Cl and CF2CBrCl were not mutagenic, and CF2CHCl was only weakly mutagenic. CF2CBrCl was detectable as weakly mutagenic, however, in the modified Ames test using rapidly growing cells. Although these results are reassuring, the effects of long-term exposure to halogenated anesthetics are still not fully known.

The effects of enflurane on motor nerve terminals and muscle endplates were studied in the rat phrenic nerve-diaphragm preparation using standard microelectrode recording techniques. Muscle endplate interaction with enflurane was suggested by depression of the amplitude of miniature endplate potentials (MEPP's) without change in frequency, increased duration of MEPP's and endplate potentials (EPP's) increased threshold for generation of muscle action potentials, and inhibition of the endplate depolarization induced by succinylcholine. Evidence of nerve terminal effects of enflurane was limited to a greater relative decline of EPP amplitude during tetanus, indicative of failure to maintain transmitter output at rapid rates of stimulation. It is concluded that the depressant effect of enflurane on indirectly elicited muscle twitch is primarily due to an impairment of the action of muscle endplate on adjacent membrane; however, the relative importance of prejunctional depression, seen only during rapid nerve stimulation, cannot be assessed from the present data.

Effects of fluroxene and enflurane on myocardial mechanics of isolated papillary muscles obtained from cats with experimental congestive heart failure and from cats with normal hearts were compared. Significant impairment of myocardial performance, with elevated right ventricular pressure and reduce

Hepatic metabolism of halothane, methoxyflurane, cyclopropane, Ēthrane, and Forane was studied in miniature swine, using a modification of a technique which demonstrated that the liver extracts (metabolizes) a greater fraction of halothane from hepatic blood flow at lower than at higher anesthetic partial pressures. Animals were exposed to constant, low subanesthetic concentrations of each anesthetic for periods of 20 hours to one week and measurements of extraction made thereafter. We found considerable hepatic metabolism of halothane and methoxyfiurane, little or none of Ēthrane, and none of cyclopropane or Forane. These results may be related to toxicity since toxic effects of inhalation anesthetics may be due to their metabolites.

Thirty-six mongrel dogs were ventilated with oxygenated fluorocarbon liquid (FX-80) for an hour and then reconverted to breathing gaseous oxygen. For several days after breathing this liquid, the dogs were hypoxemic while they breathed air. The authors attributed this to residual fluorocarbon in the lung and/or partial airway closure. By ten days after liquid ventilation, Pao2's had returned to pre-experimental control levels. Pathologic examination of the lungs three hours after termination of liquid ventilation disclosed an acute exudative inflammatory reaction largely confined to the bronchioles. By 72 hours the acute reaction had subsided and the dominant change consisted of vacuolated intra-alveolar macrophages, presumably containing fluorocarbon. At ten days, macrophages were still present, but generally in much smaller numbers; after a month only scattered small groups were found. At 18 months the lungs were normal.

In 15 patients anesthetized with Forane and in an additional 15 patients anesthetized with Forane and nitrous oxide, the authors found that surgical stimulation induced increases in ventilation which significantly reduced PaCO2 The mean reductions in CO2 from control values prior to surgical stimulation ranged from 5 to 13 torr, the magnitudes being similar in the two groups and for all depths of anesthesia. The reductions were sufficient to cause all average CO2 values to be less than 50 torr even at deep levels of anesthesia. Prior to operation, the respiratory depression for a given anesthetic concentration appeared to be somewhat greater when Forane was given without nitrous oxide.

Cardiac arrhythmias were produced in the cat by inhalation of 1 per cent halopropane, 10 per cent CO2 and 89 per cent O2 and also by injection of epinephrine during inhalation of 1 per cent halopropane and 99 per cent O2. Dextro-H56/28, which has local anesthetic properties but only 1/40th the beta receptor blocking activity of the levo form of H56/28, had a weak, brief antiarhythmic effect on the halopropane-CO2 arrhythmia and did not significantly increase the threshold dose of epinephrine required to produce an arrhythmia during halopropane administration. However, levo-H56/28, when tested against the halopropane- CO2 and halopropane-epinephrine arrhythmias, had a marked, prolonged antiarrhythmic effect which was attributed to its beta-adrenergic blocking action.

Specific activities of enflurane, isoflurane, and methoxyflurane defluorinases were measured in microsomes prepared from the livers of Fischer 344 rats; the ratio of these activities was 23:3:1. Pretreatment with phenobarbital significantly increased the defluorinase activities of all three agents. Factors that influence anesthetic drug metabolism are discussed; tissue solubility is considered to be the most important.

Reactions of N-acetylcysteine with the halothane metabolite, 2-chloro-1,1-difluoroethylene (CF2CHCl), and two related probable metabolites, 2-bromo-1,1-difluoroethylene (CF2CHBr) and 2-bromo-2-chloro-1,1difluoroethylene (CF2CBrCl), afforded the saturated conjugates, RSCF2CH2Cl, RSCF2CH2Br, and RSCF2CHBrCl, as well as the unsaturated analogs, RSCFCHCl and RSCFCHBr; R = −CH2CH(COOH)NHCOCH3. The mutagenic and genotoxic potential of these conjugates was evaluated in the Salmonella/microsome system described by Ames and a “rec” DNA repair system developed by Kada employing recombination proficient and deficient strains of Bacillus subtilis. When screened for mutagenicity with Salmonella typhimurium strains TA1535 and TA100, the saturated and the unsaturated conjugates were found to be nonmutagenic. However, in a preliminary test using strain TA100 in logarithmic growth, compounds RSCF2CHBrCl and RSCFCHCl were mutagenic. Furthermore, screening for DNA-damaging ability in the B. subtilis “rec” assay with strains H17 and M45 revealed that the urinary halothane metabolite, RSCF2CHBrCl, and the unsaturated analogs, RSCFCHCl and RSCFCHBr, preferentially inhibited the growth of strain M45, which is deficient in its ability to repair DNA. In view of the reported correlation between known mutagens and their differential lethal action on rec− versus rec+ bacteria, the present findings of the DNA-damaging effects of the nonvolatile halothane metabolites and related probable metabolites suggest a possible relationship between halothane metabolism and reported toxic effects associated with occupational anesthetic exposure.

The minimum alveolar concentration (MAC) of aliflurane was measured in ten dogs. A value of 1.84 volumes per cent was determined, which correlates well with predictions based on lipid solubility. Induction of anesthesia and recovery were rapid, as would be anticipated with an agent of relatively low solubility in blood (blood-gas partition coefficient = 1.7). Circulatory responses over a relatively narrow range of aliflurane concentrations (0.8 to 1.4 MAC) remained stable, but the development of tachypnea, irregular ventilatory patterns, and increased muscle tone were frequently encountered during aliflurane anesthesis.

Two important measures may be derived from patient responses to a range of anesthetic doses. The AD50, corresponding to MAC, estimates the median anesthetic concentration--that dose where half the patients are anesthetized and half are not. The AD95 approaches the theoretical "minimum" anesthetic concentration by estimating the dose that anesthetizes 95 per cent of a patient population. The AD50 and AD95 are logical extensions of the MAC concept and can be evaluated with current experimental methodology. Recomputed from available data , the AD50's of nine inhaled anesthetics proved to be numerically identical to their MAC values. The AD95's of nine inhaled anesthetics proved to be numerically identical to their MAC values. The AD95's were 5 to 40 per cent greater than the AD50's.)Key workd: Potency, anesthetic, MAC, AD50, AD95; Pharmacology, dose-response curves.)

The actions of diethyl ether, enflurane, and isoflurane at the neuromuscular junction were examined in isolated guinea pig lumbrical muscles. These anesthetics depressed the ability of carbachol to depolarize the endplate region; this depression of depolarization did not show competitive kinetics. None of the anesthetics altered the affinity of the acetylcholine receptor for d-tubocurarine, i.e., the dissociation constant of d-tubocurarine was unchanged. Since diethyl ether, enflurane, and isoflurane produced no observable alteration of the receptor, the antagonism of the drug-induced depolarization of the neuromuscular junction appears to be exerted at a stage subsequent to reaction with the receptor. (Key words: Anesthetics, volatile, diethyl ethers; Anesthetics, volatile, euflurane; Anesthetics, volatile, isoflurane; Neuromuscular relaxants, d-tubocurarine; Neuromuscular junction.).

1,1-Difluoro-2-bromo-2-chloroethylene, a probable metabolite of halothane, was purified by preparative gas chromatography and tested for mutagenicity in the Salmonella/mammalian liver system developed by Ames and colleagues. 1,1,1-Trifluoro-2-chloroethane which had been isolated from the breath or rabbits anesthetized with halothane was also tested for mutagenicity in a similar manner. Both compounds were found to be nonmutagenic in this bacterial system. Although neither this study nor any other has yet been able to demonstrate that halothane or any of its metabolites is genetically active, nevertheless, unnecessary occupational exposure to the drug should be avoided due to the possibility that future studies could reveal adverse effects secondary to halothane.

Responses to ligation of the left anterior descending coronary artery (blood pressure, heart rate, ECG, arrhythmias, myocardial tissue loss, and mortality) were investigated in chronically prepared rats anesthetized with one of various halogenated hydrocarbon anesthetics. Halothane (inhaled concentrations of 0, 0.25, 0.5, 1.0, and 2.0%) reduced arrhythmias, mortality, and "S-T" segment changes in the ECG in a dose-related manner. The most effective antiarrhythmic concentrations were 0.5 and 1.0%. Other halogenated hydrocarbon anesthetics (chloroform, enflurane, isoflurane, methoxyflurane, and trichlorethylene) were investigated at minimal anesthetic concentrations. Of these, only chloroform and enflurane reduced arrhythmias. However, both increased mortality as a result of nonarrhythmic causes. At one-half anesthetic concentrations, chloroform (0.25%) and enflurane (0.75%) were not antiarrhythmic and mortality resulting from nonarrhythmic causes was not increased. In the chronically prepared rat, halothane at anesthetic and subanesthetic concentrations has antiarrhythmic actions against ligation-induced arrhythmias, reducing mortality. Of the other halogenated hydrocarbons tested, only enflurane and chloroform had antiarrhythmic actions, however, mortality was high with both agents because of accompanying cardiovascular depression.

The ventilatory effects of Forane were studied in ten volunteers and compared with values obtained in eight volunteers anesthetized with halothane. Paco2 averaged 60 torr with both 1.9 per cent alveolar Forane (approximately 1.45 X MAC) and 1.6 per cent halothane (1.9 X MAC). The slopes of the CO2 response curves were depressed to 30 ± 6 per cent (Mean ± SE) of awake control values by 1.28 per cent Forane (approximately 1.0 X MAC) and to 45 ± 7 per cent of controls with 1.05 per cent halothane (1.25 X MAC). Therefore, when equivalent anesthetic doses are considered, less Forane than halothane was needed to increase Paco2 and depress the slope of the CO2 response curve. In contrast to halothane, Forane in increasing concentrations did not cause progressive increases in respiratory frequency. At equal multiples of MAC, Forane produces more profound respiratory depression than halothane, and this depression results from a unique failure of respiratory frequency to increase with increasing depth of anesthesia.

Muscle twitch responses to stimulation of the ulnar nerve during Ēthrane anesthesia were studied in 47 adult surgical patients. The responses to an intravenous dose of d-tubocurarine or succinylcholine during light anesthesia were measured. The results were compared with results from similar studies

Pancuronium, gallamine, and succinylcholine produced more profound neuromuscular blockade in 36 patients anesthetized with 1.25 MAC Forane than in 36 patients anesthetized with 1.25 MAC halothane. The median effective dose of pancuronium necessary to produce 50 per cent depression of twitch height (ED20) was 0.27 mg/m2 during Forane and 0.49 mg/m2 during halothane anesthesia, giving a halothane/Forane potency ratio of 1.8. The ED20 of gallamine was 9.4 mg/m2 during Forane anesthesia and 22.5 mg/m2 during halothane anesthesia, for a potency ratio of 2.4. The ED20 of succinylcholine was 3.4 mg/m2 during Forane anesthesia and 5.1 mg/m2 during halothane anesthesia, for a potency ratio of 1.5.