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Central and peripheral pulmonary mucociliary clearance was assessed by tantalum bronchography and serial chest roentgenograms in dogs. Thiopental, 25 mg/kg, did not change clearance from awake values. Halothane 1.2 MAC, for six hours, delayed both central and peripheral clearance by at least three hours. After halothane or diethyl ether, 1.2 MAC, for two hours, recovery of mucociliary clearance was delayed for approximately three and a half hours

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

Diethyl ether elicited a dose-dependent increase in the intrinsic frequency of contraction of isolated rat atrial preparations. The maximum effect (plus 34 per cent) occurred with 230 mg ether/100 ml medium. This ether concentration corresponds to a partial pressure of 29.2 mm Hg or 3 MAC. The positive chronotropic action of ether was not reduced in atria obtained from rats pretreated with reserpine (4 mg/kg, ip) although this treatment markedly reduced the effect of tyramine on frequency of contraction. The positive chronotropic response to 0.01 muM isoproterenol was inhibited by the beta-adrenergic antagonist 0.3 mgM dl-propranolol but remained unimpaired in the presence of 0.3 mgM d-propranolol (a much weaker antagonist). In contrast, the atrial response to ether was similar in the presence of either d- or dl-propranolol. Atropine, in concentrations that completely blocked the negative chronotropic action of acetylcholine, did not increase the frequency of contraction, suggesting that the positive chronotropic effect of ether is not due to an atropine-like activity of ether. Our results indicate that the positive chronotropic effect of ether on isolated rat atrial preparations is not mediated via catecholamine release, nor does it represent direct stimulation of beta-adrenergic receptors or block of cholinergic receptors. (Key words: Anesthetics, volatile, diethyl ether; Heart, atria, diethyl ether.).

In experiments with rats, the authors compared potency ratios and slopes of dose-effect curves of isoflurane, halothane, and diethyl ether for three end points of anesthesia: loss of righting reflex (RR), abolition of purposeful movement (PM) response to painful stimuli, and abolition of heart rate (HR) response to painful stimuli. Determinations of potency were based on the direct measurement of brain concentrations of anesthetics with the use of gas chromatography. It was found that the ratio of the PM ED50 to RR ED50 was 2.41 for isoflurane, 1.74 for halothane, and 1.25 for diethyl ester. They were significantly different for all three agents. Differences between the slopes of the dose-effect curves for RR and PM were significant only with diethyl ether (7 vs. 28). The ratios of HR ED50 to PM ED50 were not significantly different for the studied agents and there were no differences found between the slopes of the dose-effect curves for PM and HR. The results suggest that heart rate response to a noxious stimuli in contrast to the righting reflex is depressed by inhalation anesthetics through a mechanism similar to that underlying the depression of purposeful movement response to a noxious stimuli. Heart rate response to a noxious stimuli might be used as an alternative index for the measurement of anesthetic potency.

The effects of three general anesthetic agents, halothane, diethyl ether, and thiopental, were studied in the guinea-pig tracheal-chain preparation. All three agents by themselves caused relaxation of the chain. In addition, they antagonized the ability of acetylcholine to cause contraction of the c

The cardiovascular effects of 3 and G per cent alveolar concentrations of diethyl ether in nine healthy young volunteers during the first and fifth hours of anesthesia were studied. Pac* was maintained at 35–39 torr and esophagcal temperature at 36 ± 0.5 C. Cardiac output was unchanged or increased at 3 and 6 per cent ether during the first hour; heart rate increased while stroke volume fell. During the fifth hour of anesthesia, cardiac output increased at both 3 and 6 per cent ether, heart rate increased further, and stroke volume rose to the awake value. Total peripheral resistance was initially unchanged but fell with duration of anesthesia. The ratio of cardiac output to oxygen consumption was unchanged at one hour and increased at five hours. Base excess fell slightly initially and slightly more by five hours.

The distribution of volatile anesthetics in the monkey brain was studied with the technique of low-temperature autoradiography, using 14C-labeled halothane, chloroform, diethyl ether, and ethylene. Animals were sacrificed 2, 5, and 20 minutes after administration of the anesthetic. Autoradiographs were prepared from coronal sections of the brain. Results indicate that the early distribution of anesthetics to the gray matter and nuclei is determined primarily by circulatory factors, while the later distribution to the white matter more closely correlates with lipid content, although many exceptions were found. Of particular interest is the high concentration of anesthetic within the reticular formation.

Alveolar anesthetic concentrations at the first response to command and those concentrations just preventing the response were determined in man during recovery from methoxyflurane, halothane, ether and fluroxene anesthesia. The authors assumed equilibration of cerebral anesthetic concentration with alveolar concentration after alveolar concentration had been kept constant for at least 15 minutes. The anesthetic concentration midway between the value permitting the response and that just preventing the response was defined as “MAC awake.” MAC awake values were 0.081 ± 0.021 (SD) per cent methoxyflurane, 0.41 ± 0.05 per cent halothane, 1.41 ± 0.22 per cent ether, and 2.20 ± 0.49 per cent fluroxene. MAC awake-to-MAC ratios were fairly close for the four agents, being 0.52, 0.52, 0.67, and 0.60 for methoxyflurane, halothane, ether, and fluroxene, respectively. When the alveolar concentrations were allowed to fall spontaneously, falsely low MAC awake values were obtained for halothane and fluroxene, while MAC awake for methoxyflurane was unchanged from that found at constant alveolar concentration.

Levels of ACTH in the peripheral plasma of ten patients during ether anesthesia alone and during and after laparotomy were determined by a modification of Lipscomb and Nelson's bioassay method. Levels of free cortisol in the plasma were determined simultaneously. Results of pituitary-adrenocortical reserve tests of all patients in the preanesthetic period were within normal limits. Plasma ACTH levels were very low (estimated less than 1 mU./100 ml.). A remarkable increase of pituitary-adrenocortical activity was noted during anesthesia, which was induced and maintained with diethyl ether-nitrous oxide at a depth of plane 2–3 of stage III. During induction of anesthesia and during surgery large amounts of ACTH were released intermittently, with two or three steep peaks in the plasma levels. In contrast, the level of free cortisol in the plasma rose gradually. Our data indicate that the increased levels of free cortisol in the plasma were the result of increased plasma ACTH activity.

The clinical signs of anesthetic depth (heart rate, mean arterial pressure, pupil diameter, pupil reactivity to light, tearing, and eye movement) were correlated with anesthetic dose in healthy young volunteers. During halothane, halothane—nitrous oxide, Forane, or Forane–nitrous oxide anesthesia at normal PaCO2 (controlled ventilation), only hypotension in the first hour of anesthesia correlated with anesthetic dose. After five hours of halothane or halothane–nitrous oxide, blood pressure remained constant as anesthetic concentration increased. During cyclopropane, diethyl ether, and fluroxene anesthesia, only pupillary dilatation and reduced pupil reactivity to light correlated with anesthetic dose. When nitrous oxide was added to halothane, ether, or fluroxene, mean arterial pressure rose and pupils dilated. During halothane–oxygen anesthesia with spontaneous ventilation, the rise in PaCO2 allowed less hypotension and increased heart rate. Tidal volume decreased and respiratory rate increased as anesthesia deepened. During Forane–oxygen anesthesia with spontaneous respiration, mean arterial pressure, tidal volume, and minute ventilation decreased as anesthesia deepened. In healthy surgical patients anesthetized with halothane or Forane only, incision of the skin modified the clinical signs significantly. While surgery continued, this change in clinical signs persisted during Forane anesthesia, but returned to control during halothane anesthesia.

Platelet aggregation induced by ADP in canine platelet-rich plasma was inhibited by volatile anesthetics. The partial pressures at which platelet aggregation was inhibited 50 per cent correlated closely with the pressures used clinically: methoxyflurane, 3.5 torr; halothane, 7.5 torr; diethyl ether

The effects of cyclopropane, halothane and diethyl ether on cerebral levels of serotonin (5-HT) and its principal metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were studied in rats. The turnover rate of cerebral 5-HT was measured, using steady-state kinetics after inhibition of monoamine oxidase or blockade of acid transport, during exposure to 15 per cent cyclopropane, 0.75 per cent halothane, or 3 per cent diethyl ether. Cerebral content of 5-HT increased slightly (14 per cent) during cyclopropane anesthesia; decreased (17 per cent) with halothane; and did not change with diethyl ether. 5-HIAA levels increased with all three anesthetics, especially with diethyl ether (100 per cent), probably due to a decrease in its rate of removal from the brain. The turnover rate of brain 5-HT remained unchanged with cyclopropane and halothane, but increased considerably with diethyl ether.

A gas chromatographic procedure for the quantitative analysis of the inhalation anesthetics in blood was devised. A blood sample was equilibrated in 10 ml. or 20 ml. glass vial. After equilibration 1 ml. of the gas in the vial was introduced into a gas chromatograph and the anesthetic concentration in blood was measured from that in gas phase by means of a calibration curve prepared from appropriate standards. A thermal conductivity detector was used for the analysis of nitrous oxide, cyclopropane and ether, while a flame ionization detector was used for halothane, methoxyflurane and low concentration of ether. Concentrations in blood of inhalation anesthetics now available can be measured accurately by this method.

Thirty human subjects were exposed for four hours to 500 ppm N-2O and 15 ppm enflurane in air and then, within five minutes, given a 35-minute battery of psychological tests. Performance of a divided-attention audiovisual task and a digit-span memory test were significantly decreased compared with control data following exposure to air. A tachistoscopic task, four tests from the Wechsler memory scale, and five others from the Wechsler Adult Intelligence Scale were unaffected. Thirty subjects exposed to 500 ppm N-2-O in air only scored significantly lower on the digit-span test only. Language: en

Addition of glucose (16.7 mM) to isolated pieces of rat pancreas increased insulin secretion 5.4-fold over basal secretion rates. Ether at 1, 1.5 and 2 MAC inhibited this insulinogenic effect of glucose in a dose-related manner by 5, 18 (P less than 0.01) and 29 (P less than 0.01) per cent, respectively.

The activities of liver microsomal enzymes were studied in preparations from unanesthetized rats and rats anesthetized for one hour with nitrous oxide, diethyl ether, halothane or chloroform. Most of the enzymes studied were cytochrome P-450-dependent oxygenases that hydroxylate endogenous substrates. The other microsomal enzymes, assayed for comparison, included the cytochrome P-450-dependent aminopyrine demethylase, glucose-6-phosphatase, a dehydrogenase, and NADPH-cytochrome P-450 reductase. No anesthetic was associated with a significant change in activity of any enzyme studied. In rats pretreated with phenobarbital no anesthetic except chloroform changed enzymic activity. All hydroxylations were inhibited markedly by chloroform, as were a microsomal dehydrogenation, hydrolysis of glucose-6-phosphate, and NADPH-cytochrome P-450 reductase activity. Administration of alpha-tocopherol did not prevent the inhibition associated with chloroform in phenobarbital-induced animals. It is concluded that cytochrome P-450-dependent hydroxylations involved in metabolic processes normally proceeding in the endoplasmic reticulum of the liver are not permanently affected by the anesthetics used in this study. The inhibitory effect of chloroform after pretreatment with phenobarbital is unspecific and affects a large number of different microsomal enzymes. Evidence that mechanisms other than lipid peroxidation may be responsible for the toxic effects of chloroform in the liver is presented.

Anesthesia may be a function of decreased cell-membrane permeability to sodium. This may be a specific effect on permeability to sodium or a nonspecific effect on overall membrane permeability. In this study the effects of six general anesthetics on passive permeability to water of the toad bladder were assessed. Active sodium transport in the bladders were blocked, mannitol was used to create an osmotic gradient, and dilution of indocyanine green dye was measured to indicate the rate of water flux from serosa to mucosa. All of the anesthetics tested decreased the flux rate at low and increased it at high concentrations. Decreased flux rates were generally seen within the wide concentration range associated with clinical anesthesia, but the calculated anesthetic membrane concentrations that maximally reduced permeability did not relate to minimal anesthetic requirements (MAR) in the toad, nor to the concentrations that decrease active sodium transport in the toad bladder. The volumes occupied in the cell membranes by the inhalational agents at maximal reduction of permeability were estimated to be about 0.03 ml/100 g membrane. Twice this volume increased permeability. The intramembraneous volumes that decreased permeability also did not correspond to intramembraneous volumes at MAR.

The mechanism of hepatic microsomal enzyme induction produced by inhalation anesthetics was examined in rats. Diethyl ether (1.6 per cent, 7 hours/day for five days) is a true inducing agent, qualitatively similar to phenobarbital. It increases cytochrome P–450, cytochrome bs, NADPH cytochrome c reductase, microsomal prottein, and biotransformation of several drugs. The time course of the induction process with diethyl ether is similar to that with phenobarbital. Methoxyflurane is not a microsomal enzyme-inducing agent in the same respect. It enhances biotransformation of only certain drugs by a nonspecific stimulation which may be related to decreased catabolism of microsomal NADPH cytochrome c reductase.

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.)

Hepatic drug-metabolizing enzymes and hepatic ultrastructure were studied in rats after two hours of anesthesia with 1 MAC halothane or diethyl ether. Twelve hours after cessation of either anesthetic smooth endoplasmic reticulum was increased in centrilobular but not in periportal hepatocytes. This change persisted at 24- and 36-hour sampling times. Microsomal cytochrome P450 and cytochrome b5 decreased after halothane anesthesia (by 7 to 20 per cent of control). Diethyl ether caused increased cytochrome P450 and cytochrome b5 (27 and 18 per cent, respectively) at the 36-hour sampling time. NADPH cytochrome c reductase did not change significantly after either agent. The authors interpret these results to mean that both agents promote conversion of rough endoplasmic reticulum to smooth endoplasmic reticulum or, alternatively, that the anesthetics decrease degradation of smooth endoplasmic membranes. Since only ether caused an increase in the microsomal content of enzymes of the drug-metabolizing enzyme system, it is concluded that these two anesthetics act on hepatic cells by dissimilar mechanisms.

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.).

The effects of isoflurane and halothane on intraocular pressure (IOP) were studied in 28 children. Measurements were made during spontaneous ventilation and at a various levels of reduced PaCO2 achieved by controlled ventilation. Control IOP values were determined prior to anesthesia following premedication with chloral hydrate, pentobarbital, pentobarbital with meperidine. At roughly equivalent levels of anesthesia, mean IOP values during spontaneous ventilation ranged frm 16.3 to 17.6 torr for each anesthetic. These values were significantly less (P less than 0.01) than control values only in those patients receiving chloral hydrate who did not cooperate. In contrast, no significant change in IOP was found in more sedated and cooperative patients who received pentobarbital and meperidine. Moderate hypocarbia and hypercarbia over a range of PaCO2 greater than 42 torr had little influence on IOP. We conclude that IOP's during isoflurane and halothane anesthesia do not differ significantly from IOP in the sedated, cooperative, healthy pediatric patient.

Arterial blood lactate, pyruvate, and excess lactate (XL) were measured and calculated in 33 patients aged 7 months to 6 years over a period of 2 hours during repair of harelip or cleft palate. When the anesthetic was diethyl ether, lactate and pyruvate levels rose significantly 60 minutes after induction of anesthesia but did not rise thereafter. Excess lactate appeared 60 minutes after induction of ether anesthesia, but it, too, showed no further increase. When the anesthetic was halothane there was no significant change in lactate, pyruvate, or XL. Changes with ether were not age-related, nor could they be correlated with changes in rectal or skin temperature. The responses of lactate, pyruvate and XL to ether anesthesia in the present study were not significantly different from those found by others in adults.

Solubility coefficients for seven inhalation anesthetic agnets were determined in maternal and fetal blood at 37 C. Halothane, isoflurane, diethyl ether, and nitrous oxide were significantly more soluble in maternal than in fetal blood, while methoxyflurane, fluroxene, and cyclopropane were significantly less soluble. Reasons for these differences cannot be accounted for by differences in the type or amount of hemoglobin present.

The effects of methoxflurane, trichloroethylene, chloroform, halothane and diethyl ether on the division of Chinese hamster fibroblasts in spinner culture have been studied. All agents caused dose-dependent inhibition of cell multiplication. Halothane increased the cell cycle time roughly in accordance with its effect on multiplication rate. There was no evidence that mitosis was greatly prolonged, and only small numbers of "c-metaphases" were seen. However, exposure to halothane resulted in a marked and rapid reduction in the prophase count, suggesting prolongation of G2 (the post-synthetic phase). Cine-photo-micrography showed frequent delay in division of cytoplasm at mitosis, and many binucleate cells were seen.

The neuromuscular effects of d-tubocurarine (dTc), pancuronium, and succinylcholine (SCh) were studied in 37 unpremeditated adult surgical patients anesthetized with 1.25 MAC enflurane in oxygen. The relaxant doses that produced 50 per cent depression of twitch height (ED50) were 1.57, 0.29, and 4.9 mg/m2 for dTc, pancuronium, and SCh, respectively. These doses are approximately 3.1, 1.7, and 1.0 times less than the amounts of dTc, pancuronium, and SCh required to produce 50 per cent depression of twitch height during halothane anesthesia but are the same as ED50 values during isoflurane anesthesia. In eight additional unpremedicated patients anesthesia was maintained at 0.71 MAC enflurane in oxygen (five patients) or 1.67 MAC enflurane in oxygen (three patients). Twitch depression following dTc, 1.5 mg/m2, was related directly to alveolar enflurane concentration. Ability to sustain tetanus decreased progressively with increasing tetanic frequencies and decreased with increasing alveolar enflurane concentrations. The authors concluded that smaller doses of dTc and pancuronium are needed for adequate relaxation during enflurane anesthesia than during equi-MAC halothane anesthesia, and that higher alveolar enflurane concentrations reduce the dose of dTc necessary to produce a given amount of paralysis. Also, neuromuscular effects of enflurane in combination with dTc or pancuronium are not significantly different from those seen during equi-MAC isoflurane anesthesia.

Tracheal mucociliary flow rates in dogs were measured with a radioactive droplet technique during thiopental anesthesia, and subsequently during enflurane, either, and nitrous oxide-morphine anesthesia on different occasions. Enflurane, at 0.6, 1.2, 1.8 MAC, produced a dose-dependent, reversible depression of mucociliary flow equal to that previously reported for halothane. Nitrous oxide-halothane and nitrous oxide-morphine depressed mucociliary flow to the same extent as halothane at equivalent MAC levels. Ether did not depress mucociliary flow significantly from the thiopental control at any MAC level.