The effects of deuteration on the metabolism of halogenated anesthetics in the rat.

The authors studied the effects of substituting deuterium for hydrogen in several volatile anesthetics on their metabolism in the Fischer rat. Substitution of deuterium in the ethyl portion of methoxyflurane increased the metabolic production of fluoride ion by 19 per cent when administered at a concentration of 0.05 per cent. Total replacement of hydrogen by deuterium resulted in a 29 per cent decrease in the amount of fluoride produced, while deuteration of only the methoxyl group produced a 33 per cent decrease in fluoride produced. Deuteration of halothane resulted in a 15 or 26 per cent decrease in serum bromide at 0.75 per cent or 1.0 per cent, respectively. Deuteration in the ethyl portions of enflurane and two experimental agents, CF2HOCF2CFBrH and CF2HOCF2CCl2H resulted in 65, 76, and 29 per cent decreases in urinary fluoride, respectively. Anesthesia with deuterated chloroform at a concentration of 0.36 per cent produced a 35 per cent decrease in serum glutamic pyruvic transaminase (SGPT). It is concluded that deuteration of volatile anesthetics changes their metabolism, in most cases producing decreases in metabolism. This effect may lessen the organ toxicity believed to occur with some of these anesthetics.     

The effects of local anesthetics on maternal and neonatal platelet function

The effects of bupivacaine (B), lidocaine (L) and 2-chloroprocaine (C) on maternal (M) and neonatal (N) platelet function were studied using in vitro beta-thromboglobulin (beta-tg) release (radioimmunoassay), and in vitro platelet aggregation. Aggregation produced by adenosine diphosphate (ADP), epinephrine and collagen was measured in the presence of 1, 10, 100, 500 or 1000 micrograms/ml concentrations of B, L or C. In addition, spontaneous in vivo beta-tg release was measured in M and N blood. In vivo beta-tg level in M and N blood was approximately double that in non-pregnant subjects (p less than 0.025). In vitro beta-tg release in M and N samples was inhibited only at concentrations exceeding 1000 micrograms/ml, and the inhibition was less in M and N samples than in non-pregnant subjects. None of the anesthetics inhibited aggregation of M or N platelets at 1 and 10 micrograms/ml. Only concentrations of 500 micrograms/ml or greater consistently inhibited platelet aggregation produced by the three aggregants in M and N samples, and L was the least effective of the three agents. Neonatal platelet aggregation was affected more by local anesthetics than was maternal aggregation. It is concluded that plasma local anesthetic concentrations achieved during normal maternal epidural anesthesia do not affect M or N platelet aggregation or beta-tg release.     

Inhibitory effects of intravenous anesthetics on mast cell function

Mast cells play a protective role in the inflammation and auto-tissue injury. The impairment of mast cell function may influence defense against infection. We investigated the effect of four IV anesthetics (thiopental, midazolam, ketamine, and propofol) on the chemotaxis and exocytosis of mast cells. Canine mast cell chemotaxis was measured by the Boyden's blindwell chamber technique using 100 microg/mL of substance P as a stimulator. We measured mast cell exocytosis by measuring released histamine from mast cells using substance P or gamma-monomeric IgG-mediated crosslinking as a stimulator. Thiopental, midazolam, and propofol exerted a dose-dependent inhibitory effect on mast cell chemotaxis. Ketamine, midazolam, and propofol had a dose-dependent inhibitory effect on mast cell exocytosis. In conclusion, midazolam and propofol inhibited both chemotaxis and exocytosis of mast cells, while thiopental only inhibited chemotaxis, and ketamine only inhibited exocytosis. IMPLICATIONS: Mast cells play an important role in the antibacterial host-defense mechanism. Thiopental, midazolam, and propofol exerted a dose-dependent inhibitory effect on mast cell chemotaxis. Ketamine, midazolam, and propofol had a dose-dependent inhibitory effect on mast cell exocytosis. The impairment of mast cell function by IV anesthetics may influence the defense against infection.     

Mechanisms of action of halogenated anesthetics on isolated cardiac muscle

The mechanisms responsible for the direct negative inotropic effects of the three currently used volatile anesthetics (halothane, enflurane and isoflurane) are reviewed. These agents interfere at each step of excitation-contraction coupling, i.e. sarcolemmal membrane, sarcoplasmic reticulum and contractile proteins. At the myofilament level, they decrease both calcium sensitivity and maximal developed force of cardiac skinned fibers of various species, a preparation in which all functional membranes are destroyed and thus allowing to study the direct effects of volatile anesthetics on myocardial contractile proteins. The effects of the three volatile anesthetics are similar at equipotent concentrations. The site of action seems to involve the regulatory proteins of the thin myofilament, especially troponin-tropomyosin complex. At the sarcolemmal level, all three anesthetics decrease Ca++ entry through the voltage-dependent calcium channels, an effect that seems slightly more important for both halothane and enflurane than for isoflurane. However, these two sites of action (contractile proteins and sarcolemmal membrane) are not sufficient to explain their overall negative inotropic effect. The third site of action involves the sarcoplasmic reticulum. Halothane and enflurane produce an initial liberation of Ca++ from internal stores, while isoflurane does not. All three agents decrease the net uptake of Ca++ and increase the permeability of sarcoplasmic reticulum to Ca++, similar to the effect of caffeine. However, the resulting effect, i.e. a reduction of sarcoplasmic reticulum Ca++ content occurs at clinical concentrations of halothane or enflurane, while much higher concentrations of isoflurane are required to produce a similar reduction. This differential effect on the sarcoplasmic reticulum function (which is quantitative but not qualitative) seems to be mainly responsible for the lesser negative inotropic effect of isoflurane as observed in intact cardiac muscles of various species including humans. The knowledge of the mechanisms of action of volatile anesthetics is important for understanding the potential consequences associated with their use in patients receiving cardiac drugs, especially calcium blockers and phosphodiesterase inhibitors.     

Gastric mucosal perfusion in dogs: effects of halogenated anesthetics and of hemorrhage.

The gastrointestinal tract is one of the first organs affected by hypoperfusion during hemorrhagic shock. The hemodynamics and oxygen transport variables during hemorrhagic shock and resuscitation can be affected by the anesthetics used. In a model of pressure-guided hemorrhagic shock in dogs, we studied the effects of three halogenated anesthetics--halothane, sevoflurane, and isoflurane--at equipotent concentrations on gastric oxygenation. Thirty dogs were anesthetized with 1.0 minimum alveolar anesthetic concentration (MAC) of either halothane, sevoflurane, or isoflurane. A gastric tonometer was placed in the stomach to determine mucosal gastric CO(2) (PgCO(2)) and for the calculation of gastric-arterial PCO(2) gradient (PCO(2) gap). The dogs were splenectomized and hemorrhaged to hold mean arterial pressure at 40-50 mm Hg over 45 min and then resuscitated with the shed blood volume. Hemodynamics, systemic oxygenation, and PCO(2) gap were measured at baseline, after 45 min of hemorrhage, and at 15 and 60 min after blood resuscitation. Hemorrhage induced reductions of mean arterial pressure and cardiac index, while systemic oxygen extraction increased (p < .05), without significant differences among groups (p > .05). Halothane group showed significant lower PCO(2) gap values than the other groups (p < .05). After 60 min of shed blood replacement, all groups restored hemodynamics, systemic oxygenation, and PCO(2) gap to the prehemorrhage levels (p > .05), without significant differences among groups (p > .05). We conclude that halothane is superior to preserve the gastric mucosal perfusion in comparison to isoflurane and sevoflurane, in dogs submitted to pressure-guided hemorrhagic shock at equipotent doses of halogenated anesthetics.     

Interaction of verapamil and halogenated inhalation anesthetics on hypoxic pulmonary vasoconstriction

Calcium channel blockers and halogenated inhalation anesthetics reduce hypoxic pulmonary vasoconstriction (HPV) when administered separately to isolated rat lungs. This study was undertaken to investigate the effect of combining the calcium channel blocker verapamil with halothane or isoflurane. HPV was elicited in three groups of experiments. First, we studied the effect of halothane 1.3 MAC and varying concentrations of verapamil. Halothane reduced HPV as a mean by 34.7%, and a dose-dependent reduction was seen with verapamil. The depressant effect of the combination of halothane and verapamil was significantly greater than when the drugs were administered alone. We further investigated in separate groups the effects of varying concentrations of halothane and isoflurane, administered both separately and in combination with a constant dose of verapamil (1.02 nmol). Both anesthetics depressed HPV in a dose-dependent fashion. Verapamil reduced HPV as a mean by 34.2% and 39.3% in the halothane and isoflurane groups, respectively. The inhibition caused by combining verapamil with an anesthetic was significantly greater than when administered separately. We conclude that verapamil in combination with halothane or isoflurane has an additive dampening effect on HPV.     

The effects of anesthetics on G-protein-coupled receptors

Although anesthetics have been often used clinically, the mechanisms of action of anesthetics have not yet been clarified. Recently, major advances have been made in our understanding of the physiology and pharmacology of G-protein-coupled receptor (GPCR)-mediated signaling. Several lines of studies have shown that GPCRs are targets for anesthetics and that some anesthetics inhibit the functions of Gq-coupled receptors, including muscarinic acetylcholine (ACh) M1, metabotropic type 5 glutamate, 5-hydroxytryptamine (5-HT) type 2 A, and substance P receptors. Many additional GPCRs have been classified as "orphan" receptors (oGPCRs) because their endogenous ligands have not been identified yet. Given that known GPCRs are targets for anesthetics, these oGPCRs may represent a rich group of receptor targets for anesthetics. This review highlights the effects of anesthetics on Gq-coupled receptors, and discusses whether GPCRs other than Gq-coupled receptors, and proteins that convey GPCR signals are also targets for anesthetics.     

挥发性吸入麻醉药对肺的作用

挥发性吸入麻醉药对肺的作用目前尚未有定论，其中有较多争议之处。不同种类、不同吸入浓度以及不同生理条件下的吸入麻醉药对肺的作用不同，可以引起肺的损伤作用、导致肺内分流增加，也可以产生肺的缺血／再灌注损伤的保护作用，其机制尚未完全清楚。     

Interaction of halogenated anesthetics with dobutamine in rat myocardium.

BACKGROUND: Halogenated anesthetics potentiate the positive inotropic effects of alpha- and beta-adrenoceptor stimulations, but their interactions with dobutamine remain unknown. METHODS: The effects of halothane, isoflurane, sevoflurane, and desflurane (1 and 2 minimum alveolar concentration) on the inotropic responses induced by dobutamine (10(-8)-10(-4) M) were studied in rat left ventricular papillary muscles in vitro. Inotropic effects were studied under low (isotony) and high (isometry) loads. The authors also studied the lusitropic effects in isotonic (R1) and isometric (R2) conditions. Data are the mean percentage of baseline +/- SD. RESULTS: Dobutamine induced a positive inotropic effect (active isometric force: 185+/-36%, P < 0.001) and a positive lusitropic effect under low load (R1: 78+/-9%, P < 0.001), but not under high load (R2: 95+/-21%, not significant). Halothane, isoflurane, and sevoflurane did not modify the positive inotropic effect of dobutamine. Even in the presence of alpha-adrenoceptor blockade, isoflurane did not potentiate the positive inotropic effect of dobutamine. Desflurane significantly enhanced the positive inotropic effect of dobutamine (active isometric force: 239+/-35%, P < 0.001), but this potentiation was abolished by pretreatment with reserpine. In contrast to halothane, isoflurane, sevoflurane, and desflurane did not significantly modify the lusitropic effects of dobutamine. CONCLUSIONS: Halogenated anesthetics, except desflurane, did not modify the positive inotropic effects of dobutamine. Desflurane enhanced the positive inotropic effect of dobutamine, but this effect was related to the desflurane-induced release in intramyocardial catecholamine stores.     

The effects of enflurane,isoflurane, and intravenous anesthetics on rat diaphragmatic function and fatigability

We examined the effect of isoflurane, enflurane, midazolam, ketamine, propofol, and thiopental on diaphragmatic functions under unfatigued and fatigued conditions in 228 rat isolated muscle strips. Diaphragmatic twitch characteristics and tetanic contractions were measured before and after muscle fatigue, which was induced by repetitive tetanic contraction with or without exposure to one of the anesthetics at clinically relevant plasma concentrations, and at 10 and 100 times this concentration, or at 1, 2, and 3 minimum alveolar anesthetic concentration (MAC). Isoflurane, midazolam, ketamine, propofol, and thiopental did not induce a direct inotropic or lusitropic effect under unfatigued and fatigued conditions. Enflurane did not change contraction or relaxation in fresh isolated diaphragm, but enflurane at 2-3 MAC enhanced diaphragmatic fatigability itself and fatigue-induced impairment of twitch characteristics and tetanic tensions. These effects were greater at 3 MAC than at 2 MAC. Our findings suggest that the reduction of diaphragm function previously reported in in vivo experiments using propofol, midazolam, and isoflurane is not related to a direct effect on intrinsic diaphragmatic contractility. Our results also indicate that large concentrations of enflurane may impair the diaphragmatic function at sites other than excitation-contraction coupling. IMPLICATIONS: Enflurane did not change contraction or relaxation in fresh isolated rat diaphragm, but enhanced diaphragmatic fatigability itself and fatigue-induced impairment of twitch characteristics and tetanic tensions. Isoflurane, midazolam, ketamine, propofol, and thiopental had no direct effects on diaphragmatic functions under unfatigued and fatigued conditions. Isoflurane and these i.v. anesthetics may be advantageous over enflurane to anesthetize and/or sedate patients who are predisposed to diaphragmatic fatigue.     

Differential effects of anesthetics on mitochondrial K(ATP) channel activity and cardiomyocyte protection

BACKGROUND: Mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) channels play a pivotal role in mediating cardiac preconditioning. The effects of intravenous anesthetics on this protective channel have not been investigated so far, but would be of importance with respect to experimental as well as clinical medicine. METHODS: Live cell microscopy was used to visualize and measure autofluorescence of flavoproteins, a direct reporter of mitoK(ATP) channel activity, in response to the direct and highly selective mitoK(ATP) channel opener diazoxide, or to diazoxide following exposure to various anesthetics commonly used in experimental and clinical medicine. A cellular model of ischemia with subsequent hypoosmolar trypan blue staining served to substantiate the effects of the anesthetics on mitoK(ATP) channels with respect to myocyte viability. RESULTS: Diazoxide-induced mitoK(ATP) channel opening was significantly inhibited by the anesthetics R-ketamine, and the barbiturates thiopental and pentobarbital. Conversely, urethane, 2,2,2-trichloroethanol (main metabolite of alpha-chloralose and chloral hydrate), and the opioid fentanyl potentiated the channel-opening effect of diazoxide, which was abrogated by coadministration of chelerythrine, a specific protein kinase C inhibitor. S-ketamine, propofol, xylazine, midazolam, and etomidate did not affect mitoK(ATP) channel activity. The significance of these modulatory effects of the anesthetics on mitoK(ATP) channel activity was substantiated in a cellular model of simulated ischemia, where diazoxide-induced cell protection was mitigated by R-ketamine and the barbiturates, while urethane, 2,2,2-trichloroethanol, and fentanyl potentiated myocyte protection. CONCLUSIONS: These results suggest distinctive actions of individual anesthetics on mitoK(ATP) channels and provide evidence that the choice of background anesthesia may play a role in cardiac protection in both experimental and clinical medicine.