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Adenosine decreases the minimum alveolar concentration of halothane in dogs.

Adenosine has sedative properties, and adenosine-receptor agonists have been found to reduce anesthetic requirements in rodents. This study determined whether adenosine, in hypotensive doses, reduces anesthetic requirements in halothane-anesthetized dogs. In seven animals, minimum alveolar concentration (MAC) for halothane was determined by a tail-clamp technique at three time points: after 2 h of halothane anesthesia, during adenosine-induced hypotension (mean arterial pressure: 55 mmHg), and 1 h after adenosine was discontinued. In other dogs, the effects of aminophylline, dipyridamole, or the specific adenosine-receptor antagonist 8-phenyl-theophylline (8-PT) on the halothane-adenosine interaction were studied. Adenosine significantly reduced halothane MAC, by 49%, from 0.76 +/- 0.05 to 0.39 +/- 0.05 vol% (mean +/- SEM). This effect was blocked by the concurrent administration of aminophylline (n = 5, P less than 0.05) or 8-PT (n = 4 of 4). When dipyridamole, which increases the plasma concentrations of endogenous adenosine, was administered alone, halothane MAC was reduced from 0.79 +/- 0.03 to 0.67 +/- 0.05 vol% (n = 5, P = 0.09). We conclude that exogenous adenosine substantially reduces halothane MAC in dogs and that this effect is blocked by the concurrent administration of the adenosine-receptor antagonists aminophylline or 8-PT. Relatively small alterations of endogenous adenosine concentrations, however, do not substantially reduce halothane MAC.

Adenosine↗

Myocardial epinephrine sensitization with subanesthetic concentrations of halothane in dogs.

The authors investigated myocardial epinephrine sensitization by subanesthetic concentrations of halothane. The dose-response relationship for the action of halothane was examined with etomidate plus varying subanesthetic concentrations of halothane in dogs. The arrhythmogenic threshold of epinephrine was decreased in a dose-dependent manner at end-tidal concentrations of halothane between 0.1 and 0.3%. At end-tidal halothane is greater than 0.3%, and no further reduction of arrhythmogenic threshold of epinephrine occurred. The plasma concentrations of epinephrine producing four or more premature ventricular contractions in 15 s were 201.3 +/- 34.3, 98.1 +/- 13.9, 60.3 +/- 8.63, 57.9 +/- 12.8, 54.5 +/- 8.61, and 53.9 +/- 4.86 ng/ml (mean +/- SEM), at 0, 0.1, 0.3, 0.5, 1.0, and 1.5% of halothane at end-tidal concentrations, respectively. The results suggest that in the presence of etomidate, halothane produces myocardial sensitization to epinephrine at subanesthetic concentrations as low as 0.1%. Increasing halothane to 0.3% produces a further reduction in the arrhythmogenic dose of epinephrine.

Anesthesia↗

Halothane, enflurane, and isoflurane depress the peripheral vagal motor pathway in isolated canine tracheal smooth muscle.

Volatile anesthetics are potent bronchodilators, but the site of action for the dilation is unclear. To determine the site of action of halothane, enflurane, and isoflurane on the peripheral vagal motor pathway, isolated strips of canine trachealis muscle were stimulated before and during exposure to halothane at 0.3, 1.0, 1.7, or 2.4 MAC, enflurane at 1 MAC, or isoflurane at 1 MAC. The sites and methods of stimulation were: 1) postsynaptic nicotinic cholinergic receptors in the intramural parasympathetic ganglia, with 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP); 2) postganglionic cholinergic nerve fibers, with electrical field stimulation (EFS); and 3) muscarinic cholinergic receptors of the smooth muscle, with acetylcholine (ACh). The concentration-response curve to DMPP was significantly shifted to the right by 0.3 MAC halothane, whereas 0.3 MAC halothane had no significant effect on the concentration-response curves to ACh and EFS. At concentrations greater than 1 MAC of halothane, enflurane, or isoflurane, concentration-response curves to all three stimuli were shifted significantly to the right; i.e., the contractile responses to ACh, EFS, and DMPP were reduced. At all concentrations of halothane the force of contraction was significantly more reduced during stimulation with DMPP than during stimulation with ACh, and at halothane concentrations greater than or equal to 1.7 MAC the response to EFS was significantly more reduced than that to ACh. We conclude that halothane, enflurane, and isoflurane attenuated airway constriction by several mechanisms, including 1) reduced excitability of the postsynaptic nicotinic receptors of the intramural parasympathetic ganglia and 2) an effect on the smooth muscle and/or on the muscarinic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The effects of halothane on ventricular tachycardia in intact dogs.

Halothane has either proarrhythmic or antiarrhythmic effects in a variety of clinical circumstances. This investigation tested the hypothesis that halothane would display different effects on ventricular tachycardia (VT) produced by different electrophysiologic mechanisms in intact dogs. Four models of VT produced by abnormal automaticity, reentry, delayed-afterdepolarization-induced triggered activity, and early-afterdepolarization-induced triggered automaticity (groups 1-4, respectively) were studied. In groups 1 and 2, the left anterior descending coronary artery (LAD) was ligated. In group 1 (n = 5), 24 h after LAD ligation and infarction, all dogs demonstrated incessant VT with 94.7 +/- 2.3% of beats of ventricular origin. This ectopy presumably was due to abnormal automaticity. Halothane reduced the frequency of ventricular ectopy until at 2% halothane only 34.8 +/- 15% of beats were of ventricular origin. One week after LAD ligation, programmed stimulation produced nonstimulated extrasystoles of presumably reentrant origin in six dogs. In three, halothane 1% abolished extrasystoles while increasing the ventricular refractory period by 23 +/- 3.8% (P less than 0.05). In the three other dogs, halothane had no effect (two dogs) or worsened the severity of VT (one dog), while the refractory period increased by 7.7% (P greater than 0.05). In group 3 dogs, ouabain was infused until VT secondary to triggered activity occurred. Halothane restored sinus rhythm in 4 of 5 dogs. Overall the percentage of sinus beats increased from 11.1 +/- 2.8 to 97.4 +/- 2.6% when halothane 2% was added during ouabain toxicity. Cesium chloride infusion increased the QT interval and produced complex VT in 5 dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Halothane alters control of intracellular Ca2+ mobilization in single rat ventricular myocytes.

In an attempt to understand the cellular mechanisms underlying volatile anesthetic-induced myocardial depression, halothane-induced negative inotropy was investigated in an animal model through continuous monitoring of intracellular Ca2+ concentration [( Ca2+]i) in rat ventricular myocytes loaded with fura-2. Single cells were stimulated with 15 mM caffeine or 15 mM extracellular K+ (K+O) or were paced by extracellular glass suction pipette electrode. With each stimulus modality, halothane (0.6-1.5%) caused a significant (P less than 0.05) and dose-dependent depression of the Ca2+ transient. Caffeine and electrically stimulated Ca2+ transients were reduced, in 1.5% halothane, to 35 +/- 14 and 42 +/- 8% of control, respectively. Resting or basal [Ca2+]i was unaffected by halothane. Halothane did not elicit spontaneous Ca2+ transients in these cells. Single cells stimulated by trains of electrical stimuli at 1.0, 1.5, and 2.0 Hz showed a change in [Ca2+]i from prestimulus levels to a stimulated baseline steady state that appeared to increase with stimulus frequency. Halothane at 0.7% increased the change in resting to stimulated baseline [Ca2+]i and depressed net transients (P less than 0.05) at 1.0 and 1.5 Hz. In contrast, 0.1 microM ryanodine depressed the Ca2+ transients in myocytes stimulated by trains of stimuli, but did not potentiate the change in stimulated baseline [Ca2+]i at any pacing rate. The results are consistent with the hypothesis that halothane reduces Ca2+i availability by causing a net loss of Ca2+ from the sarcoplasmic reticulum. The results from experiments using onset of pacing to induce a sudden increase in Ca2+i load in previously quiescent myocytes suggest that halothane may act to limit sarcoplasmic reticulum and/or sarcolemmal uptake/extrusion mechanisms, as compared to ryanodine, which depletes sarcoplasmic reticulum Ca2+ stores without affecting reuptake and extrusion.

Animals↗

Halothane does not alter Ca2+ affinity of troponin C.

Troponin C has been suggested as a possible target for the negative inotropic action of volatile anesthetics. This study has examined the effect of halothane on the structure and response of isolated cardiac troponin C to Ca2+ and the response of skinned soleus and cardiac muscle fibers to Ca2+. The high-affinity Ca(2+)-binding sites of cardiac troponin C were assessed by measurement of the change in intrinsic tyrosine fluorescence and ultraviolet circular dichroism in response to Ca2+ in the presence and absence of halothane. Halothane (0.9 mM, 1.4%) did not alter the 45% enhancement in intrinsic tyrosine fluorescence that occurs with saturation of the high-affinity sites or change the Ca2+ concentration at which half-maximal enhancement occurred. The molar ellipticity in the far ultraviolet region, a measure of the secondary structure, increased to a similar extent with addition of 10(-6) M Ca2+ in the absence and presence of 1.0 mM (1.6%) halothane. The binding rate of the sulfhydryl reagent, 5,5'-dithiobis (2-nitrobenzoic acid), to troponin C in response to Ca2+ titration was used as a measure of the integrity of the low-affinity Ca(2+)-binding site in troponin C in the presence and absence of 1.0 mM (1.6%) halothane. The rate of reaction was stimulated twofold, and the half maximal effect was observed at pCa 4.8 +/- 0.2 in both control and halothane-treated samples. Halothane (5 mM; 7.8%) did not change the pCa/tension response of skinned soleus fibers; the data were fit to the Hill equation and yielded dissociation constants of 6.2 x 10(-7) M for control and halothane-treated specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Halothane changes the relationships between lung resistances and lung volume.

The authors hypothesized that relaxation of airway smooth muscle by halothane lessens the dependence of airway resistance on lung volume, and that halothane alters the relationship between pulmonary resistance and lung volume by changing both the airway and tissue components of pulmonary resistance. The relationship among airway resistance, tissue resistance, and lung volume was examined in mongrel dogs before and during the administration of halothane, both in airways with reduced smooth muscle tone (after vagotomy) and during moderate increases in smooth muscle tone caused by vagus nerve stimulation (VNS). Resistance were measured at several levels of positive end-expiratory pressure (PEEP, 4-15 cmH2O) using an alveolar capsule technique. Before halothane administration, airway resistance increased at low PEEP; VNS accentuated this increase. Tissue resistance increased at low PEEP only during VNS. Halothane had no significant effect on any resistance before VNS. During VNS, halothane markedly blunted increases in airway resistance and tissue resistance as PEEP decreased. The authors conclude that during stimulation of airway smooth muscle in dogs, halothane attenuates increases in airway resistance and tissue resistance with reductions in lung volume in dogs. Thus, moderate changes in lung volume have little effect on these resistances during halothane anesthesia under these conditions.

Airway Resistance↗

Halothane effects on human malignant hyperthermia skeletal muscle single calcium-release channels in planar lipid bilayers.

Malignant hyperthermia (MH) may be life-threatening when genetically predisposed individuals are administered triggering anesthetic agents that are believed to produce intracellular calcium release. To test this theory, the effects of halothane on normal and MH human skeletal muscle calcium-release channels were studied. Single calcium-release channels were incorporated from isolated sarcoplasmic reticulum membrane vesicles into a planar lipid bilayer, and halothane effects on the conductance and gating properties were measured by electrophysiologic techniques. Among the subjects studied, seven were MH-susceptible, and 13 channels were recorded from this group. Five subjects were negative for MH, and 10 channels were recorded from this group. Among the 13 channels recorded from the MH group, 7 were affected by halothane, which increased the probability of the channel to change from the inactive, closed state to an open state. This effect of halothane to increase open-state probability was associated with an overall increase in channel conductance. Thus, halothane affected the activation/inactivation process of the halothane-sensitive calcium-release channel from MH muscle as well as the gating properties of the MH calcium-release channel, as evidenced by the increased conductance. In 6 of the 13 channels recorded from MH muscle, halothane (2.2-17.6 microM) was without effect on these properties of the channel. Halothane (2.2-17.6 microM or 0.0057-0.0456 vol%) also had no measurable effect on the 10 channels from the negatively diagnosed subjects. Results of this study support a defect in the ryanodine-sensitive calcium-release channel from MH human muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium Channels↗

A comparison of the vasodilating effects of halothane and isoflurane on the isolated rabbit basilar artery with and without intact endothelium.

Although volatile anesthetics result in cerebral arterial dilation, the precise mechanisms underlying this effect are not known. In vitro tension recordings were used to study the vasodilating potencies of halothane and isoflurane in isolated cerebral vessels and to examine the possible role of the endothelium in modulating any effects observed. Cylindrical segments of the rabbit basilar artery and midline ear artery from the same animal were placed in a flow-through bath of 37 degrees C oxygenated (95% O2/5% CO2) physiologic salt solution and stretched to a resting tension of approximately 2,000 dynes. They were then constricted with 3.0 x 10(-2) M K+, 1.0 x 10(-3) M norepinephrine, or 5.0 x 10(-6) M serotonin and exposed to either halothane or isoflurane at concentrations of approximately 0.5, 1.0, 1.5, and 2.0 MAC in varied order for 15 min at each concentration. A 30-min period of perfusion with anesthetic-free, vasoconstrictor-containing perfusate separated successive exposures to an anesthetic. Vessels prepared in this fashion retained their responsiveness to both vasoconstrictors and volatile anesthetics for as long as 4 h. They also relaxed appropriately to acetylcholine, indicating that the endothelium was intact. Concentrations of volatile anesthetic in the tissue perfusate were directly measured using gas chromatography, and the relationship between bath concentrations (expressed as MAC fractions) and the degree of relaxation were determined. The data were analyzed by parallel line regression. Halothane was found to be a significantly more potent vasodilator of the isolated basilar artery than was isoflurane. For example, in K(+)-constricted vessels, the concentration of halothane needed to produce a 50% reduction in tension was 1.32 MAC, compared with 1.66 MAC for isoflurane. Comparable differences were found in the basilar artery in the presence of other constrictors. However, there was no significant difference between the two agents in their effects upon the ear artery. In a separate series of experiments, the endothelium of basilar artery segments was removed by drying. Removal was confirmed by observing a diminished dilator response to acetylcholine. These vessels were subsequently constricted with K+, and relaxation dose-response curves were obtained for both halothane and isoflurane. There were no differences in the dose-response curves for deendothelialized versus intact vessels, with halothane still the more potent relaxant after endothelial removal. These data demonstrate that halothane and isoflurane cause a dose-dependent relaxation of rabbit cerebral vessels, regardless of the vasoconstrictor used. Halothane was a more potent relaxant of the basilar artery when expressed on a MAC-fraction basis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Comparison of low concentrations of halothane and isoflurane as bronchodilators.

BACKGROUND: Although high concentrations of all currently used inhalational anesthetics are thought to be good bronchodilators, studies using traditional measures of airway tone fail to show differences in airway responsiveness during halothane, enflurane, and isoflurane use. Using a more sensitive technique, the authors compared the ability of halothane and isoflurane to dilate histamine-constricted airways at equivalent MAC concentrations. METHODS: Responses of histamine-constricted individual airways to increasing doses of halothane and isoflurane were directly measured using high-resolution computed tomography (HRCT). Fifteen studies were performed in five dogs. All dogs were initially anesthetized with thiopental 15 mg/kg followed by a 10-mg.kg-1 x h-1 maintenance dose. Following tracheal intubation, the lungs were mechanically ventilated (15 ml/kg, 15 bpm). The airways were constricted with intravenous histamine 200 micrograms/min. On alternate days, the dogs subsequently received increasing concentrations of either halothane or isoflurane (0.6, 1.1, and 1.7 MAC). On a separate day, the dogs received atropine 0.2 mg/kg after the histamine infusion and the study was repeated. RESULTS: Histamine decreased airway area 34 +/- 2.5% (mean +/- SEM). All preconstricted airways showed a significant dose-dependent dilation to halothane and isoflurane at concentrations of 0.6, 1.1, and 1.7 MAC. Halothane significantly dilated airways to a greater extent than isoflurane at 0.6 and 1.1 MAC (P < 0.001). This effect was most pronounced in airways less than 3 mm in diameter. At 1.7 MAC, there was no significant difference between the two agents (P = 0.42). Atropine (0.2 mg/kg) reversed the airway constriction elicited by intravenous histamine. The histamine-preconstricted airways area increased 370 +/- 34% (P < 0.0001) after atropine. CONCLUSIONS: Halothane and isoflurane dilate histamine-constricted airways in a dose-dependent manner. However, at low concentrations, halothane was a more effective bronchodilator than isoflurane at equivalent MAC doses.

Animals↗

Halothane binding to soluble proteins determined by photoaffinity labeling.

BACKGROUND: Recently, halothane and isoflurane have been shown to bind in a saturable manner to serum albumin using NMR and gas chromatography methods. To validate a novel direct photoaffinity labeling method developed in our laboratory, the authors also determined the binding characteristics of halothane to serum albumin, and then extended this approach to other soluble proteins in an initial attempt to understand the interaction of volatile anesthetics and proteins. METHODS: Serum albumin (BSA), bacterial luciferase (BL), poly-(L-lysine)(PLL), and poly-(L-glutamate)(PLG) were dissolved in 0.154 M NaCl containing 14C-halothane with or without other volatile anesthetics or ligands, and exposed to 254 nm UV light for 10 s. Covalently bound label was quantitated by scintillation counting after precipitation, filtration, and washing. Binding parameters were calculated by nonlinear least-squares fitting of rectangular hyperbolas or logistic equations. RESULTS: Serum albumin bound halothane in a saturable manner at an apparent KD between 0.3 and 0.5 mM. Other volatile anesthetics inhibited binding (KI, in mM): halothane (0.36), chloroform (1.26), methoxyflurane (2.66), isoflurane (1.47), diethyl ether (45.5), and ethanol (1,040). Oleate and BSA conformational changes (low pH) also inhibited label incorporation. Binding to BL and PLL at pH 7 was nonsaturable and not displaced by unlabeled halothane or the BL substrate decanal. Conversion of PLL to an alpha-helical conformation (pH > 10) increased binding and created a saturable component with an apparent KD of 0.55 mM. Alkaline conditions decreased binding to PLG consistent with the loss of alpha-helical domains. CONCLUSIONS: Photoaffinity labeling produced results in close agreement with more conventional methods for studying halothane binding, and should be a useful tool for the study of volatile anesthetic binding sites. Halothane binding to soluble proteins depended on their type and conformation, and, in some cases, was saturable within the clinical concentration range, increasing the tenability of discrete proteinaceous sites of action for the inhalational anesthetics.

Affinity Labels↗

Evidence for an interaction of halothane with the L-type Ca2+ channel in human myocardium.

BACKGROUND: The present study was aimed at investigating the underlying mechanisms for the cardiac depressant effect of halothane. To test the hypothesis, whether there is an interaction of halothane with the L-type Ca2+ channels in human myocardium and whether this interaction has functional consequences for force generation in the human myocardium, effects of halothane were studied in human myocardial membranes and isolated cardiac preparations. METHODS: The experiments were performed on isolated, electrically driven ventricular preparations (1 Hz, 37 degrees C) and cardiac membranes with radioligand binding experiments using 3H-PN 200-110. Myocardium from human failing and non-failing hearts was obtained at cardiac surgery. RESULTS: Halothane produced a negative inotropic effect, which was similar in nonfailing and failing myocardium. Halothane shifted the concentration-response curve for the positive inotropic effect of the L-type Ca2+ channel agonist BayK 8644 to the right. The density of dihydropyridine receptors as judged from 3H-PN 200-110 radioligand binding experiments was similar in nonfailing and failing myocardium, whereas the density of beta-adrenoceptors was reduced. Halothane concentration dependently reduced the binding of 3H-PN 200-110, an antagonist at the 1,4 dihydropyridine receptor site of the Ca2+ channel, to myocardial membranes. Furthermore, halothane produced a rightward shift of the competition curve of BayK 8644 for binding of 3H-PN 200-110 to cardiac membranes. CONCLUSIONS: In human ventricular myocardium, halothane exhibits an interaction with the L-type Ca2+ channel by interfering with its dihydropyridine binding sites. This may explain, at least in part, the observed negative inotropic effect of this agent and could hypothetically play a general role in its anesthetic effects.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

Halothane-induced cytotoxicity to rat centrilobular hepatocytes in primary culture is not increased under low oxygen concentration.

BACKGROUND: Halothane can be metabolized by both oxidative and reductive pathways in the liver. This anesthetic can induce direct liver injury preferentially localized in centrilobular areas, probably in relation with lower oxygen tension. The reductive pathway has been related to liver damage; however, a correlation between lower oxygen concentration in centrilobular areas, the extent of reductive metabolism of halothane, and the degree of liver injury has not yet been demonstrated. This study was designed to better evaluate the toxicity of the reduced metabolites by using centrilobular and periportal rat hepatocyte subpopulations. METHODS: Adult rat hepatocytes, either as whole cell preparations or after separation in centrilobular and periportal cell subpopulations, were placed in primary culture and exposed to either 2% or 4% halothane under various oxygen concentrations. The enriched centrilobular hepatocyte subpopulations isolated by the digitonin-collagenase method were characterized by immunolocalization of glutamine synthetase. Three oxygen concentrations were tested: 5%, 20%, and 95%, and the main parameters measured were cell viability and fluoride ion formation. RESULTS: Viability of centrilobular hepatocytes was similar under 5% and 20% O2, but the unpurified hepatocyte population was more susceptible to 5% O2 (P < 0.01). Significantly higher cytochrome P-450 content was found in whole hepatocyte populations under 5% versus 20% oxygen, indicating that centrilobular hepatocytes that contained higher cytochrome P-450 monooxygenase activities were less sensitive to low oxygen concentrations. Halothane toxicity to centrilobular hepatocytes was enhanced under 95% versus 20% O2 (P < 0.05). By contrast, no significant difference was observed when the cells were maintained under 5% O2, although fluoride ions, indicative of reductive metabolism of halothane, were found in much higher amounts in the culture medium. Moreover, under 20% O2, halothane toxicity was significantly greater in centrilobular versus unpurified hepatocytes (P < 0.05). CONCLUSIONS: Isolated centrilobular hepatocytes appear to be more sensitive to halothane than their periportal counterparts in vitro. However, the authors' results support the conclusion that increased reductive metabolism of halothane induced by decreasing oxygen concentration is not a critical parameter for the occurrence of liver damage in these cells.

Animals↗

Human chest wall function while awake and during halothane anesthesia. I. Quiet breathing.

BACKGROUND: Data concerning chest wall configuration and the activities of the major respiratory muscles that determine this configuration during anesthesia in humans are limited. The aim of this study was to determine the effects of halothane anesthesia on respiratory muscle activity and chest wall shape and motion during spontaneous breathing. METHODS: Six human subjects were studied while awake and during 1 MAC halothane anesthesia. Respiratory muscle activity was measured using fine-wire electromyography electrodes. Chest wall configuration was determined using images of the thorax obtained by three-dimensional fast computed tomography. Tidal changes in gas volume were measured by integrating respiratory gas flow, and the functional residual capacity was measured by a nitrogen dilution technique. RESULTS: While awake, ribcage expansion was responsible for 25 +/- 4% (mean +/- SE) of the total change in thoracic volume (delta Vth) during inspiration. Phasic inspiratory activity was regularly present in the diaphragm and parasternal intercostal muscles. Halothane anesthesia (1 MAC) abolished activity in the parasternal intercostal muscles and increased phasic expiratory activity in the abdominal muscles and lateral ribcage muscles. However, halothane did not significantly change the ribcage contribution to delta Vth (18 +/- 4%). Intrathoracic blood volume, measured by comparing changes in total thoracic volume and gas volume, increased significantly during inspiration both while awake and while anesthetized (by approximately 20% of delta Vth, P < 0.05). Halothane anesthesia significantly reduced the functional residual capacity (by 258 +/- 78 ml), primarily via an inward motion of the end-expiratory position of the ribcage. Although the diaphragm consistently changed shape, with a cephalad displacement of posterior regions and a caudad displacement of anterior regions, the diaphragm did not consistently contribute to the reduction in the functional residual capacity. Halothane anesthesia consistently increased the curvature of the thoracic spine measured in the saggital plane. CONCLUSIONS: The authors conclude that (1) ribcage expansion is relatively well preserved during halothane anesthesia despite the loss of parasternal intercostal muscle activity; (2) an inward displacement of the ribcage accounts for most of the decrease in functional residual capacity caused by halothane anesthesia, accompanied by changes in diaphragm shape that may be related to motion of its insertions on the thoracoabdominal wall; and (3) changes in intrathoracic blood volume constitute a significant fraction of delta Vth during tidal breathing.

Adult↗

Halothane impairs the hemodynamic influence of endothelium-derived nitric oxide.

BACKGROUND: The endogenous vasodilator endothelium-derived nitric oxide (EDNO) contributes to the regulation of vascular tone and organ perfusion. It has been suggested that some volatile anesthetics may diminish the influence of EDNO and thereby decrease regional blood flow. METHODS: Radioactive microspheres were used to determine regional hemodynamics in rats. The authors tested the hypothesis that halothane inhibits EDNO and, therefore, should diminish the response to nitric oxide synthesis inhibition by NW-nitro-L-arginine methyl ester (L-NAME) compared with either conscious or barbiturate-anesthetized rats. RESULTS: NW-nitro-L-arginine methyl ester decreased blood flow to the brain by 23% (P < 0.005) in conscious rats to a level similar to that seen with either anesthetic agent. In both conscious and barbiturate-anesthetized rats, L-NAME increased blood pressure (BP) by 24 +/- 2 (P < 0.001) and 20 +/- 1 (P < 0.001) mmHg and total peripheral resistance (TPR) by 132% (P < 0.001) and 105% (P < 0.001), respectively. In contrast, during halothane anesthesia, both the pressor response (only 7 +/- 1 mmHg) and the increase in TPR (only 22%) were greatly diminished (P < 0.001). NW-nitro-L-arginine methyl ester decreased cardiac output (CO) by 47% (P < 0.001) and heart rate (HR) by 28% (P < 0.001) in conscious rats. In barbiturate-anesthetized rats, L-NAME decreased CO by 38% (P < 0.005) and HR by 13% (P < 0.001). In halothane-anesthetized rats, L-NAME changed neither CO nor HR. Thus halothane anesthesia largely eliminated the systemic response to EDNO synthesis inhibition. In conscious rats, L-NAME decreased blood flow to the heart (30%) and kidneys (47%). In barbiturate-anesthetized rats, L-NAME did not alter blood flow to the heart but decreased renal blood flow by 35% (P < 0.005). In halothane-anesthetized rats, L-NAME did not alter blood flow to either the heart or the kidneys. Overall, halothane blunted or blocked the systemic and regional hemodynamic responses to EDNO synthesis inhibition seen in conscious and barbiturate-anesthetized rats. CONCLUSIONS: Halothane anesthesia greatly diminished or eliminated all systemic and regional hemodynamic responses to L-NAME. These data indicate that halothane anesthesia inhibits EDNO-mediated regulation of systemic and organ hemodynamics.

Animals↗

A subtype of alpha 1 adrenoceptor mediates depression of conduction in Purkinje fibers exposed to halothane.

BACKGROUND: An action of epinephrine at alpha adrenoceptors has been reported to slow conduction in Purkinje fibers exposed to halothane. In Purkinje fibers one pharmacologically distinguishable alpha 1-adrenoceptor subtype (alpha 1B) sensitive to the noncompetitive antagonist chloroethylcholinidine mediates decreases in automaticity. Another alpha 1 subtype (alpha 1A), sensitive to the competitive antagonist WB4101, increases spontaneous rate and action potential duration by a mechanism thought to involve hydrolysis of membrane phosphoinositides by phospholipase C. This study examined the dose-response relation and receptor-effector mechanisms underlying depression of conduction in canine Purkinje fibers by epinephrine with halothane. METHODS: Conduction velocity was determined in vitro by measuring the conduction time between action potentials recorded from two Purkinje fibers located about 6 mm apart along the length of free running portions of the ventricular conduction system, the false tendons. Velocity was evaluated at 1-min intervals during trials of rapid exposure to different agonists in groups of 6-12 preparations. RESULTS: Epinephrine (0.2-5.0 microM) transiently decreased Purkinje conduction velocity in a dose-related manner by as much as 33% (at 5 microM epinephrine with 0.86 mM (2.8%) halothane). Velocity decreased by 5% (P < or = 0.01) at an epinephrine concentration similar to "just-threshold" dysrhythmogenic plasma epinephrine concentrations (0.2 microM epinephrine with 0.46 mM halothane) reported in halothane-anesthetized dogs. The decreases of conduction velocity were blocked by prazosin but not by metoprolol, were produced by phenylephrine but not by clonidine, and were antagonized by equimolar (0.5 microM) concentrations of WB4101 more so (P < or = 0.01) than by chloroethylclonidine. WB4101 (0.1 microM) produced 87% inhibition of the response to 0.2 microM epinephrine after chloroethylclonidine pretreatment, indicating mediation by the alpha 1A subtype. Other agonists linked to cardiac phospholipase C activation, including endothelin 1 (40 nM) and the muscarinic agonist carbamylcholine (1 mM), also decreased conduction velocity in fibers exposed to halothane. CONCLUSIONS: Clinically relevant concentrations of epinephrine transiently depress conduction in Purkinje fibers exposed to halothane by activating cardiac alpha 1 adrenoceptors, largely but not exclusively the WB4101-sensitive alpha 1A subtype, reportedly coupled to stimulation of phospholipase C and generation of the second messengers diacylglycerol and inositol trisphosphate. Anesthetic potentiation of cardiac alpha 1-adrenoceptor effects may contribute to the generation of halothane-epinephrine dysrhythmias by abnormally slowing conduction and facilitating reentry.

Animals↗

Chest wall responses to rebreathing in halothane-anesthetized dogs.

BACKGROUND: The pattern of respiratory muscle use during halothane-induced anesthesia differs markedly among species breathing quietly. In humans, halothane accentuates phasic activity in rib cage and abdominal expiratory muscles, whereas activity in the parasternal intercostal muscles is abolished. In contrast, halothane abolishes phasic expiratory muscle activity during quiet breathing in dogs, but parasternal muscle activity is maintained. Respiratory muscle responses to CO2 rebreathing were measured in halothane-anesthetized dogs to determine if species differences present during quiet breathing persist over a wide range of central respiratory drive. METHODS: Chronic electromyogram electrodes were implanted in three expiratory agonists (the triangularis sterni, transversus abdominis, and external oblique muscles) and three inspiratory agonists (the parasternal intercostal muscle, costal and crural diaphragm) of six mongrel dogs. After a 1-month recovery period, the dogs were anesthetized in the supine position with halothane. The rebreathing response was determined by Read's method during anesthesia with stable 1 and 2 minimum alveolar end-tidal concentrations of halothane. CO2 concentrations were measured in the rebreathing bag using an infrared analyzer. Chest wall motion was measured by fast three-dimensional computed tomographic scanning. RESULTS: Halothane concentration did not significantly affect the slope of the relationship between minute ventilation (VE) and PCO2 (0.34 +/- 0.04 [M +/- SE] and 0.28 +/- 0.05 l.min-1.mmHg-1 during 1 and 2 minimum alveolar concentration anesthesia, respectively). However, 2 minimum alveolar concentration anesthesia did significantly decrease the calculated VE at a PCO2 of 60 mmHg (from 7.4 +/- 1.2 to 4.0 +/- 0.6 l.min-1), indicating a rightward shift in the response relationship. No electromyographic activity was observed in any expiratory muscle before rebreathing. Rebreathing produced electromyographic activity in at least one expiratory muscle in only two dogs. Rebreathing significantly increased electromyographic activity in all inspiratory agonists. Rebreathing significantly increased inspiratory thoracic volume change (delta Vth), with percentage of delta Vth attributed to outward rib cage displacement increasing over the course of rebreathing during 1 minimum alveolar concentration anesthesia (from 33 +/- 6% to 48 +/- 2% of delta Vth). CONCLUSIONS: Rebreathing did not produce expiratory muscle activation in most dogs, demonstrating that the suppression of expiratory muscle activity observed at rest persists at high levels of ventilatory drive. Other features of the rebreathing response also differed significantly from previous reports in halothane-anesthetized humans, including (1) an increase in the rib cage contribution to tidal volume during the course of rebreathing, (2) recruitment of parasternal intercostal activity by rebreathing, (3) differences in the response of ventilatory timing, and (4) the lack of effect of anesthetic depth on the slope of the ventilatory response. These marked species differences are further evidence that the dog is not a suitable model to study anesthetic effects on the activation of human respiratory muscles.

Anesthetics, Inhalation↗

Isoform-dependent effects of halothane in human skinned striated fibers.

BACKGROUND: Reports of the effects of halothane on isoform contractile proteins of striated muscles are conflicting. To determine whether halothane affects cardiac and skeletal contractile proteins differently, the authors examined the effects of two doses of halothane (0.44 and 1.26 mM, equivalent to 0.75 and 2.25 vol%, respectively) on the Ca++ sensitivity and maximal force in human skinned cardiac, type I (slow twitch), and type II (fast twitch) skeletal muscle fibers. METHODS: Left ventricular muscle strips and skeletal muscle biopsy specimens were obtained from eight and ten patients undergoing cardiac and orthopedic surgery, respectively. Sarcolemma and sarcoplasmic reticulum were destroyed with ethylene glycol bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid plus Brij 58. Ca++ sensitivity was studied by observing the isometric tension developed by skinned fibers challenged with increasing concentrations of Ca++. Muscle fiber type was determined in each skeletal fiber by the difference in strontium-induced tension measurements. RESULTS: Halothane shifted the Ca++ tension curves toward higher Ca++ concentrations and increased the Ca++ concentrations for half-maximal activation in both cardiac and type I skeletal muscle fibers (from 1.96 microM and 1.06 microM under control conditions to 2.92 microM and 1.71 microM in presence of 0.75 vol% halothane, respectively) without changing the slope of this relationship (Hill coefficient). In contrast, no significant effect was observed in type II fibers. Halothane also decreased the maximal activated tension in the three groups of fibers with a lesser effect in type II fibers. CONCLUSIONS: Halothane decreases Ca++ sensitivity and maximal force in human skinned cardiac and type I fibers at 20 degrees C. It is concluded that the negative inotropic effects of halothane depend on contractile proteins isoforms.

Anesthetics, Inhalation↗