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PubMed1990

Halothane alters the oxygen consumption-oxygen delivery relationship compared with conscious state.

The authors' objectives were as follows: 1) to characterize for the first time the relationship between whole body O2 delivery (DO2) and O2 consumption (VO2) in adult conscious dogs; and 2) to asses the effects of the inhalational anesthetic, halothane, on that relationship. DO2 was varied over a wide range in chronically instrumented dogs by gradual inflation and deflation of a hydraulic occluder implanted around the thoracic inferior vena cava to alter venous return and cardiac output. VO2 was measured at different values of DO2 in dogs in the fully conscious state and again during halothane anesthesia. A "binning" technique indicated that halothane decreased VO2 (P less than 0.01) at any given value of DO2 over a broad range of VO2. A two-line piecewise linear regression analysis technique indicated that halothane decreased (P less than 0.01) the critical O2 delivery (COD) from 20 +/- 3 to 10 +/- 1 ml.kg-1.min-1 and increased (P less than 0.01) O2 extraction at COD from 31 +/- 3 to 40 +/- 2%. However, the DO2-VO2 plots measured in both conscious and halothane-anesthetized dogs did not exhibit a discrete discontinuity but rather were closely fit (correlation coefficient = 0.98) by an exponential equation of the following form: O2 extraction = B1.(1 - exp (-DO2/B2))/DO2, where B1 is the delivery-independent estimate of VO2 and B2 is the "delivery constant," i.e., the DO2 associated with a VO2 equal to 63% of B1. Halothane decreased B1 (P less than 0.01) from 5.3 +/- 0.1 to 3.9 +/- 0.1 ml.kg-1.min-1 and decreased B2 (P less than 0.01) from 5.6 +/- 0.3 to 3.6 +/- 0.3 ml.kg-1.min-1 compared with that measured in conscious dogs. Thus, compared with the conscious state, halothane anesthesia alters the fundamental relationship between DO2 and VO2 and may have a beneficial effect on tissue oxygenation at low values of DO2.

Animals↗
PubMed1991

Halothane potentiates the antitumor activity of gamma-interferon and mimics calmodulin-blocking agents.

This study reports effects of halothane on tumor cells in vitro. Cells from the human colon cancer cell line HT-29 were exposed to various concentrations of halothane for 8-72 h. The effect of this exposure on this colon cancer cell line, with and without coincubation with the biologic response modifier gamma-interferon (IFN-gamma), was studied. Using the tumor target cell survival (TTCS) assay, concentrations of halothane from 0.5 to 2% markedly augmented the antitumor activities of IFN-gamma against HT-29. The tumor cell cytostatic effects of IFN-gamma in the 0.75-6-unit/ml range were increased nearly 400% by concentrations of halothane as low as 1%. These results were confirmed in a separate cytolytic assay (Indium-111 release assay), which revealed that halothane concentrations in the 2-4% range markedly increased the cytolytic capacity of IFN-gamma at doses of IFN-gamma between 75 and 1,250 units/ml. The cytolytic activity of IFN-gamma was increased nearly 300% by doses of halothane as low as 1%. A nearly identical pattern of augmentation of IFN-gamma-induced antitumor activity was observed when the known calmodulin inhibitor trifluoperazine (TFP) was coincubated with IFN-gamma. At concentrations of 4-10 microM, the antitumor activity of IFN-gamma was increased nearly 400%. These observations suggest that the pattern of halothane potentiation of the antitumor activity of IFN-gamma is similar to that exhibited by known calmodulin inhibitors.

Antineoplastic Agents↗
PubMed1991

Effects of halothane on delayed afterdepolarization and calcium transients in dog ventricular myocytes exposed to isoproterenol.

The effects of halothane on isoproterenol-induced delayed after-depolarizations (DADs) were investigated in canine ventricular myocytes. In addition, the effects of halothane on the intracellular free calcium transient were determined in fura-2-loaded myocytes exposed to isoproterenol to explore the mechanisms underlying halothane effects on DADs. Isoproterenol (100 nM) induced DADs and/or undriven action potentials in myocytes stimulated electrically with the use of trains of 10 stimuli delivered at basic drive cycle lengths of 200-1,000 ms. Isoproterenol (100 nM) increased the peak ratio (350/380 nm excitation) of stimulated myocyte calcium transients; furthermore, isoproterenol induced a second spontaneous component in the calcium transients of 62% of treated myocytes (n = 72). Halothane (1.5%, 0.53 mM) significantly decreased the amplitude of isoproterenol-induced DADs (P less than 0.01). Halothane not only reduced the peak ratio of the stimulated calcium transient, but also eliminated the second spontaneous component in myocytes previously exposed to isoproterenol (n = 14). Elevated extracellular calcium concentrations (5 mM) restored the amplitudes of DADs and the second components of the calcium transients in myocytes exposed to isoproterenol and halothane. These data suggest that halothane opposes isoproterenol-induced DADs by altering intracellular calcium stores. The authors' findings do not support a role for DAD-induced triggered activity in the genesis of anesthetic-catecholamine dysrhythmias.

Animals↗
PubMed1991

Depression of baroreflex control of heart rate by halothane in growing piglets.

The purpose this study was to examine the effects of halothane on baroreflex control of heart rate in developing swine. Serial tests of baroreflex function were performed over the first 2 months of life in eight piglets in the conscious state and during anesthesia with 0.45, 0.9, and 1.35% halothane. Systemic blood pressure was increased with phenylephrine (pressor test) and decreased with nitroprusside (depressor test), and stimulus-response curves relating mean blood pressure to heart rate were constructed. Baroreflex sensitivity was determined as the slope of the linear portion of the curve. Halothane markedly depressed baroreflex sensitivity at all ages in a dose-dependent manner (conscious greater than 0.45% greater than 0.9%, 1.35%). Increasing age was accompanied by decreasing baroreflex sensitivity in both the conscious and the anesthetized states. The difference in baroreflex sensitivity between conscious and anesthetized states did not change with age for the depressor test (tachycardia response), but it did change with age for the pressor test (bradycardia response). For this test, conscious values converged toward anesthetized values at higher ages; therefore, there was relatively less depression by halothane at older ages. Halothane also decreased resting heart rate and decreased the limits and narrowed the range of the baroreflex heart rate response. Increasing age was accompanied by a decreasing resting heart rate and by decreasing limits and a narrowing range of the baroreflex response. The effect of halothane on heart rate variables was similar at all ages. Halothane decreased resting blood pressure and decreased the lower limit and widened the span of the baroreflex blood pressure range.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Effect of Bay K 8644 on the magnitude of isoflurane and halothane contracture of skeletal muscle from patients susceptible to malignant hyperthermia.

Isoflurane has a lesser ability than halothane to induce contracture in malignant hyperthermia (MH) muscle in vitro. This does not necessarily imply that isoflurane is not as potent an MH trigger as halothane in vivo. A hypothesis was tested that in vitro treatment with Bay K 8644, an activator of both the dihydropyridine receptors as well as the sodium channels of the T-tubules, potentiates isoflurane-induced MH-susceptible skeletal muscle contracture. In addition to the usual halothane-caffeine test, other muscle bundles were exposed to 10 microM Bay K 8644-halothane and equipotent anesthetic concentrations (expressed in multiple minimum alveolar concentration [MAC]) of isoflurane either alone or combined with Bay K 8644. In 14 MH-susceptible muscle bundles, the mean maximum contracture induced by 2 MAC isoflurane was 0.20 +/- 0.22 g (mean +/- SD), and this value was significantly less than that obtained with 2 MAC halothane (0.68 +/- 0.40 g). Bay K 8644 did not induce muscle contracture on its own but consistently enhanced both the 0.5 MAC isoflurane and halothane to the same maximal isometric tension (1.09 +/- 0.35 g and 1.11 +/- 0.37 g, respectively). Such an effect was not observed in the MH-nonsusceptible group. Under the conditions of this in vitro study, 0.5 MAC isoflurane appears to be as potent as halothane in inducing muscle contracture in skeletal muscle bundles from individuals susceptible to MH.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Direct inhibitory mechanisms of halothane on canine tracheal smooth muscle contraction.

Halothane directly relaxes airway smooth muscle. To determine the direct inhibitory mechanisms of halothane on canine tracheal smooth muscle contraction, the effects of this anesthetic on the levels of several intracellular second messengers were investigated by measuring intracellular Ca2+ concentration ([Ca2+]i), Ca2+/phospholipid-dependent protein kinase (PKC) translocation, and intracellular cyclic adenosine monophosphate concentration ([cAMP]i). When carbachol (1 microM) was used to increase [Ca2+]i to the same concentration as that induced by high-K+ (72.7 mM), the carbachol-induced contraction was more than twice as great, indicating that carbachol enhances the sensitivity of contractile elements to Ca2+ or activates a Ca(2+)-independent mechanism. Similarly, 12-deoxyphorbol 13-isobutylate, a potent PKC activator, markedly potentiated high-K(+)-induced muscle contraction without an increase of [Ca2+]i. The addition of halothane (0.33, 0.75, 1.15, and 1.47 mM) decreased [Ca2+]i and the muscle tension induced by carbachol. However, the decrease of muscle tension was more marked than that of [Ca2+]i at the higher concentrations. Although [Ca2+]i in the presence of verapamil and carbachol was not affected by halothane, the anesthetic markedly decreased muscle force by decreasing the "Ca2+ sensitization" or the Ca(2+)-independent enhancement of tension observed with carbachol. Halothane (0.75 and 1.47 mM) significantly released the membrane-associated PKC to cytosol, which decreased PKC activity. [cAMP]i of the smooth muscle stimulated by carbachol was moderately but significantly increased by halothane. However, when equivalent relaxation was induced with forskolin, which acts via adenylate cyclase activation, a much higher [cAMP]i was observed, which suggests that halothane acts via an additional pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of halothane, propofol, and thiopental on peripheral airway reactivity.

BACKGROUND: General anesthetics modify airway responsiveness by several mechanisms, including direct effects on airway smooth muscle and reductions in neural reflex activity. Halothane has been shown to reduce responsiveness through both of these mechanisms. The airway effects of barbiturates are controversial, and the effects of propofol are unknown. METHODS: To compare the direct effects of halothane, thiopental, and propofol in vivo, canine peripheral airways were constricted with two stimuli, histamine and hypocapnia, which are thought to directly contract smooth muscle. The authors then investigated the role of ATP-sensitive potassium (KATP) channels as a mechanism for attenuating these responses. Basenji-Greyhound (BG) dogs were anesthetized with either halothane (1.5 MAC), thiopental (7.5 mg.kg-1 x min-1 intravenously) plus fentanyl (25 micrograms intravenously every 20-30 min), or propofol (0.6 mg.kg-1 x min-1 intravenously). A wedged bronchoscope technique was used to measure peripheral airway resistance (RP). After a stable baseline was obtained, dose-response curves to histamine (50, 100, or 200 micrograms intravenous bolus) or hypocapnia (0% CO2 for 2 min with 100, 200, or 400 ml/min collateral flow) were constructed. On separate occasions, the same sublobar segments were pretreated with glibenclamide (2 mg/ml aerosol), a KATP channel blocker, and dose-response curves to hypocapnia were repeated. RESULTS: Dose-response curves to histamine were similar during all three anesthetics. Halothane decreased airway responsiveness to hypocapnia, compared with either thiopental or propofol (P < 0.05). Pretreatment with glibenclamide abolished the effect of halothane on hypocapnia-induced airway constriction. CONCLUSIONS: These results indicate that propofol afforded no benefit over thiopental or halothane in reducing peripheral airway responsiveness. Furthermore, the beneficial effects of halothane in reducing responsiveness to hypocapnia appear to be mediated by the opening of KATP channels.

Airway Resistance↗
PubMed1993

Effects of halothane on EDRF/cGMP-mediated vascular smooth muscle relaxations.

BACKGROUND: Halothane has been reported to inhibit endothelium-dependent relaxation in a variety of vessels. These studies were done to determine whether this inhibition is caused by interference with synthesis, release, or action of endothelium-derived relaxing factor (EDRF) on cyclic guanosine monophosphate (cGMP) levels within the vascular smooth muscle. METHODS: Rat aortic rings were suspended in aerated Krebs solution (37 degrees C) and were contracted to a stable plateau with EC60-70 norepinephrine (NE). Relaxations caused by acetylcholine (ACh; 1 x 10(-8)-1 x 10(-6) M), nitric oxide (NO; 5 x 10(-9)-1 x 10(-6) M), or nitroglycerin (NG; 2 x 10(-9)-3 x 10(-7) M) in rings contracted with NE were compared in the presence and absence of halothane. Tissue cGMP contents were measured using a radioimmunoassay method. RESULTS: In the presence of halothane (0.5, 1.0, and 2.0 MAC), the ACh-induced relaxations were significantly attenuated in a concentration-dependent manner, an effect that was reversible. Halothane (2 MAC) significantly attenuated NO-induced relaxations at all concentrations and NG-induced relaxations at low concentrations (5 x 10(-9)-3 x 10(-8) M) but not at higher concentrations (1 x 10(-9)-3 x 10(-7) M) in denuded vessels. Nitric oxide-stimulated (5 x 10(-8)-5 x 10(-6) M) cGMP content was significantly attenuated by halothane (2 MAC) at NO concentrations between 1 x 10(-7) and 5 x 10(-6) M. CONCLUSIONS: Nitric oxide, either endogenous or exogenous, interacts with the enzyme guanylate cyclase to stimulate the production of cGMP. Halothane interfered with the relaxations caused by NO (in rings without endothelium) and decreased the NO-stimulated cGMP content. These results suggest that the site of action of halothane in attenuating endothelium-dependent relaxation in the rat aorta is within the vascular smooth muscle, rather than on the synthesis, release, or transit of the EDRF from the endothelium and that its action may involve an interference with guanylate cyclase activation.

Animals↗
PubMed1993

Comparative efficacy of antiarrhythmic agents in preventing halothane-epinephrine arrhythmias in rats.

BACKGROUND: Because the relative efficacy of antiarrhythmic agents on halothane-epinephrine arrhythmias has not been well characterized, this study was undertaken to comparatively evaluate the antiarrhythmic action of Na(+)-, K(+)- and Ca(2+)-channel blockers on epinephrine-induced ventricular arrhythmias during halothane anesthesia in rats. METHODS: Rats were anesthetized at random with either halothane (1.5%), isoflurane (2.0%), or pentobarbital (50 mg/kg intraperitoneally), and the lungs were mechanically ventilated with oxygen. The rats were studied in three consecutive protocols. Protocol I determined the arrhythmogenic thresholds of epinephrine during the three types of anesthesia in 33 rats. Protocol II determined the arrhythmogenic thresholds of epinephrine during halothane anesthesia in 64 rats receiving saline (control) or one of five antiarrhythmic agents. Protocol III measured the duration of epinephrine-induced arrhythmias during halothane anesthesia in 42 rats receiving saline (control) or one of five antiarrhythmic agents. RESULTS: In protocol I, the arrhythmogenic doses of epinephrine during halothane, isoflurane, or pentobarbital anesthesia were 1.7 +/- 3.2, 11.1 +/- 0.6, and 39.0 +/- 3.9 micrograms/kg, respectively, and the corresponding plasma concentrations were 4.3 +/- 0.8, 103.7 +/- 9.2, and 246.7 +/- 28.9 ng/ml, respectively. In protocol II, the arrhythmogenic doses were similar in rats receiving saline and in those receiving lidocaine. The arrhythmogenic doses in rats receiving verapamil, flecainide (Na(+)- and K(+)-channel blocker), E-4031 (K(+)-channel blocker), or amiodarone(K(+)-channel blocker with Na(+)-, Ca(2+)-, and beta-blocking activity) increased significantly, i.e., 4.2, 4.2, 5.5, and 31.7 times control (P < 0.01). In protocol III, lidocaine had no effect on the duration of arrhythmias. Flecainide, E-4031, and verapamil markedly reduced the duration of arrhythmias induced by epinephrine, 8 micrograms/kg intravenously (P < 0.01), whereas only amiodarone markedly reduced the duration of arrhythmias induced by epinephrine, 16 micrograms/kg intravenously (P < 0.01). CONCLUSIONS: It was concluded that agents with K(+)-channel blocking properties were the most effective in preventing halothane-epinephrine arrhythmias in rats.

Amiodarone↗
PubMed1993

Anesthetics and automaticity of dominant and latent pacemakers in chronically instrumented dogs. I. Methodology, conscious state, and halothane anesthesia: comparison with and without muscarinic blockade during exposure to epinephrine.

BACKGROUND: Supraventricular dysrhythmias are common during anesthesia, but have been incompletely investigated. Mechanisms may involve altered automaticity of subsidiary pacemakers and participation of vagal reflexes. The following hypotheses were tested: (1) shifts from the sinoatrial (SA) node to subsidiary pacemakers require intact vagal reflexes and (2) halothane sensitizes the heart to epinephrine-induced atrial pacemaker shifts. METHODS: Epicardial electrodes were implanted in eight dogs on both atrial appendages, the right ventricle, along the sulcus terminalis, and at the His bundle. Weekly testing awake (control), awake with atropine methylnitrate, with 1 and 2 micrograms epinephrine.kg-1.min-1 (3 min-infusions), and under 1.25 and 2 MAC halothane was performed. Electrograms were analyzed for the site of earliest activation (SEA), which was scored 1-6 depending on the distance from the SA node, and expressed as the SEA value. RESULTS: In conscious dogs (control) and at 1.25 MAC halothane, epinephrine increased the SEA values (shifted activation from SA node) and blood pressure, and decreased heart rate; however, with atropine, SEA values were unaffected by epinephrine, although blood pressure and heart rate were elevated. At 2 MAC, atropine did not affect the epinephrine-induced increase in SEA values. Halothane increased SEA values when combined with 1 micrograms epinephrine.kg-1.min-1. CONCLUSIONS: Pacemaker shifts account for atrial dysrhythmias in the conscious state and during 1.25 MAC halothane with epinephrine, and require vagal participation. Halothane sensitizes the heart to epinephrine-induced atrial dysrhythmias. Atropine and halothane facilitate His bundle beats during exposure to epinephrine.

Anesthesia↗
PubMed1994

The effect of adenosine-induced hypotension on systemic and splanchnic hemodynamics during halothane or sevoflurane anesthesia in the rat.

BACKGROUND: It has been suggested that the liver may be at risk for ischemic damage during adenosine-induced hypotension. This notion, however, is somewhat inconsistent with the understanding that adenosine is a powerful vasodilator of the splanchnic circulation. To help clarify the effect of adenosine-induced hypotension on splanchnic hemodynamics, we studied the systemic and splanchnic hemodynamic responses to adenosine, both alone and in the presence of halothane or sevoflurane. METHODS: Systemic and splanchnic hemodynamics were determined during the infusion of adenosine in 36 rats allocated randomly to one of three study groups: (1) awake, (2) halothane anesthesia (1.0 MAC), or (3) sevoflurane anesthesia (1.0 MAC). Adenosine was infused at a rate sufficient to decrease the mean arterial pressure by 35-38% from awake control values. Cardiac output and organ blood flows were measured using the radiolabeled microsphere technique. RESULTS: Adenosine infusion produced stable hypotension of rapid onset due to a reduction in systemic vascular resistance. Stroke volume increased, but cardiac output remained unchanged in the awake and sevoflurane groups because of a decrease in heart rate. Infusion of adenosine during halothane anesthesia increased cardiac output enough to compensate for the decrease in cardiac output due to halothane alone. In the splanchnic circulation, there was an increase in portal tributary (42%, P < 0.01) and hepatic arterial (38%, P < 0.05) blood flows during adenosine infusion in awake rats. This resulted in an overall increase in total liver blood flow (42%, P < 0.01). Halothane anesthesia was associated with a decrease in portal tributary blood flow (28%, P < 0.05). In contrast, sevoflurane anesthesia was associated with an increase in hepatic arterial flow (35%, P < 0.05) but with no change in portal tributary blood flow. During halothane anesthesia, adenosine infusion increased portal tributary (90%, P < 0.01) and hepatic arterial (37%, P < 0.05) blood flows, thereby increasing total liver blood flow to values similar to those in awake adenosine-infused rats. During sevoflurane anesthesia, adenosine infusion increased portal tributary blood flow (48%, P < 0.01), but hepatic arterial blood flow did not increase beyond the values observed during sevoflurane anesthesia alone. CONCLUSIONS: These findings demonstrate that adenosine is a potent vasodilator of portal tributary and hepatic arterial vasculature in the rat and that the splanchnic hemodynamic effects of adenosine predominate over those of halothane and sevoflurane.

Adenosine↗
PubMed1994

Effects of subanesthetic halothane on the ventilatory responses to hypercapnia and acute hypoxia in healthy volunteers.

BACKGROUND: The peripheral chemoreceptors are responsible for the ventilatory response to hypoxia (acute hypoxic response) and for 30% of the normoxic hypercapnic ventilatory response. To quantify the effects of subanesthetic concentrations of halothane on the respiratory control system, in particular on the peripheral chemoreceptors, we studied the response of humans to carbon dioxide and oxygen at two subanesthetic concentrations of halothane. METHODS: Square-wave changes in end-tidal carbon dioxide tension (7.5-11.3 mmHg) and step decreases in end-tidal oxygen tension (arterial hemoglobin oxygen saturation 82 +/- 2%; duration of hypoxia 5 min) were performed in nine healthy male subjects during 0, 0.05 (HA-1), and 0.1 minimum alveolar concentration (HA-2) halothane. Each hypercapnic response was separated into a fast, peripheral component and a slow, central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and off-set. RESULTS: Fifty-six carbon dioxide responses and 27 oxygen responses were obtained. The peripheral carbon dioxide sensitivities averaged to 0.76 +/- 0.14 l.min-1.mmHg-1 (control), 0.50 +/- 0.12 l.min-1.mmHg-1 (HA-1), and 0.30 +/- 0.08 l.min-1.mmHg-1 (HA-2; P < 0.01 vs. control). The central carbon dioxide sensitivity did not differ significantly among treatment groups (control, 1.47 +/- 0.22 l.min-1.mmHg-1; HA-1, 1.41 +/- 0.51 l.min-1.mmHg-1; and HA-2, 1.23 +/- 0.30 l.min-1.mmHg-1). The time constants of the central chemoreflex loop showed a large decrease during the administration of 0.1 minimum alveolar concentration halothane. The acute hypoxic response declined from 15.0 +/- 3.9 l.min-1 to 10.9 +/- 2.9 l.min-1 (HA-1) and 4.8 +/- 1.4 l.min-1 (HA-2; P < 0.01 vs. control and HA-1). All values are means +/- SEM. CONCLUSIONS: The results show depression of the ventilatory responses to hypoxia and hypercapnia during inhalation of subanesthetic concentrations of halothane. The depression is attributed to a selective effect of halothane on the peripheral chemoreflex loop. The oxygen and carbon dioxide responses mediated by the peripheral chemoreceptors are affected proportionally. It is argued that the decrease in central time constants is caused by an effect of halothane on central neuronal dynamics.

Administration, Inhalation↗
PubMed1994

Differential effects of halothane and isoflurane on contractile force and calcium transients in cardiac Purkinje fibers.

BACKGROUND: Halothane and isoflurane have been shown to differentially effect mechanisms of contraction in working myocardial fibers. The aim of this study was to compare effects of halothane and isoflurane on contractile force (CF) and Ca2+ transients in canine cardiac Purkinje fiber preparations. METHODS: Fiber preparations (n = 29) were superfused with Krebs-Ringer solution and stimulated at 40-60 pulses/min at 30 degrees C in the absence and presence of 0.55% and 1.01% isoflurane or 0.27% and 0.78% halothane. Isometric tension (CF), and intracellular Ca2+ transients (luminescence, L) were measured after microinjecting the Ca2+ sensitive photoprotein aequorin into Purkinje fibers. Peak CF and peak L, rate of rise (slope) of CF and L, time to attain peak CF and L, and duration of CF and L at half-peak CF and L, were measured at 5 mM extracellular CaCl2. Changes in peak CF and peak L also were measured during incremental increases in CaCl2 from 3.6 to 9.0 mM. RESULTS: Both anesthetics depressed peak CF and peak L and the rate of increase in peak CF and L in a concentration-dependent fashion, and effects of halothane were greater than those of isoflurane. Time to attain peak L and duration of L at half-peak L was decreased or unchanged by isoflurane and was increased by halothane, whereas time to attain peak CF and duration of CF at half-peak CF was shortened by both. The change in peak CF response as a function of the change in peak L with increasing extracellular CaCl2 was attenuated similarly by both halothane and isoflurane. CONCLUSIONS: Halothane depresses peak CF and Ca2+ transients and prolongs Ca2+ transients more than does isoflurane at equivalent minimum alveolar concentration in Purkinje fibers. This suggests Ca2+ concentration is differentially altered by anesthetics in this tissue. Peak CF at equivalent peak Ca2+ transients, however, appears to be attenuated similarly by both anesthetics. These differences in anesthetic effect are qualitatively similar to those found in cardiac tissue of other species. These findings add to our understanding of effects of volatile anesthetics on contractile properties and myoplasmic Ca2+ in cardiac Purkinje fibers.

Animals↗
PubMed1994

Effects of halothane and propofol on purified brain protein kinase C activation.

BACKGROUND: Protein kinase C (PKC) has been implicated as a target for general anesthetic action in the central nervous system. Previous reports have described either stimulation or inhibition of PKC activity by general anesthetics. This study examines the effects of halothane and propofol on the activity of purified rat brain PKC under various assay conditions. METHODS: PKC was assayed in vitro using three previously characterized artificial substrates and three different lipid preparations in the absence or presence of halothane or propofol. RESULTS: Both halothane (50% effective concentration = 2.2 vol%) and propofol (50% effective concentration = 240 microM) markedly stimulated histone H1 phosphorylation by PKC in the presence of a lipid vesicle preparation consisting of phosphatidylcholine, phosphatidylserine, and diacylglycerol. Less marked or no stimulation of PKC by both anesthetics was observed in the presence of a phosphatidylserine/diacylglycerol dispersion or using protamine or poly(lysine, serine) as substrate. Neither anesthetic significantly stimulated PKC activity in the presence of phosphatidylserine/diacylglycerol/Triton X-100 mixed micelles using histone H1, protamine or poly(lysine, serine) as substrate. Slight inhibition of PKC activity by halothane was observed under specific assay conditions with protamine as substrate. The activity of the catalytic fragment of PKC or of two lipid-independent second messenger-regulated protein kinases with conserved catalytic domains was not significantly affected by halothane. CONCLUSIONS: Both halothane and propofol stimulated purified brain PKC activity in vitro assayed with physiologically relevant lipid bilayers in the absence or presence of Ca2+. This effect appears to be mediated through the lipid-binding regulatory domain of PKC. The potencies of halothane and propofol in stimulating PKC in vitro are consistent with submaximal activation of PKC at clinically effective anesthetic concentrations, the pharmacologic significance of this effect requires confirmation in an intact cellular system.

Anesthesia, General↗
PubMed1994

Direct myocardial effects of halothane and isoflurane. Comparison between adult and infant rabbits.

BACKGROUND: Infants may be more sensitive than adults to myocardial depression by potent inhalation anesthetics. Most studies of cardiovascular effects of inhalation agents in infants are performed in vivo with multiple factors producing the observed effects. The purpose of this study was to determine if newborns are more sensitive than adults to the direct actions of halothane and isoflurane on global electrophysiologic, contractile and metabolic functions of the heart. METHODS: Direct myocardial effects of the agents were determined using isolated rabbit hearts perfused at constant pressure. Three doses of halothane and isoflurane were administered to 37 infant (3-8 days old) and 36 adult rabbit hearts. Heart rate and rhythm, atrioventricular conduction time, left ventricular function (systolic, diastolic, and developed pressures; maximum and minimum values of the differential wave (dP/dt); and time constant of isovolumic LV relaxation), coronary flow and O2 consumption, and fractional O2 extraction were measured and compared between age and anesthetic groups. RESULTS: Halothane was a more potent depressant of cardiac function than isoflurane and developmental differences were more evident with this agent. The most striking developmental differences in anesthetic effects were the significantly greater prolongation of atrioventricular conduction time and the time constant of isovolumic LV relaxation by halothane in infant compared with adult hearts. Infant hearts were also more sensitive to depression of left ventricular developed pressure and maximum value of the differential wave and to elevation of diastolic pressure by halothane. For both agents heart rate was less depressed in infants than in adults. There were no developmental differences in anesthetic effects on coronary flow and O2 metabolism. CONCLUSIONS: Developmental changes in myocardial physiology make the newborn less sensitive to direct depression of heart rate by halothane and isoflurane, but more sensitive to depression of contraction-relaxation and atrioventricular conduction by halothane.

Aging↗
PubMed1994

Dose-dependent effects of halothane on the carbon dioxide responses of expiratory and inspiratory bulbospinal neurons and the phrenic nerve activities in dogs.

BACKGROUND: Expiratory bulbospinal and inspiratory bulbospinal neurons in the ventral respiratory group provide drive for thoracoabdominal expiratory and phrenic and thoracic inspiratory motor neurons. Potent inhalational agents such as halothane may have differential effects on inspiratory and expiratory neurons, but detailed studies comparing neurons at a homologous level are lacking. METHODS: The dose-dependent effects of anesthesia with 1.0-2.5 minimum alveolar concentration halothane on the CO2 responses of single expiratory and inspiratory bulbospinal neurons of the ventral respiratory group and on phrenic neural activities were studied in nonpremedicated, anesthetized, paralyzed, vagotomized dogs. Hyperventilation with O2 and the addition of CO2-O2 mixtures were used to produce low, medium, and high steady-state levels of central CO2 drive. RESULTS: Peak neuron discharge frequency decreased progressively with increasing halothane dose at all levels of CO2 drive for both types of neurons. The sensitivities of inspiratory and expiratory bulbospinal neuronal activities to halothane were not significantly different from one another, whereas the sensitivity to halothane of the peak phrenic activity was markedly greater than those of the neurons. Increasing halothane dose caused a downward, predominantly parallel shift of the CO2 response curves. Phrenic nerve activity also showed a decrease in slope of the CO2 response. CONCLUSIONS: The activities of respiratory premotor neurons are less depressed by increasing doses of halothane than is phrenic nerve activity. The greater depression of phrenic activity may result from additional anesthetic actions on the efferent motor pathways, resulting in decreased descending synaptic inputs to phrenic motor neurons.

Animals↗
PubMed1995

Clinical characteristics of sevoflurane in children. A comparison with halothane.

BACKGROUND: For pediatric patients, sevoflurane may be an alternative to halothane, the anesthetic agent used most commonly for inhalational induction. The induction, maintenance, and emergence characteristics were studied in 120 unpremedicated children 1-12 yr of age randomly assigned to receive one of three anesthesia regimens: sevoflurane with oxygen (group S), sevoflurane with nitrous oxide and oxygen (group SN), or halothane with nitrous oxide and oxygen (group HN). METHODS: Anesthetic was administered (via a Mapleson D, F or Bain circuit) beginning with face mask application in incremental doses to deliver maximum inspired concentrations of 4.5% halothane or 7% sevoflurane. End-tidal concentrations of anesthetic agents and vocal cord position were noted at the time of intubation. Elapsed time intervals from face mask application to loss of the eyelash reflex, intubation, surgical incision, and discontinuation of the anesthetic were measured. Heart rate, systolic, diastolic, and mean blood pressures, and end-tidal anesthetic concentrations were measured at fixed intervals. Anesthetic MAC-hour durations were calculated. The end-tidal concentration of anesthetic was adjusted to 1 MAC (0.9% halothane, 2.5% sevoflurane) for at least the last 10 min of surgery. Intervals from discontinuation of anesthetic to hip flexion or bucking, extubation, administration of first postoperative analgesic, and attaining discharge criteria from recovery room were measured. Venous blood was sampled at anesthetic induction, at the end of anesthesia, and 1, 4, 6, 12, and 18-24 h after discontinuation of the anesthetic for determination of plasma inorganic fluoride content. RESULTS: Induction of anesthesia was satisfactory in groups SN and HN. Induction in group S was associated with a significantly greater incidence of excitement (35%) than in the other groups (5%), resulting in a longer time to intubation. The end-tidal minimum alveolar concentration multiple of potent inhalational anesthetic at the time of intubation was significantly greater in patients receiving halothane than in patients receiving sevoflurane. Induction time, vocal cord position at intubation, time to incision, duration of anesthesia, and MAC-hour duration were similar in the three groups. During emergence, the time to hip flexion was similar among the three groups, whereas the time to extubation, time to first analgesic, and time to attaining discharge criteria were significantly greater in group HN than in groups S and SN. Mean heart rate and systolic blood pressure decreased during induction in group HN but not in groups S and SN. The maximum serum fluoride concentration among all patients was 28 microM. CONCLUSIONS: Sevoflurane with nitrous oxide provides satisfactory anesthetic induction and intubating conditions; however, induction using sevoflurane without nitrous oxide is associated with a high incidence of patient excitement and prolonged time to intubation. There were greater decreases in heart rate and systolic blood pressure during induction with halothane than with sevoflurane; however, these differences may be dose-related. The more rapid emergence with sevoflurane when compared with halothane is consistent with the low solubility of sevoflurane in blood and tissues. Children receiving sevoflurane for up to 9.6 MAC-hours did not develop high serum fluoride concentrations.

Anesthesia, Inhalation↗
PubMed1995

Halothane inhibits signaling through m1 muscarinic receptors expressed in Xenopus oocytes.

BACKGROUND: Interactions between volatile anesthetics and muscarinic acetylcholine receptors have been studied primarily in binding assays or in functional systems derived from tissues or cells, often containing multiple receptor subtypes. Because interactions with muscarinic signaling systems may explain some effects and side effects of anesthetics and form a model for anesthetic-protein interactions in general, the author studied anesthetic inhibition of muscarinic signaling in an isolated system. METHODS: mRNA encoding the m1 muscarinic receptor subtype was prepared in vitro and expressed in Xenopus oocytes. Effects of halothane on methylcholine-induced intracellular Ca2+ release was measured. Angiotensin II receptors were expressed to evaluate anesthetic effects on intracellular signaling. RESULTS: m1 Receptors expressed in oocytes were functional, and could be inhibited by atropine and pirenzepine. Halothane depressed m1 muscarinic signaling in a dose-dependent manner: half-maximal inhibition of 10(-7) M methylcholine was obtained with 0.3 mM halothane. The effect was reversible and could be overcome by high concentrations of muscarinic agonist. Angiotensin II signaling was unaffected by 0.34 mM halothane. CONCLUSIONS: m1 Muscarinic signaling is inhibited by halothane, and lack of halothane effect on angiotensin signaling indicates that the intracellular signaling systems of Xenopus oocytes are unaffected. Therefore, the most likely site of halothane action is the receptor and/or G protein. Oocytes provide a versatile system for detailed investigation into the molecular mechanism of anesthetic-protein interactions.

Animals↗