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PubMed1990

Contributions of liver perfusion flow rate and enzyme inhibition to altered verapamil clearance with halothane: a study in the isolated perfused rat liver.

Verapamil clearance is reduced during halothane administration. This study evaluated relative contributions of reduced hepatic flow rate and hepatic metabolizing enzyme inhibition by halothane as a cause of reduced verapamil clearance. An isolated perfused rat liver model was utilized in which flow rate could be fixed during halothane administration. Perfusions were performed on five to six livers under each of the following conditions: (a) control--40 mL/min flow rate with no anesthetic exposure; (b) 1.5% halothane--40 mL/min; (c) 2.25% halothane--40 mL/min; (d) reduced flow--20 mL/min with no anesthetic exposure; and (e) reduced flow with 1.5% halothane--20 mL/min. Halothane caused dose-dependent decreases in both total hepatic and intrinsic clearance rates (P less than 0.05). With no anesthetic exposure, a flow reduction of 50% (20 mL/min) also gave a large reduction (P less than 0.05) in hepatic clearance of verapamil compared with the control condition (40 mL/min). The addition of 1.5% halothane to the reduced flow condition was not associated with further reduction in hepatic clearance rate. Results of this study suggest that although both reduced hepatic perfusion and hepatic enzymatic inhibition by halothane administration are associated with decreased verapamil clearance, a greater proportion of this decrease appears to be due to reductions in hepatic flow. The present results may apply to other drugs used in anesthesia that have high hepatic extraction ratios; thus, clearance of these drugs may be more dependent on hepatic blood flow than on hepatic enzyme activity.

Animals↗
PubMed1992

Hemodynamic and organ blood flow responses to halothane and sevoflurane anesthesia during spontaneous ventilation.

This study compared systemic hemodynamic and organ blood flow responses to equipotent concentrations of halothane and sevoflurane during spontaneous ventilation in the rat. The MAC values for halothane and sevoflurane were determined. Cardiac output and organ blood flows were measured using radiolabeled microspheres. Measurements were obtained in awake rats (control values) and at 1.0 MAC halothane or sevoflurane. The MAC values (mean +/- SEM) for halothane and sevoflurane were 1.10% +/- 0.05% and 2.40% +/- 0.05%, respectively. The PaCO2 increased to a similar extent in both groups compared with control values. During halothane anesthesia, heart rate decreased by 12% (P < 0.01), cardiac index by 26% (P < 0.01), and mean arterial blood pressure by 18% (P < 0.01) compared with control values. Stroke volume index and systemic vascular resistance did not change. During sevoflurane anesthesia, hemodynamic variables remained unchanged compared with control values. Coronary blood flow decreased by 21% (P < 0.01) and renal blood flow by 18% (P < 0.01) at 1.0 MAC halothane, whereas both remained unchanged at 1.0 MAC sevoflurane. Cerebral blood flow increased to a greater extent with halothane (63%; P < 0.01) than with sevoflurane (35%; P < 0.05). During halothane anesthesia, hepatic arterial blood flow increased by 48% (P < 0.01), whereas portal tributary blood flow decreased by 28% (P < 0.01). During sevoflurane anesthesia, hepatic arterial blood flow increased by 70% (P < 0.01) without a concomitant reduction in portal tributary blood flow. Total liver blood flow decreased only with halothane (16%; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Inhalation↗
PubMed1994

Halothane sensitivity in replicate mouse lines selected for diazepam sensitivity or resistance.

We have previously shown that mice selected for sensitivity to diazepam are also more sensitive to halothane, and that halothane augments the gamma-aminobutyric acid (GABA)-mediated chloride flux response in brain tissue from diazepam-sensitive (DS) mice to a greater degree than in diazepam-resistant (DR) mice. These findings suggest that the GABAA receptor is an important site of halothane action. To confirm this correlation, halothane requirement was determined in two independently developed replicate lines of DS and DR mice. Association of the traits of diazepam and halothane sensitivity in replicate lines of DS mice diminishes the probability that the original finding was due to a false-positive correlation, and instead suggests that it results from the common action of genes controlling diazepam sensitivity. Halothane median effective concentration (EC50) was determined by using the end-point of loss of righting reflex in two replicate lines of mice selected for diazepam sensitivity (resistant mice = diazepam high performance-1 and -2 [DHP-1 and DHP-2], sensitive mice = diazepam low performance-1 and -2 [DLP-1 and DLP-2]). DLP-1 and DLP-2 mice were sensitive to halothane, whereas DHP-1 and DHP-2 mice were resistant to halothane. Halothane EC50 in the DLP-1 and DHP-1 mice was 0.86 +/- 0.01 (SE) and 1.10 +/- 0.04 atm%, respectively (P < 0.0001), and that in the DLP-2 and DHP-2 mice was 0.88 +/- 0.01 and 0.97 +/- 0.02 atm%, respectively (P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Respiratory reflexes in response to nasal administration of halothane to anesthetized, spontaneously breathing dogs.

OBJECTIVE: To characterize and determine the sensory innervation of respiratory reflexes elicited by nasal administration of halothane to dogs. ANIMALS: 10 healthy Beagles. PROCEDURE: Dogs underwent permanent tracheostomy and, 2 to 3 weeks later, were anesthetized with thiopental and alpha-chloralose administered IV. The nasal passages were functionally isolated so that halothane could be administered to the nasal passages while dogs were breathing 100% O2 via the tracheostomy. Respiratory reflexes in response to administration of halothane at concentrations of 1.25, 1.75, and 2.5 times the minimum alveolar concentration (MAC), and 5% (administered in 100% O2 at a flow rate of 5 L/min) were recorded. Reflexes in response to administration of 5% halothane were also recorded following transection of the infraorbital nerve, transection of the caudal nasal nerve, and nasal administration of lidocaine. RESULTS: Nasal administration of halothane induced an inhibition of breathing characterized by a dose-dependent increase in expiratory time and a resultant decrease in expired volume per unit time. Effects were noticeable immediately after the onset of halothane administration and lasted until its cessation. Reflex responses to halothane administration were attenuated by transection of the caudal nasal nerve and by nasal administration of lidocaine, but transection of the infraorbital nerve had no effect. CONCLUSIONS AND CLINICAL RELEVANCE: Nasal administration of halothane at concentrations generally used for mask induction of anesthesia induces reflex inhibition of breathing. Afferent fibers in the caudal nasal nerve appear to play an important role in the reflex inhibition of breathing induced by halothane administration.

Administration, Intranasal↗
PubMed2003

Assessment of halothane and sevoflurane anesthesia in spontaneously breathing rats.

OBJECTIVE: To characterize halothane and sevoflurane anesthesia in spontaneously breathing rats. ANIMALS: 16 healthy male Sprague-Dawley rats. PROCEDURE: 8 rats were anesthetized with halothane and 8 with sevoflurane. Minimum alveolar concentration (MAC) was determined. Variables were recorded at anesthetic concentrations of 0.8, 1.0, 1.25, and 1.5 times the MAC of halothane and 1.0, 1.25, 1.5, and 1.75 times the MAC of sevoflurane. RESULTS: Mean (+/- SEM) MAC for halothane was 1.02 +/- 0.02% and for sevoflurane was 2.99 +/- 0.19%. As sevoflurane dose increased from 1.0 to 1.75 MAC, mean arterial pressure (MAP) decreased from 103.1 +/- 5.3 to 67.9 +/- 4.6 mm Hg, and PaCO2 increased from 58.8 +/- 3.1 to 92.2 +/- 9.2 mm Hg. As halothane dose increased from 0.8 to 1.5 MAC, MAP decreased from 99 +/- 6.2 to 69.8 +/- 4.5 mm Hg, and PaCO2 increased from 59.1 +/- 2.1 to 75.9 +/- 5.2 mm Hg. Respiratory rate decreased in a dose-dependent fashion from 88.5 +/- 4.5 to 58.5 +/- 2.7 breaths/min during halothane anesthesia and from 42.3 +/- 1.8 to 30.5 +/- 4.5 breaths/min during sevoflurane anesthesia. Both groups of rats had an increase in eyelid and pupillary aperture with an increase in anesthetic dose. CONCLUSIONS AND CLINICAL RELEVANCE: An increase in PaCO2 and a decrease in MAP are clinical indicators of an increasing halothane and sevoflurane dose in unstimulated spontaneously breathing rats. Increases in eyelid aperture and pupil diameter are reliable signs of increasing depth of halothane and sevoflurane anesthesia. Decreasing respiratory rate is a clinical indicator of an increasing dose of halothane.

Anesthesia, Inhalation↗
PubMed1998

1,1,1-Trifluoro-2,2-dichloroethane (HCFC-123) and 1,1,1-trifluoro-2-bromo-2-chloroethane (halothane) cause similar biochemical effects in rats exposed by inhalation for five days.

1,1,1-Trifluoro-2,2-dichloroethane (HCFC-123) and 1,1,1-trifluoro-2-bromo-2 chloroethane (halothane) are gases with anesthetic properties. HCFC-123 is used as a refrigerant, fire extinquishing agent, and solvent, while halothane is a clinical anesthetic. Much information is available on chronic toxicity of HCFC-123 in animals, while the information available for halothane is from short-term animal exposures or chronic, low level human exposures. Thus, there is little biochemical information available on similar endpoints for these two chemicals, which share common metabolites. In the present study, male rats were exposed to 5000 ppm HCFC-123, 5000 ppm halothane, or room air for 6 hr per day for 5 consecutive days. Rats exposed to both test compounds gained little or no weight during the study. Liver weights were slightly decreased in the rats exposed to HCFC-123 and halothane compared to controls. The serum triglycerides were decreased to approximately 20% of control level in rats exposed to both HCFC-123 and halothane, and serum cholesterol was decreased to less than 80% of control by both compounds. Both test compounds increased hepatic beta-oxidation by approximately 3-fold over control, and HCFC-123 caused a significant increase in hepatic cytochrome P450 content, while the increase in cytochrome P450 was not statistically significant in the halothane-treated rats. The results indicate that HCFC-123 and halothane share not only common metabolic pathways, but also several common biological effects, specifically those associated with peroxisome proliferation. These data indicate that human experience with halothane may be useful in the risk assessment of HCFC-123.

Administration, Inhalation↗
PubMed2005

Ca2+ cytochemical changes of hepatotoxicity caused by halothane and sevoflurane in enzyme-induced hypoxic rats.

AIM: To investigate the relation between hepatotoxicity of halothane and sevoflurane and altered hepatic calcium homeostasis in enzyme-induced hypoxic rats. METHODS: Forty-eight rats were pretreated with phenobarbital and randomly divided into six groups (eight in each group) and exposed to O(2)/ N(2)/1.2 MAC anesthetics for 1 h: normal control (NC), 21% O(2)/79% N(2); hypoxic control (HC), 14% O(2)/86%N(2); normal sevoflurane (NS), 21% O(2)/ N(2)/1.2MAC sevoflurane; hypoxic sevoflurane (HS), 14% O(2)/ N(2)/1.2MAC sevoflurane; normal halothane (NH)21%O(2)/79%N(2)/1.2MAC halothane; hypoxic halothane (HH), 14% O(2)/N(2)/1.2MAC halothane. Liver specimens and blood were taken 24 h after exposure to calcium and determined by EDX microanalysis. RESULTS: The liver of all rats given halothane (14% O(2)) had extensive centrilobular necrosis and denaturation. Morphologic damage was accompanied with an increase in serum glutamic pyruvic transminase. In groups NH and HH, more calcium was precipitated in cytoplasm and mitochondria. CONCLUSION: These results suggest that halothane increases cytosolic Ca(2+) concentration in hepatocytes. Elevation in Ca(2+) concentration is implicated in the mechanism of halothane-induced hepatotoxicity. sevoflurane is less effective in affecting hepatic calcium homeostasis than halothane.

Alanine Transaminase↗
PubMed1999

Halothane attenuates nitroglycerin-induced vasodilation and a decrease in intracellular Ca2+ in the rat thoracic aorta.

UNLABELLED: Although halothane inhibits endothelium-mediated vasorelaxation, the sites of inhibition remain controversial. Because the cytosolic concentration of Ca2+ ([Ca2+]i) has crucial roles for tension development, we examined the effects of halothane on nitroglycerin-induced vasorelaxation from the standpoint of [Ca2+]i. Isolated spiral strips of rat thoracic aorta without endothelium were suspended for isometric tension recordings in a physiologic salt solution. Muscle contraction was evoked with 10(-8) M norepinephrine, followed by endothelium-independent vasorelaxation with nitroglycerin 10(-7) and 10(-6) M. The effects of halothane 1.5% and 3% on nitroglycerin-induced vasorelaxation were evaluated along with the concomitant measurement of [Ca2+]i using fura-2-Ca2+ fluorescence. In other muscle strips, incremental doses of norepinephrine were administered during halothane exposure to induce contractions comparable to those without halothane. Nitroglycerin dose-dependently reduced norepinephrine-induced muscle contractions, but the decrease in [Ca2+]i reached a plateau at 10(-7) M, which indicates that nitroglycerin induced [Ca2+]i-dependent and [Ca2+]i-independent vasorelaxation. Both concentrations of halothane inhibited nitroglycerin-induced decreases in muscle tension and [Ca2+]i, not only when the same dose of norepinephrine was used for contraction during halothane exposure, but also at incremental doses of norepinephrine. In conclusion, halothane inhibits nitroglycerin-induced vasorelaxation partly by suppressing Ca2+ changes in the smooth muscle. IMPLICATIONS: We examined nitroglycerin-induced vasorelaxation in the rat thoracic aorta, along with the concomitant measurement of the cytosolic concentrations of Ca2+, and found that halothane attenuated endothelium-independent vasorelaxation by suppressing Ca2+ dynamics in the smooth muscle.

Anesthetics, Inhalation↗
PubMed1975

[Swelling and loss of potassium in perfused livers following the influence of the vapours of carbon tetrachloride, chloroform and halothane on the perfusion medium (author's transl)].

Erythrocyte free perfused rat livers were treated with vaporous carbon tetrachloride, chloroform and halothane by equilibration in the oxygenator system. The potassium loss, the amount of swelling and the alteration of the perfusion rates were measured during the experiments as criteria of acute toxicity. In contrast to the well known behaviour of perfused livers during the intoxication with phalloidin the amount of liver swelling did not marekdly depend on the perfusion rates in acute CCl(4) poisoning. The mechanism of swelling must be different in both intoxications. Exposure of perfused livers to high concentrations of CCl(4) for several minutes only produced a marked K-+-loss within a short time. This injury could not be fully compensated after finishing the exposure. Dose response diagrams are presented for carbon tetrachloride, chloroform and halothane by use of the following criteria: potassium loss, swelling (increase of wet weight) and perfusion rates (ml.min-1.g-1). As total doses the amounts of solutes vaporized during the exposition were listed. In these diagrams chloroform appears to be more toxic than halothane. CCl4 occupies a middle position between chloroform and halothane. The course of dose response diagrams of halothane is different from those of CCl(4) and CHCl(3). The halothane diagrams increase critically at high doses, whereas the courves for CCl(4) and CHCl(3) rise continuously. With respect to effects on the hepatic microcirculation halothane seems to be less toxic than CCl(4). The results are discussed on the basis of the periods of exposition and the maximal concentrations of the solutes in the perfusion medium. With respect to these data CCl(4) is much more toxic than CHCl(3) and halothane. On the other hand there is no marked difference in acute hepatotoxicity between CHCl(3) and halothane.

Acute Disease↗
PubMed1975

[The effects of combining halothane and neuroleptanalgesia on the preganglionic sympathetic activity, the respiratory centre and the circulation (author's transl)].

The effects of Halothane, Fentanyl and droperidol in combination on the circulatory system, the preganglionic sympathetic nerve activity and the respiratory centre were examined in 21 experiments carried out on cats which were relaxed and artificially ventilated with nitrous oxide in oxygen. The results showed that even the minimal dosage of 0.5 vol-% Halothane combined with 0.0042 mg/kg Fentanyl and 0.15 mg/kg droperiodol led to a significant decrease of blood pressure and a depression of the sympathetic and phrenic nerve activity both in rest and in stress during asphyxia. A dosage of 1 vol-% Halothane produced a significant increase in the above mentioned effects when at rest, while the doubled dosage of Fentanyl and droperidol combined with the original Halothane dosage of 0.5 vol-% produced no marked increase in its effects. A comparison of these results with those of previous experiments using only the inhalation of Halothane shows that an anaesthesia consisting of 0.5 vol-% Halothane combined with Fentanyl and droperidol has virtually equal effects on the decrease of blood pressure and on the depression of central sympathetic nerve activity as the inhalation of 1 vol-% Halothane alone. Using a combination of 1 vol-% Halothane, Fentanyl and droperidol the effects induced by 2 vol-% Halothane are reached.

Animals↗
PubMed1992

Free radical metabolism of halothane in vivo: radical adducts detected in bile.

Two radical adduct species have been detected in the bile of living rats treated with halothane and phenyl-N-t-butylnitrone (PBN). The treatment of rats with 12% oxygen was required for radical adduct detection. Analysis of the corresponding EPR spectra obtained when deuterated PBN and deuterated halothane or [2-13C]halothane was used shows that these two species result from the spin trapping of two halothane-derived free radicals. Coupling constants were aN = 15.72 G, a beta H = 2.09 G, a gamma H = 0.79 G, and aF = 0.63 G(3F) and aN = 15.16 G, a beta H = 4.14 G, a gamma H = 0.48 G, and aF = 0.3 G(3F) for the two species. Two radical adducts with similar coupling constants were detected when halothane was reduced by zinc dust in the presence of PBN, suggesting that the formation of these two distinct species from halothane can be attributed to the one-electron reduction of halothane and the formation of diastereomeric radical adducts. The identification of both radical adducts as halothane-derived species indicates that there is no in vivo EPR evidence for lipid radical formation during halothane intoxication, as had previously been reported.

Animals↗
PubMed1992

Atypical reactions to halothane in a subgroup of homozygous malignant hyperthermia(MH)-susceptible pigs: indication of a heterogenous genetic basis for the porcine syndrome.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle. In genetically susceptible pigs, MH can be induced by volatile, halogenated anaesthetics such as halothane. Within a series of pharmacological investigations, a fulminant MH could be induced in 59 of 66 homozygous halothane-susceptible pigs by a challenge with 3% halothane for 15 minutes. The typical MH was characterized by sudden appearance of tachycardia, muscle rigidity with typical extension of the hindlimbs, increase of body temperature, acidosis-caused by rapid increase of CO2 and lactate production-, hyperkalaemia and increased activity of creatine kinase (CK) and aspartate transaminase (AST). In seven homozygous MH-susceptible pigs, this typical MH could not be induced by halothane. These animals responded with sudden appearance of bradyarrhythmia and decrease of arterial pressure. In these MH-atypical pigs (MHA) neither the typical extension of hindlimbs nor a hyperthermia occurred. Compared to a group of 6 MH-susceptible pigs with typical reactions to halothane (MHS), the biochemical alterations were significantly retarded in MHA-pigs. These atypical reactions to halothane could be the effect of decreased cardiac output. Concerning the atypical reactions, we observed a familiar predisposition in MH-susceptible pigs. Although atypical reactions were not found in a group of homozygous halothane-nonsusceptible pigs (MHN), a possible explanation for atypical reactions could be a MH-independent halothane-susceptibility of the myocardium+ in MHA-pigs. On the other side the data may indicate that a primary defect in both the skeletal muscle and also the myocardium is involved in MH. The different reactions to halothane in MH-susceptible pigs could point to a genetic heterogeneity.

Animals↗
PubMed1991

Halothane inhibits agonist-induced inositol phosphate and Ca2+ signaling in A7r5 cultured vascular smooth muscle cells.

Halothane, an anesthetic with marked depressant effects on the circulation, was studied for its ability to inhibit inositol phosphate and Ca2+ signaling evoked by the vasoactive hormone arginine vasopressin (AVP) and Ca2+ responses elicited by platelet-derived growth factor and by thapsigargin in cultured A7r5 vascular smooth muscle cells. Changes in apparent [Ca2+]i were measured using the indicator indo-1 and flow cytometry, whereas inositol phosphate levels were determined using myo-[3H]inositol and column chromatography. Preincubation with clinically relevant concentrations of halothane resulted in dose-dependent depression of [Ca2+]i responses evoked on stimulation with AVP. Halothane (2.0%) inhibited the increases in [Ca2+]i by 34-45%. In cells incubated in Ca(2+)-free medium plus 0.5 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, the halothane effect was more marked, with 1.5% halothane inhibiting the responses by approximately 53-61%. However, when Ca2+ influx was stimulated by addition of 5 mM Ca2+ in the continued presence of the agonist, the [Ca2+]i response was inhibited by only 15%, suggesting that release of Ca2+ rather than Ca2+ influx is more sensitive to inhibition by the anesthetic. The effects of halothane on Ca2+ homeostasis are not explained solely by anesthetic-induced depletion of Ca2+ from intracellular stores, because the anesthetic inhibited increases in [Ca2+]i elicited by thapsigargin in cells suspended in Ca(2+)-free medium by only 31%. Halothane inhibited inositol phosphate formation elicited by AVP, suggesting an additional means by which the anesthetic may alter agonist-induced Ca2+ responses. The current results also demonstrate that halothane actions are not specific solely to responses evoked by AVP, which acts via a guanine nucleotide-binding protein-linked signaling pathway, but include responses stimulated by platelet-derived growth factor, an agonist that elevates [Ca2+]i via receptor-latent tyrosine kinase activity. The current results demonstrate that, in vascular smooth muscle cells, halothane alters Ca2+ homeostasis, an action that may underlie the in vivo vasodilator effects of the anesthetic.

Animals↗
PubMed1991

Effects of halothane in low concentrations on cerebral blood flow, cerebral metabolism, and cerebrovascular autoregulation in the baboon.

Halothane in anesthetic concentrations causes cerebral vasodilatation and decreases cerebral oxygen consumption (CMRO2). The purpose of this study was to evaluate cerebral blood flow (CBF) and CMRO2 changes associated with low concentrations of halothane. In eight normoventilated baboons with background anesthesia maintained with phencyclidine and nitrous oxide, CBF and CMRO2 were studied during the administration of end-tidal concentrations of halothane (0.125, 0.25, 0.375, 0.5, 0.75, and 1.0 vol%). Arterial blood pressure was supported by an infusion of angiotension II amide at 0.75 and 1.0 vol% of halothane to maintain an adequate cerebral perfusion pressure. In addition, cerebrovascular autoregulation was tested before and during the administration of 0.375, 0.75, and 1.0 vol% of halothane. Cerebrovascular autoregulation was assessed by observing the response of CBF to an acute increase in mean arterial pressure produced by angiotensin. CMRO2 decreased as the concentration of halothane was increased. At low halothane concentrations (0.125-0.375 vol%), CBF decreased; however, at concentrations above 0.375 vol%, CBF increased with a decrease in cerebrovascular resistance. Autoregulation was intact during 0.375 vol% of halothane, but with 0.75 and 1.0 vol% of halothane, CBF was passively dependent on cerebral perfusion pressure, suggesting impaired autoregulation.

Animals↗
PubMed1978

Transcutaneous oxygen tension measurement II. The influence of halothane and hypotension.

The influence of halothane-oxygen mixtures on three different transcutaneous oxygen electrodes was investigated. The influence of hypotension caused by halothane and halothane-nitroprusside on transcutaneous oxygen tension measurement (tcPO2) in halothane-anaesthetized patients was examined as well. The electrodes differed with respect to polarization voltages (630 mV or 500 mV) and electrolyte composition (silver chloride or silver bromide). A change dependent on halothane concentration was demonstrated in the electrode readings, both with a polarization voltage of 630 mV and with silver bromide as electrolyte. Using an electrode with 500 mV in polarization voltage and silver chloride as electrolyte, no changes were observed in the readings. During induced hypotension, the tcPO2 values fell in proportion to the mean arterial blood pressure. In patients with a mean arterial blood pressure over 11kPa a tcPO2/PaO2 ratio of 0.6 was found. It is concluded that tcPO2 monitoring during halothane anaesthesia can be influenced in at least two ways, apart from changes in PaO2: (1) by oxygen electrode error due to the halothane; and (2) by changes in skin blood flow. In comparison to the changes in tcPO2 due to the haemodynamic effects of halothane anaesthesia, the changes due to halothane error are small.

Anesthesia, Inhalation↗
PubMed1986

Effect of halothane on myocardial cyclic AMP and cyclic GMP content of mice.

Halothane, in anesthetic concentrations (0.6-1.8 volumes/100 ml), produced a dose-dependent decrease in myocardial cyclic AMP (cAMP) content and an increase in cyclic GMP (cGMP) content in mice exposed to a continuous flow of the anesthetic carried in air for 15 min. Atropine (up to 20 mg/kg i.p.) did not alter significantly the myocardial cyclic nucleotides content or the effect of halothane on cAMP and cGMP content. Prazosin and yohimbine had no significant effect on cAMP or cGMP content in the absence of halothane. Both alpha adrenergic antagonists inhibited the halothane-induced increase in cGMP content (ID50, 0.24 and 0.54 mumol/kg i.p. for prazosin and yohimbine, respectively). In contrast, the decrease in cAMP content induced by halothane was not altered by alpha adrenergic antagonists. Propranolol (2 mg/kg i.p.) diminished myocardial cAMP level and prevented the halothane effect on myocardial cAMP content. Pretreatment with 6-hydroxydopamine did not change the cGMP response to halothane. Thus, the action of halothane on myocardial cyclic nucleotides content appears to be predominantly a peripheral effect, not related to cellular mechanisms mediated by muscarinic receptors. The results suggest that the increase in cGMP content induced by halothane does not require intact adrenergic nerve endings and that cellular processes associated with the alpha adrenoceptor system may be involved; the decrease in cAMP content may be due to an inhibition of the beta stimulatory action of catecholamines on adenylate cyclase.

Adrenergic alpha-Antagonists↗
PubMed1987

Absence of beta-adrenergic receptor involvement in cerebrovascular dilation by halothane in monkeys.

We determined, in monkeys, whether halothane-induced cerebrovascular dilation is mediated by beta-adrenergic receptors and whether cerebrovascular tone progressively returns to baseline values during prolonged halothane anesthesia. Total cerebral blood flow (CBF), cerebral perfusion pressure, plasma halothane concentration, and arterial blood gas tensions and pH were measured in 14 rhesus monkeys mechanically ventilated with 0.5% (inspired) halothane, 33% O2 and balance N2O. Halothane was increased to 2.0% and the measurements repeated 30 and 60 min later. Then either 0.9% NaCl (controls n = 6) or propranolol (n = 8), 1.0 mg/kg was infused intravenously over 10 min, and the measurements repeated at 70, 90, 120, and 150 min. After 30 min at 2.0% halothane, CBF increased in the controls by 50% (P less than 0.05) from 92 +/- 8 (mean +/- SD) to 137 +/- 39 ml X 100 g-1 X min-1 and in the propranolol group by 30% (P less than 0.05) from 106 +/- 33 to 137 +/- 28 ml X 100 g-1 X min-1. After 2.5 hr of 2.0% halothane anesthesia, CBF remained elevated above baseline levels, but by only 28 and 23% in the control and propranolol groups, respectively. Cerebrovascular resistance was identical in both groups (0.55 +/- 0.33 vs 0.53 +/- 0.13 mm Hg X ml-1 X 100 g 1 X min 1). The results show that there is only a 10-20% return of CBF toward baseline levels after up to 2.5 hr of 2% halothane anesthesia. The results also indicate that halothane-induced cerebrovascular dilation is not mediated by beta-adrenergic receptors.

Animals↗
PubMed1988

Halothane-induced liver injury as a consequence of enhanced microsomal lipid peroxidation in guinea pigs.

We investigated the role of microsomal lipid peroxidation in halothane hepatotoxicity in guinea pigs. Animals were exposed to halothane, isoflurane or enflurane. Enhancement of microsomal lipid peroxidation was specific to halothane. The time-course of lipid peroxidation and hepatic damage following a single exposure to halothane was investigated by measuring the thiobarbituric acid (TBA)reactive products, serum transaminase activity, reduced glutathione (GSH) concentration and histopathological examination. Microsomal lipid peroxidation was enhanced most rapidly and preceded GSH depletion and hepatic injury. Metyrapone, an inhibitor of cytochrome P-450, and N-tert-butyl-alpha-phenylnitrone (BPN), a radical trapping agent, inhibited halothane-induced lipid peroxidation and the incidence and severity of liver injury. The metabolism of halothane was considered to be inhibited by metyrapone and the reactivity of radical intermediates was considered to be decreased by BPN. Microsomal lipid peroxidation was initiated by radical metabolites of halothane but did not result from GSH depletion. Inhibition of microsomal lipid peroxidation reduced the halothane hepatotoxicity. These results demonstrated that the halothane-induced liver injury was caused by microsomal lipid peroxidation in guinea pigs.

Administration, Inhalation↗