Antagonism Of Anesthesia Research Articles

Synthesis and Characterization of a Diazirine-Based Photolabel of the Nonanesthetic Fropofol.

The mechanisms of general anesthetics have been debated in the literature for many years and continue to be of great interest. As anesthetic molecules are notoriously difficult to study due to their low binding affinities and multitude of binding partners, it is advantageous to have additional tools to study these interactions. Fropofol is a hydroxyl to fluorine-substituted propofol analogue that is able to antagonize the actions of propofol. Understanding fropofol's ability to antagonize propofol would facilitate further characterization of the binding interactions of propofol that may contribute to its anesthetic actions. However, the study of fropofol's molecular interactions has many of the same difficulties as its parent compound. Here, we present the synthesis and characterization of ortho-azi-fropofol (AziFo) as a suitable photoaffinity label (PAL) of fropofol that can be used to covalently label proteins of interest to characterize fropofol's binding interactions and their contribution to general anesthetic antagonism.

The Effect of Repetitive Intraperitoneal Anesthesia by Application of Fentanyl-Medetomidine and Midazolam in Laboratory Rats

ABSTRACTBackground: Literature reviews show numerous options for anesthesia in the small laboratory animals. Many methods are associated with complications, such as high technical effort, difficult monitoring, respiratory and cardiovascular depression, and prolonged sedation. In the present study, we report first time results after repeated use of an intraperitoneal combined anesthesia with a high tolerability. Methods: Three hundred and seventy-four anesthesias were performed on 38 adult male lewis rats (280–460g). Each animal was anesthetized repeatedly over a period of three months, using an intraperitoneal combination of Fentanyl-Medetomidine and Midazolam (FMM). The time required for the animals to lose ear pinch response and the ability to perform a righting and pedal withdrawal reflex was measured. For evaluation of the clinical state, a four-point vitality scale was developed. The anesthesia was antagonized with Naloxone, Flumazenil, and Atipamezole (s.c.). Results: The animals lost all three reflex responses within 5 (± 2.4) min of injection. Without antagonism of anesthesia, the ear pinch response returned on average within 125 (± 21.5) min. After antagonism of anesthesia, the rats needed 5 (± 2.9) min to regain all three reflex responses. No significant differences of vitality-index were measured after repeated use of FMM during the investigation period. Conclusions: A repeatable and secure anesthesia is indispensable for any experimental studies that require multiple anesthesia of a single animal. Intraperitoneal combination of FMM provides an adequate procedure to induce a well tolerable, repeatable state of anesthesia, which conforms to all the necessary requirements for laboratory rats.

Evaluation of Medetomidine–Ketamine–Butorphanol Anesthesia with Atipamezole–Naltrexone Antagonism in Captive Male Guanacos (Lama guanicoe)

Seven captive adult male guanacos (Lama guanicoe) weighing 112.0 +/- 10.9 kg (mean +/- standard deviation) were anesthetized with a combination of medetomidine (90.0 +/- 8.8 microg/kg), ketamine (2.7 +/- 0.3 mg/kg), and butorphanol (0.3 +/- 0.03 mg/kg) administered intramuscularly to evaluate its anesthetic and cardiopulmonary effects. Inductions were smooth and rapid, with a mean time to initial effect of 3 +/- 1.5 min and a mean time to recumbency of 5.1 +/- 3.1 min. Anesthesia was predictable, smooth, and characterized by excellent muscle relaxation. Spontaneous ventilation was maintained throughout anesthesia in all animals. Marked bradycardia ranging from 24 to 52 beats/min was noted across all time points for all individuals. Median heart rates decreased during the procedures, but median heart rate, temperature, respiratory rate, and end-tidal carbon dioxide values over the 20 min monitoring period were not significantly different. Mean arterial partial pressure of oxygen (PaO2) on initial sampling was 65.9 +/- 14.8 mm Hg, with six of seven animals exhibiting hypoxemia (PaO2 <80 mm Hg). After oxygen supplementation for 20 min, mean PaO2 values showed statistically significant increases to a mean value of 127.7 +/- 32.4 mm Hg (P = 0.0014). Mean arterial partial pressure of carbon dioxide (PaCO2) showed a significant increase over the monitoring period (P = 0.0004), and mild hypoventilation (PaCO2 >45 mm Hg) was noted in four animals. Mean total duration of procedure time was 23.3 +/- 3.3 min. All guanacos received 0.45 +/- 0.04 mg/kg atipamezole and 2.7 +/- 0.25 mg/kg naltrexone administered intramuscularly for anesthetic antagonism. Recoveries were smooth and uncomplicated. Mean time to sternal recumbency after antagonist administration was 7.7 +/- 4.5 min, and time to successful standing was 12.9 +/- 5.0 min, with all animals standing on first attempt.

Comparison of three anaesthetic protocols in Bennett's wallabies (Macropus rufogriseus)

ObjectiveInvestigate physiological and sedative/anaesthetic effects of xylazine, medetomidine or dexmedetomidine combined with ketamine in free-ranging Bennett's wallabies. Study designProspective clinical trial. AnimalsTwenty-six adult free-ranging Bennett's wallabies. MethodsAnimals were darted intramuscularly with one of three treatments: xylazine and ketamine, 2.0 and 15.0 mg kg−1, respectively (XK): medetomidine and ketamine 0.1 and 5.0 mg kg−1 (MK) and dexmedetomidine and ketamine 0.05 and 5.0 mg kg−1 (DMK). Body weights were estimated. If the animal was still laterally recumbent after 45 minutes of anaesthesia, then an alpha-2 adrenoceptor antagonist, atipamezole, was administered (XK: 0.4 mg kg−1, MK: 5 mg kg−1, DMK: 2.5 mg kg−1). Heart rate (HR) and respiratory rate (fR) were recorded at 5-minute intervals and temperature at 10-minute intervals. Venous blood was taken 30 minutes after initial injection. Statistical analysis utilized anova. p < 0.05 was considered significant. ResultsAnimals became recumbent rapidly in all groups. XK animals had muscle twitches, responded to external stimuli, and three animals required additional dosing; this was not observed in the MK and DMK groups. HR (mean ± SD beats minute−1) in XK (81 ± 4) was significantly higher than MK (74 ± 2) and DMK (67 ± 4). There were no differences in fR, temperature, blood-gas and biochemical values between groups. More animals in MK (9/10) and DMK (5/6) needed antagonism of anaesthesia compared with XK (1/10). There were no adverse effects after anaesthesia. Conclusion and clinical relevanceCardio-respiratory effects were similar in all groups. There were fewer muscle twitches and reactions to external stimuli in MK and DMK. Duration of anaesthesia was shorter in XK; most animals in MK and DMK needed atipamezole to assist recovery. All three treatments provided satisfactory sedation/anaesthesia and are suitable for use in Bennett's wallabies.

Use of Tolazoline Hydrochloride to Reverse Multiple Anesthetic Episodes Induced with Xylazine Hydrochloride and Ketamine Hydrochloride in White-Tailed Deer and Goats

Two white-tailed deer (Odocoileus virginianus) fawns and two domestic (alpine) goat (Capra hircus) kids were subjected to multiple anesthetic episodes at weekly intervals for the purpose of cerebrospinal fluid and blood collection. Anesthesia was induced by intramuscular injection of xylazine HC1 (mean dosage 0.35 mg/kg, range 0.1-0.62 mg/kg) and ketamine HC1 (mean dosage 2.92 mg/kg, range 1.65-6.2 mg/kg). Anesthesia was reversed by intravenous injection of tolazoline HC1 (mean dosage 2.1 mg/kg, range 1.4-2.7 mg/kg). Antagonism of anesthesia with tolazoline resulted in the animals regaining sternal recumbency in mean times of <7 min postreversal. They regained ambulatory abilities in mean times of 10.9 and 16.8 min for the deer and the goats, respectively. Significant increases in the heart rates of all animals 2 min postreversal and significant differences in the respiratory rates postreversal were observed. A minimum of 12 successive episodes produced no clinical, s?rologie, or histopathologic evidence of drug-induced renal toxicity.

Thermodynamics of pressure—anesthetic antagonism on the phase transition of lipid membranes: Displacement of anesthetic molecules

From the depression of the phase-transition temperature of dipalmitoylphosphatidylcholine vesicle membranes by inhalation anesthetics (halothane, methoxyflurane, enflurane, and chloroform), the apparent partition coefficient, K app, of these drugs between the lipid membrane and water was estimated and the effect of hydrostatic pressure upon the partition was examined. By assuming nonzero partition of anesthetics into the solid-gel membrane, K app is defined as (1 - k) K, where K is the partition coefficient between the liquid-crystalline membrane and water, and k is the partition coefficient between the liquid-crystalline membrane and the solid-gel membrane. The value of K app was little affected by the change of temperature but was significantly decreased by the high pressure. The high pressure squeezed out the anesthetic molecules from the liquid-crystalline membrane, as evidenced by the decrease of the partition coefficient. The decrement of the number of the anesthetic molecules from that adsorbed at ambient pressure was halothane 10.4 × 10 −2, chloroform 6.42 × 10 −2, enflurane 9.58 × 10 −2, and methoxyflurane 8.45 × 10 −2% per 1 bar. The volume change due to the transfer of anesthetics from the aqueous phase to the lipid membrane, calculated from the pressure dependence of the apparent partition coefficient, was found to show a large positive value of about 15% of their molal volume. The magnitude of the volume increase is rather large and is difficult to ascribe to the breakage of anesthetic-water contact alone. The volume increase may be caused by the following factors: the structural change of the membrane, the change of the interaction forces between membrane and water due to anesthetic adsorption, the change of interaction between the anesthetics and water, etc. The positive sign indicates that anesthetics must be translocated from the lipid membrane into the aqueous phase by high pressure. Although pressure reversal of anesthesia may be caused mainly by restoration of order in the membrane and by enhancement of the cooperativity of the phase transition, displacement of anesthetics from the binding sites may also contribute to the phenomenon.

Anesthetic antagonism of the effects of high hydrostatic pressure on locomotory activity of the brine shrimp Artemia

1. 1. The locomotory activity of small groups of brine shrimp ( Artemia salina) was studied under conditions of high hydrostatic pressure, varying temperatures and exposure to several gaseous anesthetics. 2. 2. Both compression and exposure to anesthesia reduced the animal's swimming activity, while temperature increased or decreased activity as it was raised or lowered from ambient. 3. 3. The effect of the anesthetics was less during periods of simultaneous exposure to high hydrostatic pressure. 4. 4. It is concluded that pressure antagonism of anesthesia is demonstrable in invertebrate organisms and may represent a fundamental interaction of these parameters in biological systems.

A reevaluation of calcium-local anesthetic antagonism

Although it has been shown that Ca 2+ can inhibit the conduction blocking action of local anesthetic agents in lobster peripheral nerve, it is not known whether Ca 2+ directly competes for anionic membrane sites or indirectly alters the drug-membrane interaction. The present experiments were carried out during a sufficiently long time course to determine whether the blocking action of lidocaine, procaine, or tetracaine was reduced by Ca 2+ or whether Ca 2+ only delayed the onset of local anesthesia. Lidocaine HCl (5 m m) reduced the amplitude of the compound action potential by 50% in 10 min in low-Ca 2+ (5 m m) lobster physiologic saline, whereas in high-Ca 2+ (75 m m) saline, 5 m m lidocaine reduced the action potential amplitude 50% only after 25 min external bath perfusion. Similar results were seen with 2 m m procaine and 0.2 m m tetracaine. The data confirm the suggestion that Ca 2+ merely slows the passage of local anesthetic agents across glial membranes and are not compatible with a model that describes competition of Ca 2+ and local anesthetic agents for a specific binding site in nerve membranes.

Nonlinear antagonism of anesthesia in mice by pressure.

Previous studies have shown a rectilinear antagonism by pressure of nitrous oxide or isoflurane anesthesia in mice (pressure reversal). Since a rectilinear pressure reversal is predicted by the critical volume hypothesis for anesthesia, we examined this phenomenon with two other gases. We measured the doses of argon or nitrogen which abolished the righting reflex in 50% of animals (ED50) at various high pressures produced by the addition of helium. The ED50 values of argon and nitrogen alone are 16.7 +/- 1.37 and 38.3 +/- 1.62 atmospheres absolute (ATA). Fifty-five percent more argon and 27% more nitrogen is needed to produce anesthesia at 100 ATA. However the increasing anesthetic requirements with pressure were curvilinearly related to pressure, rising most steeply at pressures near the ED50 without helium. This suggests that the pressure reversal of anesthesia is not simply a reciprocal anesthetic expansion-pressure compression phenomenon as predicted by the critical volume hypothesis. It suggests that anesthetics and pressure act at different sites.

Molecular mechanism of inhibition of firefly luminescence by local anesthetics.

The kinetics of the action of local anesthetics upon firefly luciferin and luciferase systems is presented. Clinical concentrations of local anesthetics inhibited this ATP-induced luminescence in a dose-dependent manner. From the effects of temperature and pH upon the inhibitory action of the local anesthetics, it is concluded that hydrophobic ligand-enzyme interaction is the predominant cause of the inhibition, but hydrophilic interaction also contributes to the inhibition to a lesser degree. A molecular theory of anesthesia is outlined which postulates that release of electrostricted water molecules from the hydrophilic parts of the enzyme due to the protein conformational changes induced by anesthetics is the cause of the decreased luminescence. A similar mechanism is expected to occur at the cell membrane, which probably dehydrates the sodium channel and suppresses the conductance of this ion across the membrane. These events lead to a volume expansion of the total system, and the system becomes reactive to a pressure which reverses the anesthesia by shifting the equilibrium to the nonanesthetized original volume. The pressure antagonism of anesthesia can be explained by this overall volume expansion and not by a mere swelling of the cell membrane.