bluuebunny/crossref_metadata_2025_split huggingface dataset:
Halothane and Isoflurane Alter the Calcium sup 2+ Binding Properties of Calmodulin
Authors: Levin Aaron , Blanck Thomas J. J. 
Published: November 2003

Background
Ca2+ plays an important role in signal transduction and anesthetic mechanisms. To date, no one has observed a direct effect of volatile anesthetics on a Ca(2+)-binding protein. We therefore examined the effects of halothane and isoflurane on the Ca(2+)-binding properties of bovine brain calmodulin.

Methods
The fluorescence emission of calmodulin was obtained over a range of Ca2+ concentrations (10(-7)-10(-4)M) in the presence and absence of halothane and isoflurane. The intrinsic tyrosine fluorescence of calmodulin was measured at an excitation wavelength of 280 nm and an emission wavelength of 320 nm. Fluorescence measurements were carried out in 50 mM hydroxyethylpiperazineethane sulfonic acid, 100 mM KC1, and 2 mM ethyleneglycol-bis-(beta-aminoethyl ether) tetraacetic acid at pH 7.0 and 37 degrees C. Experiments were performed in polytetrafluorethylene-sealed cuvettes so that the volatile anesthetic concentrations remained constant. The titration data were analyzed in two ways. The data were fit to the Hill equation by using nonlinear regression analysis to derive the Hill coefficient and the dissociation constant. The data were also analyzed by two-way analysis of variance with multiple comparisons to determine statistically significant effects. Volatile anesthetic concentrations were measured by gas chromatography.

Results
The presence of volatile anesthetics altered the Ca(2+)-binding affinity of calmodulin in a dose-dependent fashion. At 0.57% (0.25 mM) halothane and 1.7% (0.66 mM) isoflurane, the affinity of calmodulin for Ca2+ relative to control was decreased. However, at higher concentrations of both anesthetics, the affinity for Ca2+ was increased. When the volatile anesthetics were allowed to evaporate from the experimental solutions, the observed rightward shift of the calmodulin-Ca2+ binding curve for Ca2+ at low concentrations of the anesthetics returned to the control position. The leftward shift seen at high concentrations of the anesthetics was irreversible after evaporation of 8.7% (3.3 mM) isoflurane and 5.7% (2.5 mM) halothane.

Conclusions
These data demonstrate a complex interaction of two hydrophobic volatile anesthetics with calmodulin. A biphasic effect was observed both for halothane and for isoflurane. Calmodulin, an EF-hand Ca(2+)-binding protein, undergoes a conformational shift when binding Ca2+, exposing several hydrophobic residues. These residues may be sites at which the anesthetics act.
The Changing Pharmacodynamics of Metocurine Identify the Onset and Offset of Canine Gastrocnemius Disuse Atrophy
Authors: Fung D. L. , White D. A. , Gronert G. A. , Disbrow E. 
Published: November 2003

Background
Immobilization of skeletal muscle results in disuse atrophy and resistance to nondepolarizing muscle relaxants. We studied the pharmacodynamics of metocurine (MTC) to identify the development and recovery of disuse-related resistance to MTC.

Methods
Nineteen dogs underwent cast immobilization of a hind limb for as long as 3 weeks. Before, during, and after casting, dogs were intermittently anesthetized with thiamylal-N2O-fentanyl. The blood concentration of MTC and the corresponding degree of paralysis after a brief infusion were recorded and were used to characterize the pharmacokinetics and pharmacodynamics of MTC.

Results
Pharmacodynamic study of the response to MTC demonstrated resistance by the 4th day of casting. The effect-site concentration associated with 50% paralysis of twitch increased after 3 weeks from approximately 250 to 750 ng/ml. After cast removal, resistance persisted for 2 more weeks. Six weeks after cast removal, the effect-site concentration associated with 50% paralysis of twitch was normal in every dog.

Conclusions
Within the context of this study of immobilization disuse atrophy, pharmacokinetic and pharmacodynamic characterization of antagonist responses can be used to infer muscle disuse-related changes in acetylcholine receptors.
Effect of Continuous Arteriovenous Hemofiltration Combined with Systemic Vasopressor Therapy on Depressed Left Ventricular Contractility and Tissue Oxygen Delivery in Canine Escherichia coli Sepsis
Authors: Mink S. N. , Jha P. , Wang R. , Yang J. , Bose D. , Jacobs H. , Light R. B. 
Published: November 2003

Background
In a previous study, we showed that continuous arteriovenous hemofiltration (CAVH) reversed the depression in left ventricular (LV) contractility in canine Escherichia coli sepsis by the removal of a circulating substance the molecular weight of which is less than 30,000. Despite the normalization of LV contractility, however, we were unable to demonstrate an improvement in systemic arterial blood pressure (BP), presumably because the mechanisms underlying the depression in LV contractility and the decrease in BP are different in sepsis. In the current study, we examined the effect of combined treatment with CAVH and the alpha-adrenergic agonist phenylephrine on LV mechanics and tissue oxygen delivery in our canine E. coli model.

Methods
Measurements were obtained at baseline (condition B), after 4 h of sepsis (condition S), and after 2 h of CAVH and phenylephrine (condition P) (total of 6 h of sepsis). During P, phenylephrine was infused to restore BP to that found at baseline. The slope of the end-systolic pressure-dimension relation was used as the index of LV contractility; LV anterior-posterior dimensions were measured by sonomicrometry.

Results
During combined CAVH and phenylephrine treatment, the decrease in the slope of the end-systolic pressure-dimension relation otherwise observed at S was reversed. The slope (mean +/- SD) was 57.5 +/- 32 mmHg/mm at B versus 22.2 +/- 8 mmHg/mm at S (P < 0.05, B vs. S) versus 62 +/- 37 mmHg at P (P < 0.05 S vs. P) (analysis of variance). Mean BP was restored to that found at B (123 +/- 19 mmHg versus 82 +/- 14 mmHg (P < 0.05 B vs. S) versus 116 +/- 27 mmHg (P < 0.05 S vs. P). Combination treatment with CAVH and phenylephrine also improved stroke volume (39.3 +/- 13.5 versus 32 +/- 8 versus 44 +/- 12 ml) and tissue oxygen delivery during P compared with results obtained when phenylephrine was given alone.

Conclusions
Our study offers a rationale for the combined use of phenylephrine and CAVH in the reversal of cardiac depression and hypotension in sepsis.
Multivariate Determinants of Early Postoperative Oxygen Consumption in Elderly Patients
Authors: Frank Steven M. , Fleisher Lee A. , Olson Krista F. , Gorman Randolph B. , Higgins Michael S. , Breslow Michael J. , Sitzmann James V. , Beattie Charles 
Published: November 2003

Background
Previous investigators have proposed that postoperative shivering may be poorly tolerated by patients with cardiopulmonary disease because of the associated significant increase in total-body oxygen consumption. However, the often-quoted 300-400% increase in oxygen consumption with shivering was derived from relatively few studies performed in a small number of younger persons specifically selected on the basis of clinically recognizable shivering. We hypothesized that the average elderly postoperative patient has a shivering response that is associated with a relatively small increase in total-body oxygen consumption.

Methods
One hundred eleven elderly patients (age > 60 yr) undergoing surgery were studied to assess the determinants of shivering and total-body oxygen consumption in the early postoperative period. Anesthetic technique, postoperative analgesia, and thermal management were controlled by protocol. The clinical variables associated with shivering and increased total-body oxygen consumption were determined by univariate and multivariate analyses.

Results
Mean total-body oxygen consumption in shivering patients was 38% greater than in nonshivering patients. Regardless of whether data from shivering patients were included in the analysis, oxygen consumption was directly proportional to mean body temperature. Despite similar core temperatures, men had a greater incidence of clinically recognizable shivering and greater total-body oxygen consumption than did women.

Conclusions
The metabolic demands associated with postoperative shivering in elderly patients are less than those reported previously in younger persons. These findings suggest that if hypothermia predisposes to cardiovascular complications in the postoperative period, these complications are not likely to be mediated by shivering and increased metabolism.
Improved Amplitude of Myogenic Motor Evoked Responses after Paired Transcranial Electrical Stimulation during Sufentanil/Nitrous Oxide Anesthesia
Authors: Kalkman Cor J. , Ubags Leon H. , Been Henk D. , Swaan Astrid , Drummond John C. 
Published: November 2003

Background
Measurement of motor evoked responses to transcranial stimulation (tc-MER) is a technique for intraoperative monitoring of motor pathways in the brain and spinal cord. However, clinical application of tc-MER monitoring is hampered because most anesthetic techniques severely depress the amplitude of motor evoked responses. Because paired electrical stimuli increase tc-MER responses in awake subjects, we examined their effects in anesthetized patients undergoing surgery. METHODS. Eleven patients whose neurologic condition was normal and who were undergoing spinal or aortic surgery were anesthetized with sufentanil-N20-ketamine. Partial neuromuscular blockade (single-twitch height 25% of baseline) was maintained with vecuronium. Single and paired electrical stimuli were delivered to the scalp, and compound action potentials were recorded from the tibialis anterior muscle. The amplitude and latency of the tc-MERs were measured as the interval between paired stimuli was varied between 0 (single stimulus) and 10 ms. All recordings were completed before spinal manipulation or aortic clamping.

Results
Median amplitude of the tc-MER after a single stimulus was 106 microV (10th-90th percentiles: 23-1,042 microV), and the latency to onset was 33.2 +/- 1.4 ms (SD). With paired stimuli (interstimulus interval 2-3 ms), tc-MER amplitudes increased to 285 (79-1,605) microV, or 269% of the single-pulse response (P < 0.01). Reproducibility of individual responses increased with paired stimulation. Onset latency decreased to 31.4 +/- 3.2 ms (P < 0.05). Maximum amplitude augmentation was observed with interstimulus intervals between 2 and 5 ms and in patients with low-amplitude responses after single-pulse stimulation.

Conclusions
Application of paired transcranial electrical stimuli increases amplitudes and reproducibility of tc-MERs during anesthetic-induced depression of the motor system. The effect may represent temporal summation of stimulation at cortical or spinal sites. The results of this study warrant further clinical evaluation of paired transcranial stimulation.
Pharmacokinetics of Inhaled Liposome-encapsulated Fentanyl
Authors: Hung Orlando R. , Whynot Sara C. , Varvel John R. , Shafer Stephen L. , Mezei Michael 
Published: November 2003

Background
Pulmonary administration of fentanyl solution can provide satisfactory but brief postoperative pain relief. Liposomes are microscopic phospholipid vesicles that can entrap drug molecules. Liposomal delivery of fentanyl has the potential to control the uptake of fentanyl by the lungs and thus provide sustained drug release. To demonstrate that inhalation of a mixture of free and liposome-encapsulated fentanyl can provide a rapid increase and sustained plasma fentanyl concentrations (CfenS), this study determined the pharmacokinetic profiles after the inhalation of free and liposome-encapsulated fentanyl in healthy volunteers.

Methods
After obtaining institutional approval and informed consent, ten healthy volunteers (five men, five women) were studied. Each subject received 200 micrograms intravenous fentanyl and inhaled 2,000 micrograms of free (50%) and liposome-encapsulated fentanyl (50%) on separate occasions. Frequent venous blood samples were collected, and CfenS were determined by radioimmunoassay. The pharmacokinetics and absorption characteristics of the inhaled mixture of free and liposome-encapsulated fentanyl were determined using moment analysis and least-squares numeric deconvolution.

Results
The mean (+/- SD) volume of distribution at steady-state and clearance of fentanyl after the intravenous administration were comparable to previous studies: 435 +/- 1821 and 0.584 +/- 0.209 l.min-1, respectively. The mean (+/- SD) peak Cfen was significantly greater for the intravenous administration compared to the aerosol mixture of free and liposome-encapsulated fentanyl (4.67 +/- 1.87 vs. 1.15 +/- 0.36 ng.ml-1). However, CfenS at 8 and 24 h after aerosol administration were greater compared to intravenous (0.25 +/- 0.14 and 0.12 +/- 0.16 ng.ml-1 for aerosol versus 0.16 +/- 0.10 and 0.05 +/- 0.06 ng.ml-1 for intravenous). The peak absorption rate, time to peak absorption, and bioavailability after inhalation were 7.02 (+/- 2.34) micrograms.min, -1(16) (+/- 8.0) min, and 0.12 (+/- 0.11), respectively.

Conclusions
The data suggest that this analgesic method offers a simple and noninvasive route of administration with a rapid increase of Cfen and a prolonged therapeutic fentanyl concentration. Future studies are required to determine the optimal liposome composition that would produce a sustained stable Cfen within analgesic therapeutic concentrations.
Alfentanil Slightly Increases the Sweating Threshold and Markedly Reduces the Vasoconstriction and Shivering Thresholds
Authors: Kurz Andrea , Go Janice C. , Sessler Daniel I. , Kaer Klaus , Larson Merlin D. , Bjorksten Andrew R. 
Published: November 2003

Background
Hypothermia is common in surgical patients and victims of major trauma; it also results from environmental exposure and drug abuse. In most cases, hypothermia results largely from drug-induced inhibition of normal thermoregulatory control. Although opioids are given to a variety of patients, the thermoregulatory effects of opioids in humans remain unknown. Accordingly, the hypothesis that opioid administration impairs thermoregulatory control was tested.

Methods
Eight volunteers were studied, each on 3 days: (1) a target total plasma alfentanil concentration of 100 ng/ml, (2) control (no drug), and (3) a target alfentanil concentration of 300 ng/ml. Each day, skin and core temperatures were increased sufficiently to provoke sweating. Temperatures subsequently were reduced to elicit peripheral vasoconstriction and shivering. Mathematical compensations were made for changes in skin temperature using the established linear cutaneous contributions to control of sweating (10%) and to vasoconstriction and shivering (20%). From the calculated thresholds (core temperatures triggering responses at a designated skin temperature of 34 degrees C) and unbound plasma alfentanil concentrations, the individual concentration-response relationship was determined. The concentration-response relationship for all the volunteers was determined similarly using total alfentanil concentrations.

Results
In terms of unbound concentration, alfentanil increased the sweating threshold (slope = 0.021 +/- 0.016 degrees C.ng-1.ml; r2 = 0.92 +/- 0.06). Alfentanil also significantly decreased the vasoconstriction (slope = -0.075 +/- 0.067 degrees C.ng-1.ml; r2 = 0.92 +/- 0.07) and shivering thresholds (slope = -0.063 +/- -0.037 degrees C.ng-1.ml; r2 = 0.98 +/- 0.04). In terms of total alfentanil concentration (degrees C.ng-1.ml), the sweating threshold increased according to the equation: threshold (degrees C) = 0.0014[alfentanil] + 37.2 (r2 = 0.33). In contrast, alfentanil produced a linear decrease in the core temperature, triggering vasoconstriction: threshold (degrees C) = -0.0049[alfentanil] + 36.7 (r2 = 0.64). Similarly, alfentanil linearly decreased the shivering threshold: threshold (degrees C) = -0.0057[alfentanil] + 35.9 (r2 = 0.70).

Conclusions
The observed pattern of thermoregulatory impairment is similar to that produced by most general anesthetics: a slight increase in the sweating threshold and a substantial, linear decrease in the vasoconstriction and shivering thresholds.
d-Tubocurarine Accentuates the Burn-induced Upregulation of Nicotinic Acetylcholine Receptors at the Muscle Membrane
Authors: Kim C. , Hirose M. , Martyn J. A. J. 
Published: November 2003

Background
Increases in acetylcholine receptors (AChRs) at the muscle membrane, induced by burn injury, have been associated with a hyperkalemic response to succinylcholine and resistance to d-tubocurarine-like drugs. Muscle relaxants often are administered to burn-injured patients in the intensive care unit to facilitate mechanical ventilation. This study in rats tested whether continuous administration of d-tubocurarine in subparalytic doses exaggerates the upregulation of AChRs induced by burn trauma. Subparalytic doses were used to avoid the confounding effects of immobilization.

Methods
Three days after an approximate 50% body surface area burn or sham injury, the animals received an infusion of 3.03 +/- 0.05 micrograms/h of d-tubocurarine or equal volume of saline directly to the left gastrocnemius muscle via catheter connected to a subcutaneously implanted osmotic pump. After 7 days of d-tubocurarine or saline infusion, the AChRs were quantitated using 125I-alpha-bungarotoxin. The AChRs on the d-tubocurarine or saline-infused left gastrocnemius were compared to the contralateral gastrocnemius in the same group. The right or left gastrocnemius AChRs were compared to the ipsilateral muscles between groups. These intra- and intergroup comparisons allowed the delineation of the effects of catheter irritation, burns, or d-tubocurarine on AChRs.

Results
Daily examination of the withdrawal response to toe-pinch revealed no evidence of paralysis. Weight loss in the burn-injury animals receiving d-tubocurarine or saline was similar, confirming that the infusion of d-tubocurarine did not impair the mobility of the animals to move and feed. The plasma d-tubocurarine concentration after 7 days of infusion was 26.0 +/- 12 ng/ml (mean +/- SE). Regardless of burn or sham injury or of d-tubocurarine or saline infusion, the concentration of AChRs on the left was consistently greater than in the contralateral right gastrocnemius muscles within the same group, indicating that manipulation of the area alone can result in upregulation of AChRs. The AChRs in the right gastrocnemius of burn-injured animals were greater than those in the same muscle of sham-injured animals, regardless of saline (7.24 +/- 0.9 vs. 5.7 +/- 0.5 fmoles/mg protein, P = 0.06) or d-tubocurarine (7.3 +/- 0.4 vs. 5.7 +/- 0.5, P < 0.05) infusion to the burn-injury groups. AChRs in the left gastrocnemius of burn-injury animals receiving d-tubocurarine were significantly greater than those in burn- or sham-injury animals receiving saline (13.9 +/- 1.1 vs. 9.8 +/- 1.2 and 7.1 +/- 0.5 fmoles/mg protein, respectively, P < 0.05).

Conclusions
Burn-induced upregulation of AChRs is accentuated by infusion of subparalytic doses of d-tubocurarine. Concomitant administration of d-tubocurarine to burn-injured patients may result in further exaggeration of the aberrant responses to neuromuscular relaxants.
Frequency-dependent Effects of Propofol on Atrioventricular Nodal Conduction in Guinea Pig Isolated Heart
Authors: Alphin Robert S. , Martens Jeffrey R. , Dennis Donn M. 
Published: November 2003

Background
The use of propofol has been associated with episodes of bradycardias. The mechanism(s) underlying these phenomena are not well defined. Therefore we investigated (1) the chronotropic and dromotropic effects of propofol, (2) the frequency-dependent effects of propofol on the atrioventricular (AV) node, and (3) the physiologic mechanism(s) underlying propofol's effects on AV nodal conduction.

Methods
Guinea pig isolated, perfused hearts were instrumented for measurement of atrial rate and AV nodal conduction time in spontaneously beating hearts, or stimulus-to-His bundle (S-H) intervals in atrially paced hearts. In addition, the Wenckebach cycle length, effective refractory period and S-H interval prolongation to an abrupt increase in pacing rate were measured to further define propofol's dromotropic effects and frequency-dependent behavior.

Results
Propofol, in a concentration-dependent manner, (1) slowed atrial rate and AV nodal conduction time in spontaneously beating hearts, (2) prolonged the S-H interval in atrially paced hearts, and (3) prolonged Wenckebach cycle length and effective refractory period. The negative dromotropic effect of propofol was greater during atrial pacing than in spontaneously beating hearts. Furthermore, this effect was enhanced at faster pacing rates, indicating frequency-dependent behavior. Atropine significantly antagonized propofol-induced S-H interval prolongation. The results of competition binding studies also supported a M2-muscarinic receptor-mediated mechanism.

Conclusions
We conclude that in the isolated guinea pig heart, propofol slows atrial rate and depresses AV nodal conduction in a concentration-dependent manner. The negative dromotropic effect of propofol shows frequency dependence and is predominantly mediated by M2-muscarinic receptors. Given the marked rate dependence of propofol's AV nodal actions, this anesthetic agent may impart antidysrhythmic protection to those patients susceptible to supraventricular tachycardias.
Halothane, Enflurane, and Isoflurane Do Not Affect the Basal or Agonist-stimulated Activity of Partially Isolated Soluble and Particulate Guanylyl Cyclases of Rat Brain
Authors: Zuo Zhiyi , Johns Roger A. 
Published: November 2003

Background
Evidence suggests that inhalational anesthetics interact with the nitric oxide-guanylyl cyclase signaling pathway in the central nervous system and that the inhibitation of this pathway in brain may result in an anesthetic, analgesic, or sedative effect. The mechanism of the effects inhalational anesthetics on this signaling pathway is not clear. This study attempted to determine whether inhalational anesthetics directly affect soluble or particulate guanylyl cyclase activity in a partially isolated enzyme system.

Methods
The effects of halothane (0.44-4.4%), enflurane (1.34-6.7%), and isoflurane (0.6-5.0%) on basal or stimulated soluble or particulate guanylyl cyclase activity were examined. Soluble guanylyl cyclase was isolated from whole rat brain and was stimulated by sodium nitroprusside or nitric oxide. Particulate guanylyl cyclase was isolated from rat olfactory bulb and was stimulated by rat atrial natriuretic peptide(1-28). Cyclic guanosine monophosphate content was measured by radiommunoassay. The concentrations of anesthetics in the incubation solution were confirmed by gas chromatography methods.

Results
None of the three anesthetics affected the activity of basal or stimulated soluble or particulate guanylyl cyclase at the concentrations examined in the current experimental conditions.

Conclusions
These results suggest that halothane, enflurane, and isoflurane do not directly interact with soluble or particulate guanylyl cyclases of rat brain.