bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stable Inhibition of Brain Synaptic Plasma Membrane Calcium ATPase in Rats Anesthetized with Halothane
Authors: Franks John J. , Horn Jean-Louis , Janicki Piotr K. , Singh Gurkeerat 
Published: November 2003

Background
The authors recently showed that plasma membrane Ca(2+)-ATPase (PMCA) activity in cerebral synaptic plasma membrane (SPM) is diminished in a dose-related fashion during exposure in vitro to halothane, isoflurane, xenon, and nitrous oxide at clinically relevant partial pressures. They have now extended their work to in vivo studies, examining PMCA pumping in SPM obtained from control rats decapitated without anesthetic exposure, from rats decapitated during halothane anesthesia, and from rats decapitated after recovery from halothane anesthesia.

Methods
Three treatment groups were studied: 1) C, control rats that were decapitated without anesthetic exposure, 2) A, anesthetized rats exposed to 1 minimum effective dose (MED) for 20 min and then decapitated, and 3) R, rats exposed to 1 MED for 20 min and then decapitated after recovery from anesthesia, defined as beginning to groom. Plasma membrane Ca(2+)-ATPase pumping and Ca(2+)-dependent ATPase hydrolytic activity, as well as sodium-calcium exchanger activity and Na+-K+-ATPase hydrolytic activity, were assessed in cerebral SPM. In addition, halothane effect on smooth endoplasmic reticulum Ca(2+)-ATPase (SERCA) was examined.

Results
Plasma membrane Ca(2+)-ATPase transport of Ca2+ into SPM vesicles from anesthetized rats was reduced to 71% of control (P < 0.01) compared with 113% of control for the recovered group (NS). No depression by halothane of SERCA activity, sodium-calcium exchanger, or Na+-K+-ATPase activity was noted among the CAR treatment groups.

Conclusions
Plasma membrane Ca(2+)-ATPase is selectively and stably inhibited in cerebral SPM from rats killed while anesthetized with halothane, compared with rats killed without anesthesia or after recovery from anesthesia. The studies described in this report, in conjunction with previously reported inhibition of PMCA activity in vitro by a wide range of anesthetic agents, indicate a relationship between inhibition of PMCA and action of inhalational anesthetics.
Platelet Factor 4 Injection Produces Acute Pulmonary Hypertension in the Awake Lamb
Authors: Kurrek Matt M. , Winkler Marianne , Robinson Dwight R. , Zapol Warren M. 
Published: November 2003

Background
Reversal of heparin anticoagulation by intravenous protamine sulfate consistently produces acute pulmonary vasoconstriction mediated by the release of thromboxane in the awake lamb. Recently, recombinant platelet factor 4 (rPF4) has been cloned, expressed in Escherichia coli, and infused to reverse heparin anticoagulation in the rat, without producing adverse hemodynamic or pulmonary morphologic effects. The authors sought to learn whether intravenous administration of PF4 is devoid of side effects in the pulmonary circulation of lambs.

Methods
The authors evaluated the hemodynamic response and plasma release rates of thromboxane during intravenous challenges with heparin-rPF4 (n = 2), rPF-free carrier (n = 5), rPF4 (n = 5), rPF4 after indomethacin (n = 5), protamine (n = 5) and heparin-protamine (n = 5) in 17 awake, hemodynamically monitored lambs. Each lamb underwent up to three random challenges with a 2-h recovery period between each challenge.

Results
In two lambs, systemic anticoagulation with heparin followed by reversal of anticoagulation with an intravenous bolus of rPF4 (4 mg/kg) led to acute pulmonary vasoconstriction and hypertension with the release of thromboxane (peak pulmonary artery pressure [Ppa] 40 and 33 mmHg and peak plasma thromboxane B2 50 and 30 ng/ml, respectively). Intravenous administration of rPF4 (1.5 mg/kg) alone increased the Ppa from 17.2 +/- 0.7 mmHg (mean +/- SEM) at baseline to 31.2 +/- 2 mmHg at 1 min (n = 5, P < 0.05). This was associated with an increase of plasma thromboxane B2 from 0.06 +/- 0.02 to 3.96 +/- 1.21 ng/ml. Acute pulmonary vasoconstriction lasted approximately 5 min and was completely prevented by pre-treatment with oral indomethacin (10 mg/kg). Intravenous bolus administration of rPF4 carrier (n = 5) or protamine (2 mg/kg) alone (n = 5) did not induce pulmonary hypertension or the release of thromboxane. In five lambs, intravenous heparin (200 U/kg) followed by protamine (2 mg/kg) consistently produced acute pulmonary vasoconstriction and hypertension.

Conclusions
Intravenous injection of human rPF4 into the awake lamb produces acute pulmonary vasoconstriction and hypertension associated with thromboxane release into circulating blood. The effects of rPF4 on the pulmonary vasculature should be evaluated in primates before rPF4 is substituted for protamine in reversing heparin anticoagulation in humans.
The Addition of 7.5% Glucose Does Not Alter the Neurotoxicity of 5% Lidocaine Administered Intrathecally in the Rat
Authors: Sakura Shinichi , Chan Vincent W. S. , Ciriales Ricardo , Drasner Kenneth 
Published: November 2003

Background
Recent reports of major and minor neurologic sequelae after spinal anesthesia have generated concern regarding the safety of some currently used intrathecal agents. The role of glucose, if any, in neurotoxic injury associated with spinal anesthesia is not known. The current experiments sought to determine whether the presence of 7.5% glucose alters the neurotoxicity of intrathecally administered 5% lidocaine.

Methods
Two experiments were performed. First, 48 rats were implanted with an intrathecal catheter and randomly divided into eight equal groups. Each animal received a single intrathecal infusion of 5% lidocaine (groups P1-P4) or 5% lidocaine with 7.5% glucose (G1-G4) for 0.5, 1, 2, or 4 h at a rate of 1 microliter/min. Sensory function was assessed using the tail-flick test; a deficit was defined as a complete lack of response to the heat stimulus at the proximal, mid or distal portion of the tail persisting 4 days after the infusion. In the second experiment, 60 rats were randomly divided into two groups to receive a 1-h intrathecal infusion of 5% lidocaine or 5% lidocaine with 7.5% glucose. Animals were evaluated for increase in the latency of the tail-flick reflex 4 days after infusion.

Results
In the first experiment, the two lidocaine solutions produced similar dose-dependent loss of sensory function. In the second experiment, the two solutions induced similar alterations in tail-flick latency.

Conclusions
The presence of 7.5% glucose does not affect the potential of intrathecally administered 5% lidocaine to induce sensory impairment. These findings provide further support for the hypothesis that recent injuries after spinal anesthesia resulted from a direct neurotoxic effect of the local anesthetic.
Pulsatile Versus Nonpulsatile Flow
Authors: Hindman Bradley J. , Dexter Franklin , Smith Tom , Cutkomp Johann 
Published: November 2003

Background
Although pulsatile and nonpulsatile cardiopulmonary bypass (CPB) do not differentially affect cerebral blood flow (CBF) or metabolism during hypothermia, studies suggest pulsatile CPB may result in greater CBF than nonpulsatile CPB under normothermic conditions. Consequently, nonpulsatile flow may contribute to poorer neurologic outcome observed in some studies of normothermic CPB. This study compared CBF and cerebral metabolic rate for oxygen (CMRO2) between pulsatile and nonpulsatile CPB at 37 degrees C.

Methods
In experiment A, 16 anesthetized New Zealand white rabbits were randomized to one of two pulsatile CPB groups based on pump systolic ejection period (100 and 140 ms, respectively). Each animal was perfused at 37 degrees C for 30 min at each of two pulse rates (150 and 250 pulse/min, respectively). This scheme created four different arterial pressure waveforms. At the end of each perfusion period, arterial pressure waveform, arterial and cerebral venous oxygen content, CBF (microspheres), and CMRO2 (Fick) were measured. In experiment B, 22 rabbits were randomized to pulsatile (100-ms ejection period, 250 pulse/min) or nonpulsatile CPB at 37 degrees C. At 30 and 60 min of CPB, physiologic measurements were made as before.

Results
In experiment A, CBF and CMRO2 were independent of ejection period and pulse rate. Thus, all four waveforms were physiologically equivalent. In experiment B, CBF did not differ between pulsatile and nonpulsatile CPB (72 +/- 6 vs. 77 +/- 9 ml.100 g-1.min-1, respectively (median +/- quartile deviation)). CMRO2 did not differ between pulsatile and nonpulsatile CPB (4.7 +/- 0.5 vs. 4.1 +/- 0.6 ml O2.100 g-1.min-1, respectively) and decreased slightly (0.4 +/- 0.4 ml O2.100 g-1.min-1) between measurements.

Conclusions
During CPB in rabbits at 37 degrees C, neither CBF nor CMRO2 is affected by arterial pulsation. The absence of pulsation per se is not responsible for the small decreases in CMRO2 observed during CPB.
Recovery of Hepatic Drug Extraction after Hypothermic Preservation
Authors: Kelley Scott D. , Cauldwell Charles B. , Fisher Dennis M. , Lau Marie , Sharma Manohar L. , Weisiger Richard A. 
Published: November 2003

Background
To determine whether liver preservation before transplantation impairs hepatic drug metabolism, hepatic extraction of drugs with different metabolic pathways (fentanyl, morphine, and vecuronium) in isolated rat livers was measured either immediately or after 24 h of hypothermia at 4 degrees C using a standard preservation-reperfusion sequence.

Methods
Isolated rat livers were perfused via the portal vein for 30 min to document initial viability. Test livers (n = 5) were perfused with iced Belzer solution, stored for 24 h at 4 degrees C, and flushed with 6% hetastarch. After hypothermic preservation for 24 h, or in control livers (n = 5) immediately after the 30-min perfusion, livers were perfused single-pass at a constant flow rate with solutions containing fentanyl, morphine, and vecuronium at 37 degrees C. Perfusate and bile samples were obtained at regular intervals for 64 min, after which liver tissue was harvested for analysis. Drug concentrations were measured using radioimmunoassay and gas chromatography. Metabolic capacity of the liver was estimated from the extraction fraction of each drug at steady-state.

Results
After warming to 37 degrees C, preserved livers consumed oxygen and produced bile at rates similar to that of control livers. Hypothermic preservation did not affect extraction of fentanyl and morphine. Vecuronium extraction was initially less in preserved livers, but this difference disappeared as the preserved livers returned to 37 degrees C (< 16 min). Biliary excretion and tissue concentrations of vecuronium were similar in each group.

Conclusions
Hypothermic preservation does not significantly impair extraction of these drugs in this liver preservation model. If these results apply to human liver transplantation, little danger of drug accumulation exists during the early postoperative period if hepatic function is normal.
Inhibition of Nociception-induced Spinal Sensitization by Anesthetic Agents
Authors: O'Connor Therese C. , Abram Stephen E. 
Published: November 2003

Background
Subcutaneous injection of dilute formalin in the hind paw of the rat produces a biphasic nociceptive response. Initial C-fiber activity is accompanied by flinching of the paw for about 5 min (phase 1), followed by cessation of activity and resumption of flinching beginning 15 min after injection and lasting about 40 min or more (phase 2). The second phase depends on changes in dorsal horn cell function that occur shortly after the initial C-fiber discharge. It was previously shown that isoflurane, administered during phase 1, reduced phase 2 activity, but a combination of isoflurane and nitrous oxide given throughout phase 1 did not suppress spinal sensitization. The same model was used to determine the effects of several inhalation and intravenous anesthetic agents on phase 2 of the formalin test.

Methods
The formalin test was carried out on male Sprague-Dawley rats. Animals anesthetized briefly with halothane to facilitate formalin injection, were compared to animals that received 1 MAC anesthesia from 5 min before to 6 min after formalin injection using halothane, enflurane, isoflurane, desflurane, or 70% N2O, or a combination of nitrous oxide plus 1 MAC halothane. Animals that were given intravenous saline immediately before injection of formalin were compared to animals given either 20 mg/kg intravenous thiopental just before formalin injection or 10 mg/kg intravenous propofol just before and 3 mg/kg immediately after formalin injection. Flinches/minute were counted at 1 and 5 min after formalin injection and thereafter at 5-min intervals for 1 h. The total of 1- and 5-min flinches were considered phase 1 activity and the total of 10-60-min flinches were considered phase 2. Total phase 2 activity was compared between groups using one-way analysis of variance.

Results
Animals that received halothane, enflurane, isoflurane, desflurane, or nitrous oxide during phase 1 demonstrated a significant decrease in phase 2 activity when compared to controls, while those that received a combination of nitrous oxide and halothane exhibited no difference. Animals that received intravenous thiopental anesthesia during phase 1 demonstrated no difference in phase 2 activity when compared to controls, whereas those that received propofol during phase 1 demonstrated a significant decrease of phase 2 activity.

Conclusions
Volatile anesthetics or nitrous oxide significantly suppress spinal sensitization, whereas the combination of nitrous oxide plus halothane causes no suppression. Thiopental does not affect spinal sensitization, whereas propofol causes significant suppression. These results may have important implications regarding the development of postoperative pain.
Do Standard Monitoring Sites Reflect True Brain Temperature When Profound Hypothermia Is Rapidly Induced and Reversed?
Authors: Stone Gilbert J. , Young William L. , Smith Craig R. , Solomon Robert A. , Wald Alvin , Ostapkovich Noeleen , Shrebnick Debra B. 
Published: November 2003

Background
Brain temperature is closely approximated by most body temperature measurements under normal anesthetic conditions. However, when thermal autoregulation is overridden, large temperature gradients may prevail. This study sought to determine which of the standard temperature monitoring sites best approximates brain temperature when deep hypothermia is rapidly induced and reversed during cardiopulmonary bypass.

Methods
Twenty-seven patients underwent cardiopulmonary bypass and deep hypothermic circulatory arrest in order for each to have a giant cerebral aneurysm surgically clipped. Brain temperatures were measured directly with a thermocouple embedded in the cerebral cortex. Eight other body temperatures were monitored simultaneously with less invasive sensors at standard sites.

Results
Brain temperature decreased from 32.6 +/- 1.4 degrees C (mean +/- SD) to 16.7 +/- 1.7 degrees C in 28 +/- 7 min, for an average cerebral cooling rate of 0.59 +/- 0.15 degrees C/min. Circulatory arrest lasted 24 +/- 15 min and was followed by 63 +/- 17 min of rewarming at 0.31 +/- 0.09 degrees C/min. None of the monitored sites tracked cerebral temperature well throughout the entire hypothermic period. During rapid temperature change, nasopharyngeal, esophageal, and pulmonary artery temperatures corresponded to brain temperature with smaller mean differences than did those of the tympanic membrane, bladder, rectum, axilla, and sole of the foot. At circulatory arrest, nasopharyngeal, esophageal, and pulmonary artery mean temperatures were within 1 degree C of brain temperature, even though individual patients frequently exhibited disparate values at those sites.

Conclusions
When profound hypothermia is rapidly induced and reversed, temperature measurements made at standard monitoring sites may not reflect cerebral temperature. Measurements from the nasopharynx, esophagus, and pulmonary artery tend to match brain temperature best but only with an array of data can one feel comfortable disregarding discordant readings.
Studies on the Safety of Chronically Administered Intrathecal Neostigmine Methylsulfate in Rats and Dogs
Authors: Yaksh Tony L. , Grafe Marjorie R. , Malkmus Shelle , Rathbun Michael L. , Eisenach James C. 
Published: November 2003

Background
The spinal delivery of the cholinesterase inhibitor neostigmine yields analgesia in rats and augments the analgesic effects of alpha 2 agonists in sheep. To assess its activity in humans, preclinical toxicology studies to define its safety were required in two species.

Methods
Rats with chronic intrathecal catheters received daily injections of saline (vehicle) or 5 micrograms/10 microliters or 10 micrograms/10 microliters neostigmine HCl (n = 6/group) for 4 days and were observed for general behavior and nociception (52.5 degrees C hot plate). On day 6, rats were anesthetized and submitted to whole body perfusion/fixation. For dog studies, male beagles were prepared following rigid aseptic precautions with catheters passed from the cisterna magna to the lumbar intrathecal space. Catheters were connected to an external vest-mounted pump. Based on preliminary studies, ten implanted dogs were randomly assigned to receive infusions of neostigmine for 28 days (4 mg/4 ml/day; n = 6) or saline (4 ml/day; n = 4). At 28 days, dogs were anesthetized, cisternal cerebrospinal fluid was obtained, and dogs were submitted to perfusion-fixation. Rat and dog spinal cords were embedded, sectioned, stained, and assessed by the pathologist without knowledge of treatment.

Results
In rats, neostigmine produced a dose-dependent increase in hot plate latency, and no tolerance was observed. Mild tremor was observed but was not debilitating. Histopathology revealed a mild fibrotic reaction to the catheter with mixed signs of moderate, acute, and chronic inflammation with no differences between saline or drug groups. In dogs, neostigmine had no effect on blood pressure or on the skin twitch response but produced bradycardia and an increase in muscle tone. At sacrifice, cerebrospinal fluid protein, specific gravity, and glucose were elevated in both saline and neostigmine groups. Histopathology displayed a local reaction to the spinal catheter and a mixed acute and chronic inflammatory reaction. No group differences were observed. These results suggest that, at the neostigmine concentration of 1 mg/ml in the rat and dog and in doses up to 4 mg/day in the dog, there is no evidence of spinal tissue toxicity that can be attributed to the drug. This result, observed in two species, suggests that intrathecal neostigmine given in this manner is without distinguishable toxicity in these two models.
Mechanism of the Negative Inotropic Effect of Thiopental in Isolated Ferret Ventricular Myocardium
Authors: Housmans Philippe R. , Kudsioglu Turkan S. , Bingham Jonathan 
Published: November 2003

Background
Thiopental's myocardial depressant effects are well known and most likely involve some alteration in intracellular Ca2+ homeostasis. The aim of this study was to investigate the mechanisms of thiopental's negative inotropic effects and its underlying mechanism in isolated ferret ventricular myocardium (which shows physiologic characteristics similar to human ventricular myocardium), and in frog ventricular myocardium, in which Ca2+ ions for myofibrillar activation are derived almost entirely from transsarcolemmal influx.

Methods
The authors analyzed the effects of thiopental after beta-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca2+ transient detected with the Ca(2+)-regulated photoprotein aequorin. Thiopental's effects also were evaluated in ferret right ventricular papillary muscles in which the sarcoplasmic reticulum (SR) function was impaired by ryanodine and in frog ventricular strips with little or no SR function.

Results
At concentration > or = 10(-4) M, which is in the high range of the clinically encountered free plasma thiopental concentrations, thiopental decreased contractility and the amplitude of the intracellular Ca2+ transient. At equal peak force, peak aequorin luminescence in 10(-4) M thiopental and [Ca2+]0 > 2.25 mM was slightly smaller than that in control conditions at [Ca2+]o = 2.25 mM. This indicates that thiopental causes a small increase in myofibrillar Ca2+ sensitivity. After inactivation of sarcoplasmic reticulum Ca2+ release with 10(-6) M ryanodine, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca2+ influx, thiopental caused a further decrease in contractility and in the amplitude of the intracellular Ca2+ transient, and thiopental's relative negative inotropic effect was not different from that in control muscles not exposed to ryanodine. Thiopental, > or = 10(-4) M, decreased contractility in frog ventricular myocardium.

Conclusions
These findings indicate that the direct negative inotropic effect of thiopental results from a decrease in intracellular Ca2+ availability. At least part of thiopental's action is caused by inhibition of transsarcolemmal Ca2+ influx. These effects become apparent at concentrations routinely present during intravenous induction with thiopental.
Halothane Selectively Inhibits Nonshivering Thermogenesis
Authors: Dicker Andrea , Ohlson Kerstin B. E. , Johnson Lennart , Cannon Barbara , Lindahl Sten G.E. , Nedergaard Jan 
Published: November 2003

Background
During halothane anesthesia, infants fail to increase oxygen consumption in response to a cold stimulus in the form of an increase in temperature gradient between body and environment. Based on recent observations with isolated brown-fat cells, it seemed feasible that this inability to respond could be due to an inhibition of nonshivering thermogenesis during halothane anesthesia.

Methods
The rate of oxygen consumption was measured in cold-acclimated hamsters and rats. The rate evoked by norepinephrine injection in hamsters at an environmental temperature of approximately 24 degrees C was used as a measure of the capacity for nonshivering thermogenesis. Anesthesia was induced by 3% halothane and maintained by 1.5% halothane. One experimental series with spontaneously breathing hamsters and a second control series with spontaneously breathing rats and with rats whose lungs were mechanically ventilated were conducted.

Results
Norepinephrine injection led to a fourfold increase in the rate of oxygen consumption in control hamsters; after this response had subsided, a second injection led to a similar effect. Halothane anesthesia caused an approximately 20% decrease in resting metabolic rate (P < 0.05) and a 70% inhibition of the thermogenic response to norepinephrine (P < 0.001). The halothane concentration yielding half-maximal inhibitory effect was estimated to be less than 1.0%. After the animals had recovered from halothane anesthesia, a completely restored thermogenic response to norepinephrine was observed. The inhibitory effect of halothane also was observed in hamsters maintained at normothermia and was therefore not secondary to the slight hypothermia that otherwise developed during anesthesia. In a series of control experiments, it was confirmed that rats also showed large thermogenic responses to norepinephrine injections, and it was found that, in spontaneously breathing halothane-anesthetized rats, the thermogenic response to norepinephrine was also much inhibited. Further, in halothane-anesthetized rats whose lungs were mechanically ventilated, and where blood gases were kept at virtually normal levels, the thermogenic response to norepinephrine was found to be similarly markedly inhibited.

Conclusions
A much diminished or abolished thermogenic response to injected norepinephrine was demonstrated in halothane-anesthetized animals. This implies that there would be a diminished ability to elicit nonshivering thermogenesis even when this process is physiologically induced. Such a diminished ability could in part explain the susceptibility of neonates and infants to hypothermia during halothane anesthesia.