bluuebunny/crossref_metadata_2025_split huggingface dataset:
Possible Involvement of Cyclic Adenosine Monophosphate–independent Mechanism in the Positive Chronotropic Effect of Norepinephrine in the Isolated Guinea Pig Right Atrium
Authors: Asada Mieko , Endou Masayuki 
Published: November 2003

Background
Although both positive chronotropic and inotropic effects of beta-adrenergic stimulation are thought to be mediated by cyclic adenosine 3'5'-monophosphate, phosphodiesterase III inhibitors such as amrinone and milrinone potentiate the positive inotropic effect of catecholamines with minimum influence on the heart rate in clinical setting. The aim of the current study was to compare the positive chronotropic effect of norepinephrine with that of forskolin to elucidate whether cyclic adenosine monophosphate is relevant to the chronotropic effect of norepinephrine.

Methods
Concentration-response curves for the positive chronotropic effects of norepinephrine and forskolin on the spontaneously beating right atria of guinea pigs were determined in the absence and presence of phosphodiesterase inhibitors or ion channel inhibitors. In some experiments, the left atria driven electrically were used to determine the positive inotropic effect of norepinephrine.

Results
Norepinephrine and forskolin increased the beating rate in a concentration-dependent manner. The positive chronotropic effect of forskolin was potentiated by amrinone and 3-isobutyl-1-methylxanthine, whereas the positive chronotropic effect of norepinephrine was not potentiated by the phosphodiesterase inhibitors. In contrast, the positive inotropic effect of norepinephrine was potentiated by amrinone. The hyperpolarization-activated inward current inhibitor cesium chloride and L-type voltage-dependent Ca2+ current inhibitor verapamil suppressed the chronotropic effect of norepinephrine, whereas these inhibitors did not affect the chronotropic effect of forskolin.

Conclusion
Norepinephrine increases the spontaneously beating rate by a different mechanism from that of forskolin, suggesting that cyclic adenosine monophosphate is causally unrelated to the positive chronotropic effect of norepinephrine in the guinea pig heart.
Nitrous Oxide Activates GABAergic Neurons in the Spinal Cord in Fischer Rats
Authors: Hashimoto Toshikazu , Maze Mervyn , Ohashi Yoko , Fujinaga Masahiko 
Published: November 2003

Background
Findings to date indicate that nitrous oxide exerts its antinociceptive effect by activating descending noradrenergic neurons. The mechanism whereby descending inhibitory neurons, including noradrenergic neurons, produce antinociceptive effect remains unclear. Using c-Fos protein as a marker for neuronal activation, we examined whether spinal cord neurons activated by nitrous oxide are y-aminobutyric acid-mediated (GABAergic) neurons.

Methods
Adult male Fischer (a strain in which nitrous oxide shows strong antinociceptive properties) and Lewis (a strain in which nitrous oxide lacks antinociceptive properties) rats were exposed to either air (control) or nitrous oxide. Frozen sections of the spinal cord were either stained for c-Fos or double-stained for c-Fos and glutamic acid decarboxylase (a rate-limiting enzyme for GABA synthesis) and analyzed by standard or confocal microscopy.

Results
In Fischer rats, 90 min of 75% N2O administration increased the number of c-Fos-positive cells in the spinal cord approximately threefold as compared with the control group. The c-Fos-positive cells induced by nitrous oxide were almost entirely colocalized with glutamic acid decarboxylase-positive cells. In contrast, exposure did not change the number of c-Fos-positive cells in the spinal cord in Lewis rats.

Conclusions
Exposure to nitrous oxide activates GABAergic neurons in the spinal cord. The dose-dependence of GABAergic neuronal activation in the Fischer rats and its absence in the Lewis rat correlate with antinociceptive responses previously reported in these same circumstances. Together, we interpret these data to indicate that activation of GABAergic neurons in the spinal cord are involved in the antinociceptive action of nitrous oxide.
Differential Modulation of the Cardiac L- and T-type Calcium Channel Currents by Isoflurane
Authors: Camara Amadou K. S. , Begic Zeljana , Kwok Wai-Meng , Bosnjak Zeljko J. 
Published: November 2003

Background
Volatile anesthetics exert their negative chronotropic and inotropic effects, in part by depressing the L- and T-type calcium channels. This study examines and compares the dose-dependent effects of isoflurane on atrial L- and T-type calcium currents (I(Ca,L) and I(Ca,T)) and ventricular I(Ca,L).

Methods
Whole cell I(Ca) was recorded from enzymatically isolated guinea pig cardiomyocytes. Current-voltage relations for atrial and ventricular I(Ca,L) was obtained from holding potentials of -90 and -50 mV to test a potential of +60 mV in 10-mV increments. Atrial I(Ca,T) was determined by subtraction of currents obtained from holding potentials of -50 and -90 mV. Steady state inactivation was determined using standard two-pulse protocols, and data were fitted with the Boltzmann equation.

Results
Isoflurane depressed I(Ca) in a dose-dependent manner, with Kd values of 0.23+/-0.03, 0.34+/-0.03, and 0.71+/-0.02 mM of anesthetic for atrial I(Ca,T) and I(Ca,L) and ventricular (ICa,L), respectively, and caused a significant (P < 0.05) hyperpolarizing shift in steady state inactivation. At 1.2 and 1.6 mm, isoflurane caused a significant (P < 0.05) depolarizing shift in the steady state activation in ventricular I(Ca,L) but not in atrial I(Ca,L) or I(Ca,T). In addition to the depression of I(Ca,L), isoflurane also induced a hyperpolarizing shift in the reversal potential of I(Ca) for both atrial and ventricular L-type calcium channels.

Conclusion
The results show that atrial I(Ca,T) is more sensitive to isoflurane than atrial I(Ca,L), and ventricular I(Ca,L) was the least responsive to the anesthetic. These differential sensitivities of the calcium channels in the atrial and ventricular chambers might reflect phenotypic differences in the calcium channels or differences in modulation by the anesthetic.
Predictability of Processed Electroencephalography Effects on the Basis of Pharmacokinetic–Pharmacodynamic Modeling during Repeated Propofol Infusions in Patients with Extradural Analgesia
Authors: Kuizenga Karel , Proost Johannes H. , Wierda J. Mark , Kalkman Cor J. 
Published: November 2003

Background
Pharmacokinetic-pharmacodynamic (PKPD) modeling can be used to characterize the concentration-effect relation of drugs. If the concentration-effect relation of a hypnotic drug is stable over time, an effect parameter derived from the processed electroencephalographic signal may be used to control the infusion for hypnosis. Therefore, the stability of the propofol concentration-electroencephalographic effect relation over time was investigated under non-steady state conditions.

Methods
Three propofol infusions (25 mg x kg(-1) x h(-1) for 10 min, 22 mg x kg(-1) x h(-1) for 10 min, and 12.5 mg x kg(-1) x h(-1) for 20 min) were administered to 10 patients during extradural analgesia. Each successive infusion was started immediately after the patient had regained responsiveness after termination of the preceding infusion. Electroencephalography was recorded from bilateral prefrontal to mastoid leads. Electroencephalographic amplitude in the 11- to 15-Hz band and the Bispectral Index were used as electroencephalographic effect variables. PKPD parameters were calculated with use of parametric and nonparametric models based on electroencephalographic data and arterial propofol concentrations derived during the initial infusion, and these were used to predict electroencephalographic effect during the subsequent infusions. The predictability of the electroencephalographic effects was determined by the coefficient of determination (R2) and of the -2 log likelihood of the sequential infusions.

Results
The direction of electroencephalographic changes in response to the infusions was reproducible. Although PKPD parameters could be estimated well during the initial infusion (median [range] parametric R2 = 0.74 [0.56-0.95] for electroencephalographic amplitude and 0.90 [0.27-0.99] for Bispectral Index), none of the modeling techniques could predict accurately the electroencephalographic effect during subsequent infusions (R2 = 0.00 [-0.31-0.46] for electroencephalographic amplitude and 0.15 [-.46-0.57] for Bispectral Index; P < 0.01).

Conclusions
The relation between blood propofol concentrations and the electroencephalographic effect under non-steady state conditions is not stable over time and is too complex to be modeled by any of the applied PKPD models.
Effects of Lithotomy Position and External Compression on Lower Leg Muscle Compartment Pressure
Authors: Pfeffer Susanne D. , Halliwill John R. , Warner Mark A. 
Published: November 2003

Background
Case reports have suggested that externally applied pressure from antithrombosis devices may contribute to the development of compartment syndromes during extended surgery in the lithotomy position. The purpose of this study was to assess the effects of a pneumatic compression device on directly measured intracompartment pressure in the lower leg with the leg positioned in the lithotomy position.

Methods
In 25 conscious, healthy men and women, the authors measured pressure within the tibialis anterior muscle compartment with the leg supine and in the lithotomy position with and without intermittent compression. Three different devices were used to keep the leg in the lithotomy position, supporting the leg either behind the knee, under the calf, or at the ankle.

Results
The lithotomy position with support behind the calf or knee increased intracompartment pressure to 16.5+/-3.4 versus 10.7+/-5.8 mmHg supine (mean +/- SD; P < 0.05). The addition of intermittent compression decreased pressure to 13.4+/-5.1 mmHg during lithotomy (P < 0.05) and to 9.1+/-7.0 mmHg in the supine position (P < 0.05). In contrast, the lithotomy position with support near the ankle decreased intracompartment pressure to 8.7+/-5.6 versus 13.3+/-5.1 mmHg supine (P < 0.05). The addition of intermittent compression decreased pressure to 6.5+/-5.4 mmHg during lithotomy (P < 0.05) and to 10.3+/-4.7 mmHg in the supine position (P < 0.05).

Conclusions
These results show that the lithotomy position is associated with changes in intracompartment pressure that are dependent on the method of leg support used. Furthermore, they indicate that intermittent external compression can reduce intracompartment pressure in the lower leg. Therefore, increases in intracompartment pressure during surgery in the lithotomy position with the calf or knee supported may be one of the factors that contribute to the development of compartment syndrome. Further, use of intermittent external compression may significantly reduce this pressure increase.
Phenylephrine Added to Prophylactic Ephedrine Infusion during Spinal Anesthesia for Elective Cesarean Section
Authors: Mercier Frédéric J. , Riley Edward T. , Frederickson Willard L. , Roger-Christoph Sandrine , Benhamou Dan , Cohen Sheila E. 
Published: November 2003

Background
Because ephedrine infusion (2 mg/min) does not adequately prevent spinal hypotension during cesarean delivery, the authors investigated whether adding phenylephrine would improve its efficacy.

Methods
Thirty-nine parturients with American Society of Anesthesiologists physical status I-II who were scheduled for cesarean delivery received a crystalloid preload of 15 ml/kg. Spinal anesthesia was performed using 11 mg hyperbaric bupivacaine, 2.5 microg sufentanil, and 0.1 mg morphine. Maternal heart rate and systolic blood pressure were measured at frequent intervals. A vasopressor infusion was started immediately after spinal injection of either 2 mg/min ephedrine plus 10 microg/min phenylephrine or 2 mg/min ephedrine alone. Treatments were assigned randomly in a double-blind fashion. The infusion rate was adjusted according to systolic blood pressure using a predefined algorithm. Hypotension, defined as systolic blood pressure less than 100 mmHg and less than 80% of baseline, was treated with 6 mg ephedrine bolus doses.

Results
Hypotension occurred less frequently in the ephedrine-phenylephrine group than in the ephedrine-alone group: 37% versus 75% (P = 0.02). Ephedrine (36+/-16 mg, mean +/- SD) plus 178+/-81 microg phenylephrine was infused in former group, whereas 54+/-18 mg ephedrine was infused in the latter. Median supplemental ephedrine requirements and nausea scores (0-3) were less in the ephedrine-phenylephrine group (0 vs. 12 mg, P = 0.02; and 0 vs. 1.5, P = 0.01, respectively). Umbilical artery pH values were significantly higher in the ephedrine-phenylephrine group than in the group that received ephedrine alone (7.24 vs. 7.19). Apgar scores were similarly good in both groups.

Conclusion
Phenylephrine added to an infusion of ephedrine halved the incidence of hypotension and increased umbilical cord pH.
Propofol Attenuates Capacitative Calcium Entry in Pulmonary Artery Smooth Muscle Cells
Authors: Horibe Mayumi , Kondo Izumi , Damron Derek S. , Murray Paul A. 
Published: November 2003

Background
Depletion of intracellular Ca2+ stores results in capacitative Ca2+ entry (CCE) in pulmonary artery smooth muscle cells (PASMCs). The authors aimed to investigate the effects of propofol on CCE and to assess the extent to which protein kinase C (PKC) and tyrosine kinases mediate propofol-induced changes in CCE.

Methods
Pulmonary artery smooth muscle cells were cultured from explants of canine intrapulmonary artery. Fura 2-loaded PASMCs were placed in a dish (37 degrees C) on an inverted fluorescence microscope. Intracellular Ca2+ concentration was measured using fura 2 in PASMCs using a dual-wavelength spectrofluorometer. Thapsigargin (1 microM), a sarcoplasmic reticulum Ca2+-adenosine triphosphatase inhibitor, was used to deplete intracellular Ca2+ stores after removing extracellular Ca2+. CCE was activated when extracellular Ca2+ (2.2 mM) was restored.

Results
Thapsigargin caused a transient increase in intracellular Ca2+ concentration (182+/-11%). Restoring extracellular calcium (to induce CCE) resulted in a peak (246+/-12% of baseline) and a sustained (187+/-7% of baseline) increase in intracellular Ca2+ concentration. Propofol (1, 10, 100 microM) attenuated CCE in a dose-dependent manner (peak: 85+/-3, 70+/-4, 62+/-4%; sustained: 94+/-5, 80+/-5, 72+/-5% of control respectively). Tyrosine kinase inhibition (tyrphostin 23) attenuated CCE (peak: 67+/-4%; sustained: 74+/-5% of control), but the propofol-induced decrease in CCE was still apparent after tyrosine kinases inhibition. PKC activation (phorbol 12-myristate 13-acetate) attenuated CCE (peak: 48+/-1%; sustained: 53+/-3% of control), whereas PKC inhibition (bisindolylmaleimide) potentiated CCE (peak: 132+/-11%; sustained: 120+/-4% of control). Moreover, PKC inhibition abolished the propofol-induced attenuation of CCE.

Conclusion
Tyrosine kinases activate and PKC inhibits CCE in PASMCs. Propofol attenuates CCE primarily via a PKC-dependent pathway. CCE should be considered a possible cellular target for anesthetic agents that alter vascular smooth muscle tone.
Lesions of the Basolateral Amygdala Complex Block Propofol-induced Amnesia for Inhibitory Avoidance Learning in Rats
Authors: Alkire Michael T. , Vazdarjanova Almira , Dickinson-Anson Heather , White Nathan S. , Cahill Larry 
Published: November 2003

Background
As the unitary theory of anesthesia gives way to the "multiple sites, multiple mechanisms" concept, the sites involved in mediating the components of anesthesia must be identified. In the current study, we test the hypothesis that the basolateral amygdala complex (BLAC) is a brain site involved with mediating propofol-induced amnesia.

Methods
Male Sprague-Dawley rats were divided into two groups, sham-operated control animals and rats given bilateral excitotoxic N-methyl-D-aspartate lesions of the BLAC. For each group, animals were given intraperitoneal saline or propofol (25 mg/kg) 5 min before inhibitory avoidance learning. Rats were given a foot shock (0.4 mA) upon entering the dark side of a two-sided apparatus. Rats could escape additional shock by returning to and staying in the light side. Training ended after shock avoidance for greater than 60 s. Memory was tested at 24 h. Longer latencies to enter the dark side 24 h after training imply better memory.

Results
Sham-saline-treated animals had a robust memory latency (median latency [interquartile range] = 300 [163-567] s). Sham-propofo-treated animals exhibited a significant anterograde amnesia (latency = 63 [14-111] s) (P < 0.05 vs. sham-saline-treated animal). Both the saline-injected and propofol-injected animals with BLAC lesions showed robust memory (latency = 300 [264-485] and 323 [143480] s, respectively). These latencies did not differ from performance in the sham-saline-treated group and were significantly higher than the latency of the sham-propofol-treated group (both P < 0.05).

Conclusions
Discrete BLAC lesions blocked the amnestic effect of propofol. BLAC activity appears to be a requirement for propofol-induced amnesia. This finding suggests that the BLAC is a key brain site mediating anesthetic-induced amnesia.
Autosomal Dominant Canine Malignant Hyperthermia Is Caused by a Mutation in the Gene Encoding the Skeletal Muscle Calcium Release Channel (RYR1 )
Authors: Roberts Monica C. , Mickelson James R. , Patterson Edward E. , Nelson Thomas E. , Jane Armstrong P. , Brunson David B. , Hogan Kirk 
Published: November 2003

Background
Malignant hyperthermia (MH) is an inherited disorder of skeletal muscle characterized by hypercarbia, rhabdomyolysis, generalized skeletal muscle contracture, cardiac dysrhythmia, and renal failure, that develops on exposure to succinylcholine or volatile anesthetic agents. All swine and up to 50% of human MH events are thought to be associated with mutations in the calcium release channel of the sarcoplasmic reticulum, also known as the ryanodine receptor (RYR1). Events resembling MH have been reported in other species, but none have undergone genetic investigation to date.

Methods
To determine the molecular basis of canine MH, a breeding colony was established with a male, mixed-breed, MH-susceptible (MHS) dog that survived an in vivo halothane-succinylcholine challenge. He was mated to three unaffected females to produce four litters and back-crossed to an affected daughter to produce one litter. One of his MHS sons was mated to an unaffected female to produce an additional litter. Forty-seven dogs were phenotyped with an in vitro contracture test and diagnosed as MHS or MH normal based on the North American in vitro contracture test protocol. Nine microsatellite markers in the vicinity of RYR1 on canine chromosome 1 (CFA01) were tested for linkage to the MHS phenotype. Mutational analysis in two MHS and two MH-normal dogs was performed with direct sequencing of polymerase chain reaction products and of cloned fragments that represent frequently mutated human RYR1 regions. A restriction fragment length polymorphism was chosen to detect the candidate mutation in the pedigree at large.

Results
Pedigree inspection revealed that MHS in this colony is transmitted as an autosomal dominant trait. FH2294, the marker closest to RYR1, is linked to MHS at a theta = 0.03 with a LOD score of 9.24. A T1640C mutation gives rise to an alanine for valine substitution of amino acid 547 in the RYR1 protein, generating a maximum LOD score of 12.29 at theta = 0.00. All dogs diagnosed as MHS by in vitro contracture test were heterozygous for the mutation, and all MH-normal dogs were homozygous for the T1640 allele.

Conclusions
These results indicate that autosomal dominant canine MH is caused by a mutation in the gene encoding the skeletal muscle calcium release channel and that the MHS trait in this pedigree of mixed-breed dogs is in perfect cosegregation with the RYR1 V547A mutation.
Opioid Action on Respiratory Neuron Activity of the Isolated Respiratory Network in Newborn Rats
Authors: Takeda Shinhiro , Eriksson Lars I. , Yamamoto Yuji , Joensen Henning , Onimaru Hiroshi , E. Lindahl Sten G. 
Published: November 2003

Background
Underlying mechanisms behind opioid-induced respiratory depression are not fully understood. The authors investigated changes in burst rate, intraburst firing frequency, membrane properties, as well as presynaptic and postsynaptic events of respiratory neurons in the isolated brainstem after administration of opioid receptor agonists.

Methods
Newborn rat brainstem-spinal cord preparations were used and superfused with mu-, kappa-, and delta-opioid receptor agonists. Whole cell recordings were performed from three major classes of respiratory neurons (inspiratory, preinspiratory, and expiratory).

Results
Mu- and kappa-opioid receptor agonists reduced the spontaneous burst activity of inspiratory neurons and the C4 nerve activity. Forty-two percent of the inspiratory neurons were hyperpolarized and decreased in membrane resistance during opioid-induced respiratory depression. Furthermore, under synaptic block by tetrodotoxin perfusion, similar changes of inspiratory neuronal membrane properties occurred after application of mu- and kappa-opioid receptor agonists. In contrast, resting membrane potential and membrane resistance of preinspiratory and majority of expiratory neurons were unchanged by opioid receptor agonists, even during tetrodotoxin perfusion. Simultaneous recordings of inspiratory and preinspiratory neuronal activities confirmed the selective inhibition of inspiratory neurons caused by mu- and kappa-opioid receptor agonists. Application of opioids reduced the slope of rising of excitatory postsynaptic potentials evoked by contralateral medulla stimulation, resulting in a prolongation of the latency of successive first action potential responses.

Conclusions
Mu- and kappa-opioid receptor agonists caused reduction of final motor outputs by mainly inhibiting medullary inspiratory neuron network. This inhibition of inspiratory neurons seems to be a result of both a presynaptic and postsynaptic inhibition. The central respiratory rhythm as reflected by the preinspiratory neuron burst rate was essentially unaltered by the agonists.