bluuebunny/crossref_metadata_2025_split huggingface dataset:
Despite In Vitro Increase in Cyclic Guanosine Monophosphate Concentrations, Intracarotid Nitroprusside Fails to Augment Cerebral Blood Flow of Healthy Baboons
Authors: Joshi Shailendra , Hartl Roger , Sun Lena S. , Libow Adam D. , Wang Mei , Pile-Spellman John , Young William L. , Connolly E. Sander , Hirshman Carol A. 
Published: November 2003

Background
During cerebral angiography, intracarotid infusion of sodium nitroprusside (SNP), an endothelium-independent nitric oxide donor, fails to increase cerebral blood flow (CBF) of human subjects. A confounding effect of intracranial pathology or that of radiocontrast could not be ruled out in these experiments. The authors hypothesized that, if nitric oxide was a significant regulator of CBF of primates, then intracarotid SNP will augment CBF of baboons.

Methods
In studies, CBF (intraarterial (133)Xe technique) was measured in healthy baboons during isoflurane anesthesia at (1) baseline and during (2) induced hypertension with intravenous phenylephrine, (3) concurrent infusions of intravenous phenylephrine and intracarotid SNP, and (4) intracarotid verapamil (positive control drug). In studies, the authors measured tissue cyclic guanosine monophosphate (cGMP) by radioimmunoassay after incubating vascular rings obtained from freshly killed baboons (1) with increasing concentrations of SNP and (2) after SNP exposure following preincubation with the radiocontrast agent, iohexhol.

Results
In the studies, coinfusion of intravenous phenylephrine and intracarotid SNP did not increase CBF. However, intracarotid verapamil significantly increased CBF (from 26 +/- 7 to 43 +/- 11 ml x 100 g(-1) x min(-1); P < 0.0001) without a change in mean arterial pressure. In the studies, incubation of intracranial arterial rings in SNP resulted in dose-dependent increases in cGMP concentrations. A similar increase in cGMP content was evident despite iohexhol preincubation.

Conclusions
Collectively, these results suggest that, in healthy baboons, intracarotid SNP does not decrease arteriolar resistance, although SNP could affect proximal arterial tone, as demonstrated by the increase in cGMP content of these vessels.
The α2-Adrenoceptor Agonist Dexmedetomidine Converges on an Endogenous Sleep-promoting Pathway to Exert Its Sedative Effects
Authors: Nelson Laura E. , Lu Jun , Guo Tianzhi , Saper Clifford B. , Franks Nicholas P. , Maze Mervyn 
Published: November 2003

Background
The authors investigated whether the sedative, or hypnotic, action of the general anesthetic dexmedetomidine (a selective alpha -adrenoceptor agonist) activates endogenous nonrapid eye movement (NREM) sleep-promoting pathways.

Methods
c-Fos expression in sleep-promoting brain nuclei was assessed in rats using immunohistochemistry and hybridization. Next, the authors perturbed these pathways using (1) discrete lesions induced by ibotenic acid, (2) local and systemic administration of gamma-aminobutyric acid receptor type A (GABA ) receptor antagonist gabazine, or (3) alpha2-adrenoceptor antagonist atipamezole in rats, and (4) genetic mutation of the alpha -adrenoceptor in mice.

Results
Dexmedetomidine induced a qualitatively similar pattern of c-Fos expression in rats as seen during normal NREM sleep, a decrease in the locus ceruleus (LC) and tuberomammillary nucleus (TMN) and an increase in the ventrolateral preoptic nucleus (VLPO). These changes were attenuated by atipamezole and were not seen in mice lacking functional alpha2a-adrenoceptors, which do not show a sedative response to dexmedetomidine. Bilateral VLPO lesions attenuated the sedative response to dexmedetomidine, and the dose-response curve to dexmedetomidine was shifted right by gabazine administered systemically or directly into the TMN. VLPO lesions and gabazine pretreatment altered c-Fos expression in the TMN but in not the LC after dexmedetomidine administration, indicating a hierarchical sequence of changes.

Conclusions
The authors propose that endogenous sleep pathways are causally involved in dexmedetomidine-induced sedation; dexmedetomidine's sedative mechanism involves inhibition of the LC, which disinhibits VLPO firing. The increased release of GABA at the terminals of the VLPO inhibits TMN firing, which is required for the sedative response.
Thermogenesis Inhibition in Brown Adipocytes Is a Specific Property of Volatile Anesthetics
Authors: Ohlson Kerstin B.E. , Lindahl Sten G.E. , Cannon Barbara , Nedergaard Jan 
Published: November 2003

Background
This investigation examined the possibility that the inhibitory effect of halothane on nonshivering thermogenesis (heat production) in brown adipocytes is not a universal effect of all anesthetic agents but related to the type of anesthetic.

Methods
Brown adipocytes from hamster were isolated with a collagenase digestion method and incubated with anesthetic agents. The rate of oxygen consumption was measured with an oxygen electrode. The effect of clinically relevant (and higher) doses of anesthetics of different classes on basal and norepinephrine-induced thermogenesis (oxygen consumption) was tested.

Results
Two distinct groups of anesthetics could be distinguished: thermogenesis inhibitors and noninhibitors. Thermogenesis inhibitors include volatile anesthetics such as halothane (IC(50), 1.1 mm), ether (IC(50), 20 mm), and chloroform (IC(50), 2.2 mm) (nominal concentrations), but also tribromoethanol (IC(50), 0.6 mm), all inducing inhibition of norepinephrine-induced thermogenesis without affecting the EC for norepinephrine. Thermogenesis noninhibitors include the nonvolatile anesthetics pentobarbital, propofol, ketamine, and urethane, the inhalation anesthetic nitrous oxide, and, notably, also the volatile nonanesthetics (nonimmobilizers) 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane; none of these compounds had any effect on norepinephrine-induced thermogenesis at any concentration tested.

Conclusions
There are two distinct classes of anesthetics with regard to effects on thermogenesis, thermogenesis inhibitors and thermogenesis noninhibitors. The results are important for the interpretation of studies in thermal biology in general; specifically, they indicate that conclusions concerning regulation of nonshivering thermogenesis during anesthesia depend on the type of anesthetic used. Of clinical importance is that the volatile anesthetics are inhibitory for nonshivering thermogenesis and thus for an alternative heat production when myorelaxants prevent shivering. As the distinction between thermogenesis inhibitors and thermogenesis noninhibitors corresponds to the distinction between volatile and nonvolatile anesthetics, it may be related to the mode of action of the volatile anesthetics.
Neuroprotective Effect of Urinary Trypsin Inhibitor against Focal Cerebral Ischemia–Reperfusion Injury in Rats
Authors: Yano Toshiyuki , Anraku Sakiko , Nakayama Ryosuke , Ushijima Kazuo 
Published: November 2003

Background
Acute inflammatory reactions cause neuronal damage in cerebral ischemia-reperfusion. Urinary trypsin inhibitor (UTI), a serine protease inhibitor, is cytoprotective against ischemia-reperfusion injury in the liver, intestine, kidney, heart, and lung through its antiinflammatory activity. Neuroprotective action of UTI on transient global cerebral ischemia has been documented. This is the first study to determine whether UTI is neuroprotective against transient focal cerebral ischemia.

Methods
Adult male Wistar rats were randomly assigned to the following treatment groups: 0.9% saline (control, n = 9); 100,000 U/kg UTI (n = 9); and 300,000 U/kg UTI (n = 9). Treatments were performed intravenously 10 min before right middle cerebral artery occlusion for 2 h and subsequent reperfusion. Ninety-six hours after the onset of reperfusion, the motor neurologic deficit and the cerebral infarct size were evaluated. Furthermore, immunohistochemical staining for myeloperoxidase and nitrotyrosine to count infiltrating neutrophils and nitrated cells, respectively, was performed on the brain sections.

Results
Infarct volume in the 300,000 U/kg UTI group was smaller than in the 100,000 U/kg UTI and saline control groups (P < 0.05). Treatment with 300,000 U/kg UTI showed a trend to improve neurologic outcome but did not reach statistical significance (P = 0.0693). The significant decrease in neutrophil infiltration was observed in the ischemic hemisphere treated with 300,000 U/kg UTI compared with saline control (P < 0.05). Nitrotyrosine deposition in the ischemic hemisphere was significantly reduced in the 300,000 U/kg UTI group compared with saline control and 100,000 U/kg UTI groups (P < 0.05).

Conclusions
Intravenous pretreatment with 300,000 U/kg UTI reduces focal ischemia-reperfusion injury in the rat brain, potentially opening a novel therapeutic avenue for the treatment of cerebral ischemia.
Comparative Analysis of Apoptosis-inducing Activity of Codeine and Codeinone
Authors: Hitosugi Naoko , Hatsukari Ikusuke , Ohno Rie , Hashimoto Ken , Mihara Saori , Mizukami Satoshi , Nakamura Shinichi , Sakagami Hiroshi , Nagasaka Hiroshi , Matsumoto Isao , Kawase Masami 
Published: November 2003

Background
There are relatively few studies about the antiproliferative effects of codeine-related compounds on human cancer cell lines, compared with those of morphine-related compounds. The authors previously found that codeinone, an oxidation metabolite of codeine, among 10 opioids, showed the highest cytotoxic activity (DNA fragmentation-inducing activity) against human promyelocytic leukemic cell lines (HL-60). This was counteracted by an antioxidant, N-acetyl-L-cysteine (NAC). These findings prompted us to perform a more detailed study of apoptosis induction after codeinone treatment.

Methods
Apoptosis was induced by treating HL-60 cells for 1-6 h with codeine or codeinone. DNA fragmentation was assessed by both agarose gel electrophoresis and fluorometric determination of the fragmented DNA after staining with diamidinophenylindole (DAPI). The appearance of apoptotic cells was monitored by microscopic observation after staining with Hoechst (H)-33342, and fluorescence activated cell sorter (FACS) after staining with Annexin. The release of cytochrome c and cytochrome oxidase from mitochondria and activation of caspase 3 were monitored by Western blot analysis. Intracellular caspase 3-like activity was confirmed by FACS, using cell permeable substrate. Mitochondrial manganese-containing superoxide dismutase (MnSOD) activity and mRNA expression were assayed by activity staining after separation on the polyacrylamide gel electrophoresis, and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively.

Results
Codeinone induced internucleosomal DNA fragmentation and production of Annexin-positive apoptotic cells more potently than codeine in HL-60 cells. Codeinone stimulated the release of both cytochrome c and cytochrome oxidase, and cleavage of procaspase 3 without significant changes in both the activity and expression of MnSOD.

Conclusions
Codeinone was found to possess both apoptosis and necrosis-inducing activity, in addition to the reported antinociceptive activity, further substantiating its antitumor potential.
Xenon Attenuates Cardiopulmonary Bypass–induced Neurologic and Neurocognitive Dysfunction in the Rat
Authors: Ma Daqing , Yang Hong , Lynch John , Franks Nicholas P. , Maze Mervyn , Grocott Hilary P. 
Published: November 2003

Background
With clinical data suggesting a role for excitatory amino acid neurotransmission in the pathogenesis of cardiopulmonary bypass (CPB)-associated brain injury, the current study was designed to determine whether xenon, an N-methyl-D-aspartate receptor antagonist, would attenuate CPB-induced neurologic and neurocognitive dysfunction in the rat.

Methods
Following surgical preparation, rats were randomly divided into four groups: (1) sham rats were cannulated but did not undergo CPB; (2) CPB rats were subjected to 60 min of CPB using a membrane oxygenator receiving a gas mixture of 30% O2, 65% N2, and 5% CO2; (3) CPB + MK801 rats received MK801 (0.15 mg/kg intravenous) 15 min prior to 60 min of CPB with the same gas mixture; and (4) CPB + xenon rats underwent 60 min of CPB using an oxygenator receiving 30% O2, 60% xenon, 5% N2, and 5% CO2. Following CPB, the rats recovered for 12 days, during which they underwent standardized neurologic and neurocognitive testing (Morris water maze).

Results
The sham and CPB + xenon groups had significantly better neurologic outcome compared to both the CPB and CPB + MK801 groups on postoperative days 1 and 3 (P < 0.05). Compared to the CPB group, the sham, CPB + MK801, and CPB + xenon groups had better neurocognitive outcome on postoperative days 3 and 4 (P < 0.001). By the 12th day, the neurocognitive outcome remained significantly better in the CPB + xenon group compared to the CPB group (P < 0.01).

Conclusion
These data indicate that CPB-induced neurologic and neurocognitive dysfunction can be attenuated by the administration of xenon, potentially related to its neuroprotective effect via N-methyl-D-aspartate receptor antagonism.
Dialysis Delivery of an Adenosine A1Receptor Agonist to the Pontine Reticular Formation Decreases Acetylcholine Release and Increases Anesthesia Recovery Time
Authors: Tanase Diana , Baghdoyan Helen A. , Lydic Ralph 
Published: November 2003

Background
Adenosine modulates cell excitability, acetylcholine release, nociception, and sleep. Pontine cholinergic neurotransmission contributes to the generation and maintenance of electroencephalographic and behavioral arousal. Adenosine A(1) receptors inhibit arousal-promoting, pontine cholinergic neurons, and adenosine enhances sleep. No previous studies have determined whether pontine adenosine also modulates recovery from anesthesia. Therefore, the current study tested the hypotheses that dialysis delivery of the adenosine A(1) receptor agonist N6-p-sulfophenyladenosine (SPA) into the pontine reticular formation would decrease acetylcholine release and increase the time needed for recovery from halothane anesthesia.

Methods
A microdialysis probe was positioned in the pontine reticular formation of halothane-anesthetized cats. Probes were perfused with Ringer's solution (control) followed by the adenosine A(1) receptor agonist SPA (0.088 or 8.8 mm). Dependent measures included acetylcholine release and a numeric assessment of recovery from anesthesia. An intensive, within-subjects design and analysis of variance evaluated SPA's main effect on acetylcholine release and anesthetic recovery. The adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 microm) was coadministered with SPA to test for antagonist blocking of SPA's effects.

Results
SPA significantly (P < 0.0001) decreased acetylcholine release in the pontine reticular formation and significantly (P < 0.0001) delayed recovery from anesthesia. Coadministration of SPA and DPCPX caused no decrease in acetylcholine release or delay in postanesthetic recovery. Dialysis delivery of SPA into the cerebellar cortex confirmed that the SPA effects were site-specific to the pontine reticular formation.

Conclusion
The results provide a novel extension of the sleep-promoting effects of adenosine by showing that pontine delivery of an adenosine A(1) receptor agonist delays resumption of wakefulness following halothane anesthesia. This extension is consistent with a potentially larger relevance of the current findings for efforts to specify neurons and molecules causing physiologic and behavioral traits comprising anesthetic states. These data support the conclusion that adenosine A(1) receptors in medial regions of the pontine reticular formation, known to modulate sleep, also contribute to the generation and/or maintenance of halothane anesthesia.
Spinal Carbonic Anhydrase Contributes to Nociceptive Reflex Enhancement by Midazolam, Pentobarbital, and Propofol
Authors: Wang Bing , Samanani Naaznin , Roth Sheldon H. , Archer David P. 
Published: November 2003

Background
Systemic administration of acetazolamide blocks nociceptive hyperreflexia induced by pentobarbital. The authors assessed the effect of intrathecal carbonic anhydrase inhibitors (CAIs) on nociceptive reflex enhancement by pentobarbital, propofol, and midazolam.

Methods
Twenty-seven rats with chronic indwelling subarachnoid catheters were studied. Nociceptive paw reflex latency (PWL) for paw withdrawal from radiant heat was measured in forelimbs and hind limbs. Measurements were obtained under control conditions, 15 min after lumbar intrathecal injection of 10 microl artificial cerebrospinal fluid containing the CAIs acetazolamide or ethoxyzolamide, and during the 55 min after intraperitoneal injection of three sedative drugs: 30 mg/kg pentobarbital, 50 mg/kg propofol, or 1.9 mg/kg midazolam.

Results
Control values of PWL averaged 10.9 +/- 1.5 s in the forelimbs and 11.1 +/- 1.6 s in the hind limbs (P = 0.18). Intrathecal injection of 50 microm ethoxyzolamide reduced PWL by 8% and 4% in the forelimbs and hind limbs, respectively (P = 0.01); all other CAI injections had no effect on PWL. Following anesthetic injection, PWL in the forelimbs was reduced by approximately 35-40% of control values; in the hind limbs, CAI treatment decreased the PWL reduction to 8-16% for pentobarbital (P < 0.001), 30-32% for propofol (P < 0.02), and 9-16% for midazolam (P < 0.001). The hind limb reduction of hyperreflexia by CAI was less for propofol than for midazolam or pentobarbital (P < 0.002).

Conclusion
Spinal carbonic anhydrase contributes to nociceptive hyperreflexia induced by pentobarbital and midazolam and to a lesser extent with propofol. These findings are consistent with a role for carbonic anhydrase in nociceptive signal enhancement by these drugs.
The Effects of Isoflurane and Desflurane on Intracranial Pressure, Cerebral Perfusion Pressure, and Cerebral Arteriovenous Oxygen Content Difference in Normocapnic Patients with Supratentorial Brain Tumors
Authors: Fraga Marcial , Rama-Maceiras Pablo , Rodiño Sara , Aymerich Humberto , Pose Pilar , Belda Javier 
Published: November 2003

Background
Desflurane is a volatile anesthetic agent with low solubility whose use in neurosurgery has been debated because of its effect on intracranial pressure and cerebral blood flow. The purpose of this study was to determine the variations on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) as well as on cerebral arteriovenous oxygen content difference (AVDo(2)) in normocapnic patients scheduled to undergo removal of supratentorial brain tumors with no evidence of mass effect during anesthesia with isoflurane or desflurane.

Methods
In 60 patients scheduled to undergo craniotomy and removal of supratentorial brain tumors with no evidence of midline shift, anesthesia was induced with intravenous fentanyl, thiopental, and vecuronium and was maintained with 60% nitrous oxide in oxygen. Patients were assigned to two groups randomized to receive 1 minimum alveolar concentration isoflurane or desflurane for 30 min. Heart rate, mean arterial pressure, intraparenchymal ICP, and CPP were monitored continuously. Before and after 30 min of continuous administration of the inhaled agents, AVDo(2) was calculated.

Results
There were no significant differences between groups in heart rate, mean arterial pressure, ICP, and CPP. ICP measurements throughout the study did not change within each group compared to baseline values. Mean arterial pressure decreased significantly in all patients compared to baseline values, changing from 105 +/- 14 mmHg (mean +/- SD) to 85 +/- 10 mmHg in the isoflurane group and from 107 +/- 11 mmHg to 86 +/- 10 mmHg in the desflurane group (P < 0.05 in both groups). CPP also decreased within each group compared with baseline values, changing from 95 +/- 15 mmHg to 74 +/- 11 mmHg in the isoflurane group and from 95 +/- 16 mmHg to 74 +/- 10 mmHg in the desflurane group (P < 0.05 in both groups). Cerebral AVDo(2) decreased significantly in both groups throughout the study, changing from 2.35 +/- 0.77 mm to 1.82 +/- 0.61 mm (mmol/l) in the isoflurane group (P < 0.05) and from 2.23 +/- 0.72 mm to 1.94 +/- 0.76 mm in the desflurane group (P < 0.05), without differences between groups.

Conclusions
The results of this study indicate that there are no variations on ICP in normocapnic patients undergoing removal of supratentorial brain tumors without midline shift, as they were anesthetized with isoflurane or desflurane. CPP and cerebral AVDo(2) decreased with both agents.
Midazolam Stimulates Vascular Endothelial Growth Factor Release in Aortic Smooth Muscle Cells
Authors: Tanabe Kumiko , Dohi Shuji , Matsuno Hiroyuki , Hirade Kouseki , Kozawa Osamu 
Published: November 2003

Background
Intravenous anesthetics used during perioperative periods affect the vascular signaling molecules and the vascular reactivity. Vascular endothelial growth factor (VEGF), an angiogenesis factor produced in and secreted from aortic smooth muscle cells, is a specific mitogen for vascular endothelial cells. This study investigated the effects of various intravenous anesthetics on VEGF release, and the underlying mechanism, in a rat aortic smooth muscle cell line, A10 cells.

Methods
Intravenous anesthetics (midazolam and propofol) were continuously administered to rats by infusion. Cultured A10 cells were stimulated by intravenous anesthetics (midazolam, propofol, and ketamine). VEGF was evaluated by immunoassay. The phosphorylation of mitogen-activated protein (MAP) kinases was evaluated by Western blotting.

Results
Continuous infusion of midazolam, but not propofol, increased the VEGF concentration in rat plasma. In cultured cells, midazolam stimulated VEGF release, but propofol and ketamine did not. Midazolam induced phosphorylation of p44/p42 MAP kinase and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), without affecting p38 MAP kinase. PD98059 and U0126, specific inhibitors of MAP kinase kinase, significantly reduced the midazolam-stimulated release of VEGF. SP600125, a specific inhibitor of SAPK/JNK, significantly reduced midazolam-stimulated VEGF release. Applied together, PD98059 and SP600125 produced an additive reduction in midazolam-stimulated VEGF release. Moreover, a bolus injection of PD98059 truly inhibited the midazolam-increased VEGF concentration in rat plasma in vivo.

Conclusions
Midazolam, but not propofol or ketamine, stimulates VEGF release in aortic smooth muscle cells. Its effect is mediated at least in part via activation of p44/p42 MAP kinase and SAPK/JNK.