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1. |
The NMDA Receptor Competitive Antagonist CPP Modulates Benzodiazepine Tolerance and Discontinuation |
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Pharmacology,
Volume 55,
Issue 5,
1997,
Page 217-227
Jonathan M. Koff,
Gary A. Pritchard,
David J. Greenblatt,
Lawrence G. Miller,
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摘要:
Benzodiazepine discontinuation is characterized by a syndrome of increased activity and reduced seizure threshold that is similar to effects mediated by the glutamatergic system. To elucidate the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuation, we administered lorazepam, the NMDA antagonist CPP, and the combination of these compounds either concomitantly or consecutively to mice via osmotic pumps and evaluated pentylenetetrazole-induced seizure threshold, open-field activity, and benzodiazepine receptor binding during and after chronic administration. Animals receiving lorazepam alone developed partial tolerance at 7 days and complete tolerance at 14 days to the anticonvulsant effects of lorazepam. This effect was partly attenuated by CPP coadministration with lorazepam. This combination produced only partial tolerance. A reduction in seizure threshold was observed 4 days after discontinuation of lorazepam alone. This effect was abolished by coadministration of CPP with lorazepam and by CPP administration during the withdrawal period. Benzodiazepine binding in most structures examined was significantly reduced at 14 days during chronic lorazepam administration (versus 1 day), and coadministration of CPP did not alter this decrement. After lorazepam discontinuation, binding was increased at 4 and 7 days versus chronically treated animals and versus vehicle within the cerebral cortex. This effect was abolished by coadministration of CPP as well as by CPP administration during the lorazepam withdrawal period. These data support the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuation.
ISSN:0031-7012
DOI:10.1159/000139531
出版商:S. Karger AG
年代:1997
数据来源: Karger
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2. |
Effects of Phenytoin on the Amygdala Neurons in vitro |
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Pharmacology,
Volume 55,
Issue 5,
1997,
Page 228-234
Li-Ling Cheng,
Su-Jane Wang,
Jing-Jane Tsai,
Po-Wu Gean,
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摘要:
The present study was aimed at elucidating the possible mechanisms underlying the anticonvulsant efficacy of phenytoin using intracellular recording techniques in the in vitro amygdalar slice preparation. Synaptic response mediated by the N-methyl-D-aspartate (NMDA) receptor (EPSPnmda) was isolated pharmacologically by application of a solution containing non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 µmol/l) and γ-aminobutyric acidA receptor antagonist bicuculline (20 µmol/l). Phenytoin inhibits the amplitude of EPSPnmda without affecting the postsynaptic depolarization induced by exogenous application of NMDA. In addition, phenytoin increases the magnitude of paired-pulse facilitation which is consistent with a presynaptic mode of action. These results suggest that inhibition of transmitter release due to presynaptic blockade of Na+ and/or Ca2+ channels may account largely for the anticonvulsant efficacy of phenyto
ISSN:0031-7012
DOI:10.1159/000139532
出版商:S. Karger AG
年代:1997
数据来源: Karger
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3. |
Metabolism of the Tricyclic Antidepressant Amitriptyline by cDNA-Expressed Human Cytochrome P450 Enzymes |
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Pharmacology,
Volume 55,
Issue 5,
1997,
Page 235-243
Ole V. Olesen,
Kristian Linnet,
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摘要:
The metabolism of amitriptyline was studied in vitro using cDNA-expressed human cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6 and 2E1. CYP 2C19 was the most important enzyme with regard to the demethylation of amitriptyline, the quantitatively most important metabolic pathway. CYP 1A2, 3A4, 2C9 and CYP 2D6 also participated in the demethylation of amitriptyline. CYP 2D6 was the sole enzyme mediating the hydroxylation of amitriptyline, and (E)-10-OH-amitriptyline was exclusively produced. CYP 2E1 did not metabolize amitriptyline. Concerning the quantitative relations, CYP 2C19 and 2D6 exhibited high affinities with Km values in the range of 5-13 µmol/l, whereas the affinities of 1 A2, 3A4 and 2C9 were somewhat lower with Km values ranging from 74 to 92 µmol/l. CYP 2C19 displayed the highest reaction capacity per mole with Vmax equal to 475 mol h–1 (mol CYP)–1. The other enzymes had Vmax values in the range of 90–145 mol h–1 (mol CYP)–1. Allowing for the typical relative distribution of amounts of CYP enzymes in the liver, a simulation study suggested that, at therapeutic doses, on average about 60% of the metabolism depended on CYP 2C19. At toxic doses, CYP 2C19 is expected to be saturated, and CYP 3A4 may now play a dominant role in the
ISSN:0031-7012
DOI:10.1159/000139533
出版商:S. Karger AG
年代:1997
数据来源: Karger
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4. |
Inhibition of Sympathetic Outflow by the Angiotensin II Receptor Antagonist, Eprosartan, but not by Losartan, Valsartan or Irbesartan: Relationship to Differences in Prejunctional Angiotensin II Receptor Blockade |
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Pharmacology,
Volume 55,
Issue 5,
1997,
Page 244-251
Eliot H. Ohlstein,
David P. Brooks,
Giora Z. Feuerstein,
Robert R. Ruffolo Jr.,
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摘要:
It is well established that angiotensin II can enhance sympathetic nervous system function by activating prejunctional angiotensin II type 1 (ATI) receptors located on sympathetic nerve terminals. Stimulation of these receptors enhances stimulus-evoked norepinephrine release, leading to increased activation of vascular α1-adrenoceptors and consequently to enhanced vasoconstriction. In the present study, the effects of several chemically distinct nonpeptide angiotensin II receptor antagonists were evaluated on pressor responses evoked by activation of sympathetic outflow through spinal cord stimulation in the pithed rat. Stimulation of thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses. Infusion of sub-pressor doses of angiotensin II (40 ng/kg/min) shifted leftward the frequency-response curves for increases in blood pressure, indicating augmented sympathetic outflow. Furthermore, pressor responses resulting in spinal cord stimulation were inhibited by the peptide angiotensin II receptor antagonist, Sar1,Ile8 [angiotensin II] (10 µg/kg/min). These results confirm the existence of prejunctional angiotensin II receptors at the vascular neuroeffector junction that facilitate release of norepinephrine. The nonpeptide angiotensin II receptor antagonist, eprosartan (0.3 mg/kg i.v.), inhibited the pressor response induced by spinal cord stimulation in a manner similar to that observed with the peptide antagonist, Sar1,Ile8[angiotensin II]. In contrast, equivalent doses (0.3 mg/kg i.v.) of other nonpeptide angiotensin II receptor antagonists, such as losartan, valsartan, and irbesartan, had no effect on spinal cord stimulation of sympathetic outflow in the pithed rat. Although the mechanism by which eprosartan, but not the other nonpeptide angiotensin II receptor antagonists, inhibits sympathetic outflow in the pithed rat is unknown, one possibility is that eprosartan is a more effective antagonist of prejunctional angiotensin II receptors that augment neurotransmitter release. Because eprosartan is more effective in inhibiting sympathetic nervous system activity compared to other chemically distinct nonpeptide angiotensin II receptor antagonists, eprosartan may be more effective in lowering systolic blood pressure and in treating isolated systolic hypertensio
ISSN:0031-7012
DOI:10.1159/000139534
出版商:S. Karger AG
年代:1997
数据来源: Karger
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5. |
Effect of Trilinolein on Superoxide Dismutase Activity and Left Ventricular Pressure in Isolated Rat Hearts Subjected to Hypoxia and Normoxic Perfusion |
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Pharmacology,
Volume 55,
Issue 5,
1997,
Page 252-258
Paul Chan,
Chiang-Shan Niu,
Brian Tomlinson,
Chi-Tzong Hong,
Jane-Pyng Chen,
Chuang-Ye Hong,
Shen-Kou Tsai,
Juei-Tang Cheng,
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摘要:
Oxygen-derived free radicals have been implicated in the development of myocardial injury during hypoxia/reperfusion. Antioxidants can effectively inhibit the formation of free radicals and ameliorate the myocardial damage which may occur during hypoxia/reperfusion. Trilinolein is a triacylglycerol recently purified from the traditional Chinese medicinal plant Panax pseudo-ginseng. It has linoleic-acid residues as the only type of fatty acid residue in all three esterified positions of the triacyglycerol. It has been proposed that decreased endogenous superoxide dismutase (SOD) activity may contribute to free radical-mediated reperfusion injury of the ischemic myocardium. In the present study, when isolated rat hearts were subjected to hypoxia for 10, 30, 60 and 90 min without normoxic perfusion, a significant decrease in Mn-SOD activity was shown throughout the period of hypoxia, whereas the Cu·Zn-SOD activity was increased at 10 and 30 min but was not different from the baseline at 60 and 90 min of hypoxia. In rat hearts pretreated with 10–7 mol/l trilinolein and subjected to 60 min of hypoxia without normoxic perfusion, Cu·Zn-SOD was augmented compared with baseline and compared with hearts subjected to 60 min of hypoxia without trilinolein, whereas Mn-SOD activity was still reduced compared with baseline, although less so than after 60 min of hypoxia without trilinolein. Pretreatment with trilinolein was associated with better preservation of left ventricular function during hypoxia and more rapid return to recovery during normoxic perfusion. This myocardial protective effect may be related to an antioxidant effect through potentiation of SOD, particularly Cu·Zn-SOD during hyp
ISSN:0031-7012
DOI:10.1159/000139535
出版商:S. Karger AG
年代:1997
数据来源: Karger
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6. |
Lidocaine Attenuates Mechanical and Metabolic Derangements Induced by Palmitoyl-L-Carnitine in the Isolated Perfused Rat Heart |
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Pharmacology,
Volume 55,
Issue 5,
1997,
Page 259-268
Johji Arakawa,
Akiyoshi Hara,
Naohiro Kokita,
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摘要:
The effect of lidocaine on the palmitoyl-L-carnitine (PAL-CAR)-induced mechanical and metabolic derangements was studied in Langendorff rat hearts, perfused aerobically at a constant flow rate and paced electrically. PALCAR (5 µmol/l) increased the left ventricular end-diastolic pressure, decreased the left ventricular developed pressure (i.e., mechanical dysfunction), and decreased the tissue levels of adenosine triphosphate and creatine phosphate (i.e., metabolic change). These mechanical and metabolic alterations induced by PALCAR were concentration-dependently attenuated by lidocaine (20, 50 or 100 µmol/l). Nevertheless, lidocaine (20, 50 or 100 µmol/l) did not affect the mechanical function and energy metabolism of the normal (PALCAR-untreated) heart. These results indicate that lidocaine has a cardioprotective action against the PALCAR-induced mechanical and metabolic derangemen
ISSN:0031-7012
DOI:10.1159/000139536
出版商:S. Karger AG
年代:1997
数据来源: Karger
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