Zhongguo yao li xue bao = Acta pharmacologica Sinica最新文献

Aim: To study the influence of dopamine (DA) receptor antagonists upon the rewarding property of dihydroetorphine (DHE).

Methods: Conditioned place preference (CPP) paradigm was used to characterize the rewarding effect of DHE. DA receptor antagonists were injected administered subcutaneously or peritoneally and microinjected into nucleus accumbens (NAcc).

Results: DHE (0.05, 0.5, and 5.0 micrograms.kg-1, s.c.) produced place preference (P < 0.01). Both the DA receptor antagonist haloperidol and the selective D1 receptor antagonist Sch-23390 attenuated the place preference produced by DHE (0.5 microgram.kg-1, s.c.). l-Sulpiride and spiperone, selective D2 receptor antagonists, had no such effects.

Conclusion: The D1 (but not D2) receptors in NAcc are crucial in the mediation of the rewarding effect of DHE.

Aim: To study the antagonistic effect of selective neuronal nitric-oxide synthase (nNOS) inhibitor 7-nitroindazole on the long-term potentiation (LTP) induced by l-clausenamide (Cla) in rat hippocampus in vivo.

Methods: Population spike (PS) of evoked potentials was determined by extracellular recording technique in the hippocampal dentate gyrus (DG) of anesthetized rats.

Results: 7-Nitroindazole 2 nmol icv blocked the induction of LTP elicited by high-frequency (100 Hz) stimulation or Cla 5 nmol icv (P < 0.01), and L-arginine 225 mg.kg-1 i.p. prevented the action of 7-nitroindazole (P < 0.01).

Conclusion: Nitric oxide produced by nNOS plays a role in the induction of Cla-induced LTP in hippocampus.

Aim: To explore the modulatory effect of baclofen on NMDA-activated current in rat dorsal root ganglion (DRG) neurons.

Methods: Whole-cell patch-clamp technique was used to record NMDA-activated current in isolated DRG neurons. Drugs were applied by rapid solution exchange.

Results: Preapplication of baclofen 1-100 mumol.L-1 induced a concentration-dependent inhibition of the inward NMDA-activated current markedly. NMDA (100 mumol.L-1)-activated current was inhibited by 52% +/- 14% (n = 11, P < 0.01) by preapplication of baclofen 100 mumol.L-1. The inhibitory effect of baclofen was reversible, and was removed by saclofen 100 mumol.L-1, which was a selective antagonist of GABAB receptor.

Conclusion: Preapplication of baclofen exerts an inhibitory effect on NMDA-activated current in the primary sensory neurons.

Aim: To characterize a voltage-dependent outward K+ current in cultured heart cells of 14-16-day-old embryos of yellow chick.

Methods: The patchclamp technique in the whole-cell configuration was used.

Results: The kinetics and the pharmacology of the outward K+ current in our cell mold were different from those described in white chick. Like the calcium-activated K+ current, blocker of calcium channel, CdCl2, eliminated the current of more than 95%. Isoproterenol provoked an increase of peak amplitude (137% +/- 47%, n = 16 cells) and acceleration of activation kinetics in the outward K+ current (the time reaching a peak current reduced from 36 ms +/- 10 ms to 16 ms +/- 9 ms). This effect of isoproterenol was mimiced by cAMP. In addition, a frequency-dependent decrease in peak amplitude of the current occurred after cAMP-induced phosphorylation.

Conclusion: There are species- and/or cell-type-specific difference in the K+ channels properties. In embryonic yellow chick heart cells, the phospholation of channel could not only modulate the activation kinetic properties of the calcium-activated potassium channel, but also change their recovery kinetics.

Aim: To clarify the role of vascular endothelial growth factor (VEGF) in neuronal damage induced by cerebral ischemia.

Methods: Expression of VEGF in adult rat brain was measured by immunohistochemistry. Transient middle cerebral artery occlusion (MCAO) model was induced by placing a nylon thread in the lumen of the internal carotid artery. The infarct volume was shown with 2,3,5-triphenyltetrazolium chloride (TTC) staining and quantitated by computer image analyzer with and without VEGF antibody treatment.

Results: VEGF expression was widely distributed in neuronal cells besides vascular endothelial cells, and the neuronal distribution of VEGF was specific. After intraventricular treatment with VEGF antibody (0.1 g.L-1 daily, for 7 d following the ischemia), infarct volume in the antibody treatment was increased versus vehicle-treated rats [(21.6 +/- 2.7 vs 16 +/- 6) mm3, P < 0.05] respectively.

Conclusion: Intraventricular injection of VEGF antibody increased the infarct volume after focal cerebral ischemia in rats, suggesting that expression of neuronal VEGF may be one of neuronal protective mechanisms.

Aim: To explore the capacity and characteristics of adrenal mitochondria to metabolize xenobiotics in vitro in human fetus.

Methods: Subcellular fractions of fetal adrenal were prepared by differential centrifugation. Mitochondrial P-450 system was proved by spectral analyses and SDS-PAGE. The formaldehyde formation contents were measured with Nash reagent.

Results: The erythromycin N-demethylation linearly increased in the protein concentration (1-4 mg)- and incubation time (10-30 min)-dependent manners. A typical concentration-effect relationship appeared with erythromycin 0.067-1 mmol.L-1 and a positive correlation (r = 0.641, P < 0.05) existed between erythromycin N-demethylation and gestation months. The N-demethylation values (nmol.s-1/g protein) of erythromycin (2.7 +/- 0.8), benzfetamine (1.1 +/- 0.5), and aminophenazone (0.9 +/- 0.4) in mitochondria were 89% (P > 0.05), 162% (P < 0.01), and 62% (P < 0.01), respectively, of those in microsomes. There was correlation between mitochondria and microsomes in the N-demethylation of erythromycin (r = 0.708, P < 0.05) and benzfetamine (r = 0.707, P < 0.05). Troleandomycin stimulated erythromycin N-demethylation in adrenal mitochondria as well as in adrenal and liver microsomes in vitro.

Conclusion: Fetal adrenal mitochondria, with multiple P-450 isoforms and greater capacity of demethylation, play a role in drug-metabolism during fetal development.

Aim: To verify the effectiveness of structure-activity relationship (SAR) and theoretical calculation methods for antioxidants.

Methods: Preliminary elucidation on the differences of activities of 5 antioxidants was performed by SAR. Then semiempirical quantum chemistry method AM1 was employed to calculate the delta HOF value, the difference between the heat of formation of antioxidant and its free radical, which was used as a theoretical parameter to elucidate the differences of activities of the antioxidants thoroughly.

Results: delta HOF values of antioxidants were obtained as follows: ferulic acid, 150.58 kJ.mol-1; anion of ferulic acid, 122.64 kJ.mol-1; modified ferulic acid, 137.70 kJ.mol-1; anion of modified ferulic acid, 118.99 kJ.mol-1; salvianic acid, 134.17 kJ.mol-1; rutin, 137.83 kJ.mol-1, L-EGCG, 124.39 kJ.mol-1; paeonol, 176.79 kJ.mol-1. The differences of the antioxidant activities were elucidated, and how to further enhance the antioxidant activity was investigated as well.

Conclusion: The SAR and calculation methods are rather effective to elucidate the differences of antioxidant activities, and present some new clues for structural modification of antioxidants to increase their activities.

Aim: To study correlation between inhibitions of naloxone-precipitated withdrawal jumps and nitric-oxide synthase (NOS) activity by agmatine.

Methods: NOS activities in mouse brain were measured by determination of concentration of [3H]citrulline, the product of [3H]arginine.

Results: Agmatine inhibited NOS activity in naive and morphine-dependent mouse cerebellum, forebrain, and thalamus in substrate-competitive manner in vitro. Naloxone induced withdrawal jumps and an increase in NOS activity in cerebellum, forebrain, and thalamus of abstinent mice. Pretreatment of mice with morphine plus agmatine inhibited the effect of naloxone to precipitate withdrawal jumps and increase in NOS activity. The effect of agmatine was blocked by idazoxan.

Conclusion: The inhibitory effect of agmatine on naloxone-precipitated withdrawal jumps is related to its inhibition of NOS activity by substrate competitive manner and activation of imidazoline receptors.

Aim: To study the relationship between adenosine (Ade) receptors and adenosine 5'-triphosphate (ATP)-sensitive potassium (KATP) channels in rat aorta.

Methods: Isolated rat aorta rings were suspended for isometric force recording. The vascular effects of Ade were assessed in the presence or absence of functional endothelium. The interactions of Ade and pinacidil (Pin) or glibenclamide (Gli) were investigated.

Results: In isolated aorta preconstricted with KCl 20 mmol.L-1, Ade 3-300 mumol.L-1 induced relaxation in a concentration-dependent manner; and in 48/99 preparations from 32 rats, Ade induced initial transient constriction followed by sustained relaxation. When the functions of KATP channels were blocked with Gli 1 or 100 mumol.L-1, effects of Ade were characterized by vasoconstriction rather than vasorelaxation. The combination of Pin 1 mumol.L-1 with Ade 100 mumol.L-1 showed no synergic vasodilatory effects and did not affect Ade-induced vasoconstriction. After the removal of endothelium, Ade still induced vasoconstriction and vasorelaxation, and the constrictive effects showed no difference from those in the presence of endothelium, but the potency of vasodilatory effects became weaker with slower decrease in tension.

Conclusion: The activation of KATP channels is involved in Ade receptor-induced vasodilation.

Aim: To study the effects of basic fibroblast growth factor (bFGF) on the proliferation of lymphokine-activated killer (LAK) cells from patients with bladder cancer and LAK cells cytolysis against bladder tumor cells.

Methods: LAK cell proliferation was assayed in the presence of various concentrations of bFGF combined with interleukin-2 (IL-2) by cell count. Cytotoxicity of LAK cells against bladder cancer cell line EJ cells and bladder tumor cells (BTC) from patients was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays.

Results: The proliferation of peripheral blood monocytes (PBMC) was inhibited by bFGF 5 micrograms.L-1. bFGF did not affect the stimulation of LAK cells induced by IL-2. The LAK cell numbers in the combination of IL-2 with bFGF were not significantly different compared with that treated with IL-2 alone. bFGF enhanced cytotoxicity of LAK cells against bladder cancer cell line EJ cells or BTC, respectively.

Conclusion: Although the proliferation of PBMC was inhibited by bFGF, bFGF increased LAK cell cytotoxicity against bladder neoplasm cells.