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

Aim: To study the effect of artemether (Art) on phosphorylase (PP), lactate dehydrogenase (LDH), glucose-6-phosphate dehydrogenase (G-6-PDH), and adenosine triphosphatase (ATPase) of S japonicum.

Methods: Mice infected with S. japonicum cercariae for 32-38 d were treated i.g. with Art 100-300 mg.kg-1 and killed 24-72 h after treatment for collection of schistosomes. The activities of PP, LDH, and G-6-PDH were measured by the formation of NADH or NADPH. The activity of ATPase was measured by the rate of release of inorganic phosphate (Pi) from ATP at 37 degrees C.

Results: After infected mice were treated i.g. with Art 300 mg.kg-1 for 24-48 h, the activities of total PP and PPa (active form) increased markedly in both male and female worms, while PPb (inactive form) showed no or only a slight increase. At 24-72 h after the above-mentioned mice were treated i.g. with Art 100-300 mg.kg-1, the inhibitory rates of LDH and G-6-PDH were 9%-59% (male) and 41%-75% (female) as well as 22%-42% (male) and 74%-89% (female), respectively. When Art 300 mg.kg-1 was given to infected mice for 24 h, only the activity of Mg(2+)-ATPase showed marked inhibition in both male and female worms. At 48 h, the Ca(2+)-ATPase, Mg(2+)-ATPase, and Na(+)-K(+)-ATPase were all inhibited, the inhibitory rates of 17% (male) and 19% (female), 32% (male) and 48% (female) as well as 29% (male) and 44% (female), respectively.

Conclusion: In schistosomes, the increase in the activity of AMP-independent PPa induced by Art may enhance the decomposition of glycogen and the inhibition of LDH by Art could reduce the formation of lactate. Moreover, Art exerts a potent inhibition on the G-6-PDH activity of the female S japonicum.

Aim: To determine the role of the CYP2D6 phenotype in the metabolism of propafenone (Pro) enantiomers in 16 HAN Chinese subjects.

Methods: Seven very extensive metabolizers (VEM) and nine intermediate metabolizers (IM) were enrolled from a Chinese population whose phenotype had been previously assessed with a dextromethorphan metabolic phenotyping. The blood samples (0-15 h) were taken after oral administration of a single dose (400 mg) of rac-Pro hydrochloride. Enantiomeric concentrations of propafenone in plasma were measured by a reverse-phase HPLC with precolumn derivatization.

Results: S-Pro was less metabolized and had higher plasma concentrations than R-Pro in both CYP2D6 phenotypes. Besides, the T1/2 of R-Pro was longer than that of S-Pro in IM, but not in VEM. However, there were significant differences in the metabolism of Pro enantiomers between VEM and IM. The Cmax and AUC of both isomers in the IM group were higher than those in the VEM group (P < 0.01). The Cl of Pro enantiomers in IM group was only about half of that in VEM group [(67 +/- 17) vs (133 +/- 28) L.h-1 for S-Pro, (90 +/- 24) vs (200 +/- 87) L.h-1 for R-Pro, P < 0.01]. The S/R ratios of T1/2, Tmax, Cmax, Cl, and AUC were not significantly different (P > 0.05).

Conclusion: CYP2D6 phenotype determines the pharmacokinetic variability of propafenone enantiomers and existence of IM may be relevant to diminished capacity of CYP2D6 enzyme in Chinese subjects.

Aim: To compare effects of pulmonary surfactant and inhaled nitric oxide (iNO) in improvement of survival and blood oxygenation in ventilated rabbits with acute hypoxic respiratory failure induced by repeated bronchoalveolar lavage (BAL).

Methods: After BAL all the rabbits had more than 50% reduction of dynamic lung compliance (Cdya), 50% increment of resistance of respiratory system (Rrs), and an increase of mean oxygenation index (OI) from 1 to 22. The rabbits were then randomly allocated to groups receiving (1) mechanical ventilation only (Control), (2) iNO 0.8 mumol.L-1 (20 ppm) (NO), (3) intratracheal bolus surfactant phospholipids at 100 mg.kg-1 (Surf), and (4) combined surfactant at 100 mg.kg-1 with inhaled NO at 0.8 mumol.L-1 (Surf + NO). All the rabbits were ventilated with standardized tidal volume (8-10 mL.kg-1) for another 8 h or until early death.

Results: The rabbits in both control and NO groups had the lowest survival rate, deterioration of lung mechanics and OI, whereas those in the Surf and Surf + NO groups had modestly improved Cdyn, Rrs, and OI. Only rabbits in the Surf + NO group had significantly improved survival rate and alveolar expansion.

Conclusion: Surfactant with or without iNO is more effective compared to the control and iNO groups in rabbit, suggesting that iNO is not effective unless a method to recruit alveoli is applied.

Aim: To characterize the ATP diphosphohydrolase (apyrase) of bovine endocardial endothelial cells, and to compare ecto-adeninenucleotidase activity between bovine endocardial and aortic endothelial cells (BEEC and BAEC).

Methods: The nucleotide was analyzed by reversed phase HPLC and apyrase activity was assayed by inorganic phosphate release.

Results: Apyrase inhibitors, both NaN3 10 mmol.L-1 and NaF 20 mmol.L-1, inhibited BEEC apyrase activity by 51% and 38%, respectively. The inhibitor for Na+/K(+)-ATPase, ouabain, did not affect the enzyme activity. Edetic acid 5 mmol.L-1 completely inhibited the enzyme activity. H2O2 0.5 mmol.L-1 downregulated BEEC apyrase activity in a time-dependent manner. The apyrases activities in BAEC were higher than those in BEEC, while the ecto-AMPase activity in BAEC was much weaker than that in BEEC.

Conclusion: BEEC have NaN3- and NaF-sensitive, ouabain-insensitive apyrase activity. BEEC had high ecto-AMPase activities, and low apyrases activities as compared with BAEC.

A proposed scheme between the possible interactions of pro- and anti-inflammatory cytokines, NO and G-CSF during severe inflammation/infection is presented. Taken together, these data indicate that G-CSF exhibits anti-inflammatory properties which may prove to be beneficial in situations associated with an increased activity of the cellular immune system. Since the suppressive effects of G-CSF on the production of pro-inflammatory mediators like TNF-alpha and nitric oxide are most likely neither cell type nor tissue specific, it is conceivable that NO release induced by pro-inflammatory mediators can be reduced by G-CSF in various organ systems and in different forms of shock. In this context, G-CSF might represent a counterregulatory mechanism directed against a downstream oriented inflammatory response to infection. Therefore, the investigation of G-CSF in the prophylaxis of nonneutropenic infections, sepsis, and other severe inflammatory disorders seems reasonable.

Aim: To study the effects of corticotropin (Cor) on formalin-induced hyperalgesia and the change of nitric-oxide synthase (NOS)-positive neurons in spinal dorsal horn in rats.

Methods: Measurement of pain intensity rating (PIR), NADPH-d histochemistry, and Fos immunohistochemistry were adopted.

Results: The increases of NOS-positive neurons, Fos, NOS/Fos double labelling neurons of the spinal dorsal horn and the PIR after formalin injection were markedly inhibited by intrathecal injecting (ith) Cor (0.5-1.5 U), which were obviously attenuated by L-arginine (Arg, 5-15 nmol, ith), the substrate of NOS.

Conclusion: Cor inhibits formalin-induced hyperalgesia by the decrease of NOS-positive neurons in the spinal dorsal horn of rats.

Aim: To study the effects of tetrandrine (Tet) on the changes of NMDA receptor channels in cortical neurons induced by anoxia.

Methods: Cell-attached configuration of patch-clamp techniques. Anoxia was produced by perfused cells with 95% N2 + 5% CO2 gassed bath solution.

Results: During anoxia, the open time constant (tau 2), open probability (Po) of 35-pS and 100-pS channels increased. Tet 7.5 mumol.L-1 reduced the Po of 35-pS and 100-pS channels, 15 and 30 mumol.L-1 inhibited open of 100-pS channel fully, and changed the open time constant of 35-pS from two to single exponential distribution.

Conclusion: Tet inhibition of the open of NMDA receptor channels induced by anoxia was one of its protective mechanisms.

Aim: To study the effects of shikimic acid (SA) on focal cerebral ischemic injury after middle cerebral artery thrombosis (MCAT).

Methods: Thrombosis was induced by FeCl3 in middle cerebral artery of rats. The influences of SA on neurologic deficit (ND), infarct size (IS), brain edema, and cerebral blood flow (CBF) in ischemic region were observed.

Results: SA 25 and 50 mg.kg-1 i.p. for 3 d before MCAT attenuated ND, and reduced IS by 51% and 42%; and decreased brain water content from 80.7% to 79.8% and 79.9%; and increased CBF after ischemia from 50.2% of the preischemic level to 75.5% and 73.3%, respectively. In pathologic examination, there was much less thrombosis in MCA in the rat with the pretreatment by SA 25 mg.kg-1. The extent of brain ischemia was much less than that of control.

Conclusions: SA reduced focal cerebral ischemic injury induced by middle cerebral artery thrombosis.

Although estrogen-dependent effects on the vasculature were first observed more than a century ago, many of the mechanisms by which estrogens interact with the vascular wall have been identified only in the past 15 years. Estrogens bind to vascular estrogen receptors (ER), including the ER alpha, the novel ER beta as well as to membrane-bound receptors. Estrogens have direct effects in human coronary and internal mammary arteries by inducing rapid, endothelium-independent relaxation, enhancement of endothelial function and inhibition of vasoconstriction by vasoactive agonists. Furthermore, estrogens contribute to vascular homeostasis through modulation of gene expression, changes in membrane potentials, as well as expression and function of receptors. In addition, estrogens interfere with the activity of vasoactive peptides and vascular enzymes and act as natural antioxidants. Some of these effects have also been observed for phyto-estrogens, which are important dietary components in Asian countries. In the vasculature, the sum of these actions of estrogens results in vasodilatation and inhibition of vascular cell growth. Accordingly, estrogens have been shown to improve vascular function of animals and humans and to inhibit the response to injury after balloon angioplasty and the progression of atherosclerosis. Prospective clinical studies are ongoing to determine whether replacement therapy with estrogen or derivatives provides an alternative to lower cardiovascular mortality in postmenopausal women.

Aim: To study the pharmacokinetics of 2-hydroxyflutamide (HF), a major active metabolite of flutamide (Flu), in normal and CCl4-poisoned rats.

Methods: Normal and CCl4-poisoned rats were given i.g. HF 25 mg.kg-1. HF concentrations of plasma were determined by HPLC with YWG C 18 column, Flu was used as an internal standard. The mobile phase was composed of methanol: water = 3:2 (vol), and absorbance was measured at lambda 295 nm.

Results: HF elimination was inhibited in CCl4-poisoned rats compared with normal rats. K decreased from (0.11 +/- 0.05) to (0.05 +/- 0.01) h-1 (P < 0.01), T1/2 was prolonged from (6.8 +/- 1.9) to (14 +/- 4) h (P < 0.01), Cl decreased from (0.18 +/- 0.06) to (0.12 +/- 0.02) L.kg-1.h-1 (P < 0.05), AUC increased from (149 +/- 47) to (226 +/- 54) mg.L-1.h (P < 0.05).

Conclusion: This HPLC assay was sensitive and precise, and the elimination of HF was inhibited due to CCl4 poisoning.