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

Aim: To study the efficacy and safety of drug or therapy with recurrent events in meta-analysis of multiple clinical trials.

Methods: A nonparametric approach is proposed to estimate the rates of recurrent events for meta-analysis of trials. The method was used in meta-analysis of angiotensin-converting enzyme (ACE) inhibitor clinical trials to analyze the relative rates and the excess rates between ACE inhibitor and placebo treatment groups for endpoints of hospitalizations for CHF, hospitalizations for CHF or cardiac death, and hospitalizations for CHF or any death, respectively.

Results: The estimates of those three endpoints were 69%, 74%, and 76% (P < 0.01). Compared with placebo, ACE inhibitor reduced 30 cases of hospitalizations for CHF per 1000 person-years, or 40 cardiac deaths or hospitalizations for CHF per 1000 person-years (P < 0.01).

Conclusion: The method was a simple and efficient approach to conduct meta-analysis of clinical trials with recurrent events.

Aim: To study the effect of endothelin-1 (ET-1) in the rostral ventrolateral medulla (rVLM) on cardiovascular responses in cats.

Methods: The stereotatic technique and microinjection method were used.

Results: ET-1 (4 mumol.L-1 0.5 microL) microinjected into rVLM induced mean arterial pressure (MAP) increasing (3.7 +/- 1.3) kPa, heart rate (HR) accelerating (29 +/- 7) beats.min-1, and renal nerve activity (RNA) intensifying 45% +/- 10%. The effects were dose-dependent. Before and after bilateral vagotomy, there was no significant difference in the reaction of MAP, HR, and RNA. After intravenous injection with phentolamine (5 mg.kg-1, alpha-blocker), ET-1 did not induce significant change of MAP. ET-1 raised the content of peripheral plasma argipressin (Arg) from (12.4 +/- 6.5) to (70.3 +/- 24.2) ng.L-1 with radioimmunoassay, and showed a correlation with MAP changes. ET-1 induced heart rhythm disorder (HRhD) in acute myocardiac ischemia, the occur time of HRhD was (4.8 +/- 2.9) min, and the score was 4.4 +/- 1.6, and it was significantly different from control.

Conclusion: ET-1 microinjected into rVLM could involve with control regulation of cardiovascular and sympathetic nerve activity.

Aim: To compare the effects of oxysophoridine (Oxy) and sophoridine (Sop) on experimental arrhythmias and myocardial physiologic properties.

Methods: Arrhythmias were induced by drugs and myocardial ischemia. Physiologic properties were determined on isolated heart atria.

Results: Oxy 500 mg.kg-1 (1/6 LD50) decreased the incidence of ventricular arrhythmias induced by aconitine (P < 0.01), increased the threshold dose of ouabain-induced ventricular premature (VP, P < 0.05), ventricular tachycardia (VT, P < 0.05), ventricular fibrillation (VF, P < 0.01), and cardiac arrest, (P < 0.01). After i.v. Oxy 500 mg.kg-1 into the rats with ligation of left anterior descending coronary artery, the total numbers of ectopic beats were decreased (P < 0.05), the incidence of VF was lowered, and the duration of VT was shortened (P < 0.01). Oxy 250 mg.kg-1 (1/13 LD50) i.v. shortened the duration of arrhythmias induced by BaCl2 (P < 0.01) and delayed the onset of arrhythmias induced by chloroform-epinephrine (P < 0.05). Oxy produced dose-dependent positive inotropic effects in the isolated left atrial of guinea pigs, increased the concentration of epinephrine to elicit automaticity in left atria, decreased slightly the excitability, and prolonged the functional refractory period. Sop produced the similar effects on arrhythmias as Oxy.

Conclusion: Oxy produced the similar anti-arrhythmic effects as Sop did at the equivalent effective dose.

Aim: To study the effects of propylbutyldopamine (PBDA) on the inward rectifier potassium current (Ik1).

Methods: The quasi-steady state current-voltage relationship from the isolated guinea pig ventricular cells were measured using whole-cell patch-clamp techniques with a slow ramp depolarization (8 mV.s-1).

Results: PBDA 5, 50, and 100 mumol.L-1 concentration-dependently reduced the inward rectifier potassium current. PBDA blocked Ik1 in guinea pig ventricular cells. The effect of PBDA was not blocked by the selective dopamine D2-receptor blocker, domperidone.

Conclusion: PBDA inhibited Ik1 directly, independent of the dopamine D2-receptor.

Aim: To study the effect of the antitumor compounds 5F, 6F, and A from Pteris semipinnata L on the activities of DNA topoisomerases and cell cycle of HL-60 cells, and the synergism of compound 6F in combination with genistein in vitro.

Methods: DNA topoisomerases were isolated from HL-60 cell lines, and supercoiled pBR322 DNA was used as substrate to determine the activities of DNA topoisomerase I and II. Cell cycle was analyzed by flow cytometry (FCM). Cytotoxicity assay was tested by MTT method.

Results: Compounds 5F, 6F, and A inhibited the activities of DNA topoisomerase I and II. After exposure of the cells to compound 6F, an increase in cells in the S and G2/M phases and a decrease in cells in the G0/G1 phase of the cell cycle were observed. At low concentrations (57.8 and 115.6 nmol.L-1), compound 6F enhanced the cytotoxicity against HL-60 cell line in combination with genistein, q values were > 1.15. The enhancement times of 57.8 and 115.6 nmol.L-1 of 6F by genistein were 2.60 and 4.65, respectively.

Conclusion: Compounds 5F, 6F, and A inhibited the activities of DNA topoisomerases of HL-60 cells. Compound 6F increased the number of cells in S and G2/M phases, decreased the population of G0/G1 phase cells, and enhanced the cytotoxicity of genistein, which had synergism with 6F in antitumor action.

Aim: To study the prophylactic effects of tetramethyl pyrazine (TMP) on mice with endotoxemia and its relationship with platelet-activating factor (PAF).

Methods: LD80 of lipopolysaccharides (LPS, 15 mg.kg-1) was injected into mice (i.v.) pretreated with TMP (i.p.). The survival rate and the level of serum PAF were observed. The PAF induced by LPS in vivo and in vitro, and the activities of PLA2 and acetyl-CoA: lyso-PAF acetyltransferase were determined.

Results: TMP (10, 30, 90 mg.kg-1) obviously lowered the mortality of mice and also dose-dependently decreased the level of serum PAF [(25.5 +/- 1.7), (13.4 +/- 3.2), (9.6 +/- 2.1) micrograms.L-1, vs control (29.3 +/- 2.1) micrograms.L-1, P < 0.01]. TMP (0.05, 0.5, 5, 50 mumol.L-1) dose-dependently decreased the release of PAF [(12.7 +/- 1.6), (8.9 +/- 1.2), (6.9 +/- 0.8), (5.5 +/- 1.0) micrograms.L-1 vs control (11.9 +/- 1.8) micrograms.L-1, P < 0.01] from PMO cultured with LPS (5 mg.L-1), reduced the PLA2 activity [(149.9 +/- 2.8), (117.5 +/- 2.0), (89.6 +/- 2.0), (75.0 +/- 2.8) U vs control (170.8 +/- 3.9) U, P < 0.01] and acetyl-CoA: lyso-PAF acetyltransferase activity [PAF (9.5 +/- 0.7), (5.2 +/- 0.7), (2.9 +/- 0.3), (2.5 +/- 0.3) micrograms.g-1 (protein).min-1 vs control (11.0 +/- 0.7) micrograms.g-1 (protein).min-1, P < 0.01] of PMO lysate.

Conclusion: TMP protected the mice with endotoxemia from the death by decreasing the biosynthesis of PAF through the inhibition of the activities of PLA2 and acetyl-CoA: lyso-PAF acetyl-transferase.

Aim: To elucidate the suppressive effect of kanglemycin C (Kan) on lymphocyte proliferation and T-lymphocyte subsets.

Methods: Splenocyte proliferation was quantified with [3H]thymidine ([3H]TdR) pulsing method or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetery. L3T4+ and Lyt2+ T-cell subsets were measured with fluorescence-activated cell sorter (FACS). Splenocyte viability was assessed with trypan blue exclusion.

Results: Like ciclosporin (Cic), Kan 8, 40, 80, and 400 nmol.L-1 inhibited the proliferation of 20%-80% incubated mouse splenocytes stimulated by concanavalin A (Con A) 5 mg.L-1, phytohemagglutinin (PHA) 5 mg.L-1, tetradecanoylphorbol acetate (TPA) 10 micrograms.L-1 + ionomycin (IM) 0.5 mg.L-1, and alloantigen (mixed lymphocyte reaction). Kan had no toxicity to the splenocytes at the treated doses. Suppression by Kan was declined with addition time of Kan after culture onset. Furthermore, the suppressive effect of Kan on splenocyte proliferation stimulated by lipopolysaccharides (LPS) 10 mg.L-1 was similar to that on splenocyte proliferation mediated by Con A. Unlike Cic, Kan reversed the ratio of L3T4+/Lyt2+ T-cell subsets.

Conclusion: Kan had a suppressive action on proliferation of T- and B-lymphocytes and had a selective effect on helper-inducer T-lymphocyte (Th) subset from Cic. Suppression by Kan was time-dependent and not associated with toxicity of Kan.

Aim: To investigate the effect of dl-3-n-butylphthalide (dl-NBP) on experimental subarachnoid hemorrhage (SAH) in rats.

Methods: SAH was induced by injection of autologous artery blood 0.35 mL into lateral ventricle. Regional cerebral blood flow (rCBF) in caudate nucleus was determined by hydrogen clearance method.

Results: A rapid and marked decrease in rCBF in caudate nucleus was observed 15 min after SAH and the rCBF remained at low level (about 50% pre-SAH value) within 180 min. dl-NBP (50, 100 mg.kg-1, i.g.) increased rCBF 30-180 min after the onset of SAH without significant effect on mean artery blood pressure. dl-NBP 100 mg.kg-1 increased rCBF in caudate nucleus by 26% at 15 min and by 36% at 180 min respectively after SAH. d-NBP but not l-NBP (10 mg.kg-1, i.p.) increased rCBF.

Conclusion: dl-NBP improves rCBF in caudate nucleus of rats subjected to SAH.

Aim: To study the action of free radical in the spin-labeled podophyllotoxin derivative, podophyllic acid piperindyl hydrazone nitroxide radical (GP-1) on its antitumor activity and toxicity, by comparison with those of its free radical reduced product, podophyllic acid piperindyl hydrazone (GP-1-H).

Methods: After treatment with GP-1 and GP-1-H, the inhibitory effects on the growth of mouse transplantable tumors were determined; MTT formazan formation, [3H]deoxythymidine ([3H]TdR) incorporation, cell cycle progression, and mitotic index of SGC-7901 or L1210 cells were measured; the acute toxicity and immune function of mice were assayed.

Results: At doses of 1/6 and 1/12 LD50, the inhibitory rates against Lewis lung carcinoma were 60.3% and 42.1% (GP-1), 38.9% and 10.3% (GP-1-H), respectively; more effective antitumor activity of GP-1 against P388, HePS, and S-180 than that of GP-1-H were found. In vitro, GP-1 exhibited more powerful inhibitory effects on the proliferation and DNA synthesis of SGC-7901 and L1210 cells than GP-1-H. GP-1 and GP-1-H arrested the L1210 cells at G2/M phase with a corresponding decrease of the cells in G1 phase, and increased the mitotic index of the cells; but the effects of GP-1-H were weaker than those of GP-1. After treatment with doses of 1/4 and 1/8 LD50 for 5 d, no significant difference on immune function of mice between GP-1 and GP-1-H was found.

Conclusion: GP-1 had more powerful antitumor activities than GP-1-H. The free radical in the spin-labeled podophyllotoxin derivative, GP-1, played an important role in its antitumor activity.

Aim: To examine the effects of high glucose on the mitogenic response of rabbit aortic vascular smooth muscle cells (VSMC) to endothelin-1 (ET-1).

Methods: VSMC were cultured in normal glucose (5.5 mmol.L-1), high glucose (25 mmol.L-1) or high osmolality (glucose 5.5 mmol.L-1, plus mannitol 19.5 mmol.L-1). DNA synthesis was measured by [3H]thymidine incorporation. The expression of phospho-p44/42 MAPK was determined by Western blot.

Results: At a concentration range from 10(-12) to 10(-8) mol.L-1, ET-1 stimulated [3H]thymidine incorporation and phospho-p44/42 MAPK expression in VSMC in a concentration-dependent manner. From 10(-11) to 10(-8) mol.L-1, the mitogenic effect of ET-1 was higher in VSMC cultured in high glucose at equivalent concentration than cells cultured in normal glucose or high osmolality (P < 0.05 or P < 0.01), but no marked difference was observed in the growth response between cells cultured under the latter two conditions. Similarly, ET-1 increased expression of phospho-p44/42 MAPK by 60%-65% in VSMC cultured in high glucose, compared with cells in normal glucose or high osmolality.

Conclusion: VSMC cultured in high glucose exhibited increased mitogenic response to ET-1, which seemed to be related to the enhanced expression of phospho-p44/42 MAPK.