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

Aim: To investigate the effects of simvastatin (Sim) on left ventricular hypertrophy in rats with pressure-overload cardiac hypertrophy.

Methods: The left ventricular hypertrophy (LVH) of rats was induced by partly occluding abdominal aorta below right renal artery. The rats were given i.g. Sim (1.8 and 3.6 mg.kg-1.d-1) for 8 wk. Three days after operation, left ventricular function was measured. Then the left ventricle (LV) + septum and the right ventricle (RV) were weighed. Hydroxyproline content of LV was measured.

Results: Eight weeks later, in the LVH group, LV weight (LVW), LVW/body weight (BW), LVW/RV weight (RVW), LV ending diastolic pressure (LVEDP), and hydroxyproline content increased by 36%, 51%, 28%, 92%, and 23%, respectively (all P < 0.01) compared with the sham group. LV + dp/dtmax and -dp/dtmax decreased by 39.2% and 39.4% (all P < 0.01). After the rats were given i.g. Sim 3.6 mg.kg-1.d-1, LVW, LVW/BW, LVW/RVW, left ventricle ending diastolic pressure (LVEDP), and hydroxyproline content decreased by 22%, 21%, 23%, 24%, and 11% compared with LVH group (all P < 0.01), LV + dp/dtmax and -dp/dtmax increased by 60% and 32% (all P < 0.01).

Conclusion: Sim inhibited development of LV hypertrophy and improved LV function in rats with aortic stenosis.

Aim: To study the role of N-methyl-D-aspartic acid (NMDA) and non-NMDA receptors in processing nociceptive visceral information in the spinal cord.

Methods: The firing of spinal dorsal horn neurons to colorectal distension (3-15 kPa, 20 s) by inflation with air of latex balloon was recorded in 25 anesthetized cats.

Results: 1) According to the patterns of responses to colorectal distension, the neurons with increase and decrease in firing were classified as excitatory and inhibitory, respectively. The former consisted of 17 short-latency abrupt (SLA) neurons, 11 short-latency sustained (SLS) neurons, 9 long-latency (LL) neurons. The 15 inhibited (Inh) neurons were recorded. 2) Microelectrophoretic administration of NMDA, quisqualic acid (QA), and kainic acid (KA) activated 67.6%, 78.4%, and 59.5% of the colorectal distension-excited neurons tested. Also, 60%, 86.7%, and 53.3% of Inh neurons were activated by these 3 amino acids. 3) Colorectal distension-induced excitatory responses were reduced by 35% +/- 10% and 65% +/- 14% by a selective NMDA receptor antagonist d,l-2-amino-5-phosphonovalerate (APV) and a selective non-NMDA receptor antagonist 6,7-dinitro-quinoxaline-2,3-dione (DNQX), respectively. Such DNQX-induced inhibition was significantly more potent than that by APV (P < 0.05). Colorectal distension-induced inhibitory responses were partially relieved by 30%-50% in 3/7 Inh neurons by DNQX, but not APV.

Conclusion: Both NMDA and non-NMDA receptors are involved in transmission and/or modulation of spinal visceral nociceptive information and non-NMDA receptors may play more important role than NMDA receptors.

Aim: To study the effect of nitric oxide (NO) derived from endothelial cells on Na+/H+ exchange in rabbit platelets activated by thrombin.

Methods: Intracellular Ca2+ ([Ca2+]i) and intracellular pH (pHi) were measured by the dual-wavelength fluorophotometer with the fluorescent probes Fura-2 and 2',7'-biscarboxyethyl-5,6-carboxyfluorescein (BCECF). Effects of NO on rabbit platelets were tested by cultured bovine endothelial cells (BAEC).

Results: BAEC (0.1-1 x 10(9).L-1) inhibited thrombin (100 U.L-1)-induced platelet aggregation in a concentration-dependent manner. This inhibiting effect was abolished by preincubating BAEC with NG-nitro-L-arginine 1 mmol.L-1. When the [Ca2+]i store was depleted with ionomycin in the presence of egtazic acid (EGTA), the increase in pHi induced by thrombin was inhibited. Refilling intracellular Ca2+ store partially reversed this effect. BAEC 2 x 10(8).L-1 inhibited thrombin (100 U.L-1)-induced elevation of pHi and mobilization of intracellular Ca2+ store (P < 0.01). No direct effect of endothelial cells on unstimulated rabbit platelets was observed.

Conclusion: NO derived from endothelial cells inhibited thrombin-induced rabbit platelet activation by inhibiting thrombin-induced [Ca2+]i mobilization and then inhibiting the consequent Na+/H+ exchange in rabbit platelets.

Aim: To study the in vitro cytotoxicity of 4,5-seco-5,10-friedo-abieta-3,4-dihydroxy-5(10),6,8,13-tetraene-11, 12-dione (salvicine), a novel diterpenoid quinone compound on human tumor cell lines and its effect on cell cycle progression.

Methods: Growth inhibition of human tumor cells was measured by microculture tetrazolium assay (MTT). Cell cycle was analyzed by flow cytometry.

Results: Exposing tumor cell lines tested to salvicine for 72 h, in comparison with reference drugs vincristine (VCR) and etoposide (VP-16), salvicine was as cytotoxic as VP-16 and weaker than VCR in 3 leukemia cell lines. For 12 solid tumor cell lines, salvicine exhibited cytotoxic activities and was over 5.41- and 4.15-fold stronger than VCR and VP-16, respectively. Salvicine presented better activities especially against gastric and lung carcinoma cell lines. Exposing K562 leukemia cells to 9 graded concentrations of salvicine (from 0.39 to 100 mumol.L-1) for 24 h and to salvicine 10 mumol.L-1 for 7 different periods (from 1 to 48 h), the growth inhibition of cells was enhanced along with increased concentration or prolonged exposure. Cell cycle analysis demonstrated that salvicine arrested K562 cells in G1 phase and this effect was also heightened with increased concentration or extended exposure.

Conclusion: Salvicine exhibited potent cytotoxic activities against various human tumor cell lines, and blocked K562 leukemia cells in G1 phase of cell cycle.

Aim: To study whether the protective effects of ischemic preconditioning against rat small intestine ischemia/reperfusion injury could be mediated by KATP channel opener.

Methods: Preconditioning (Pc) was induced by 3 cycles of 8-min superior mesenteric artery (SMA) occlusion and 10-min reperfusion before prolonged ischemia. Cromakalim (Cro 75 micrograms.kg-1) and glibenclamide (Gli 8 mg.kg-1) were injected i.v. 10 min before prolonged ischemia and Pc, respectively.

Results: Compared with ischemic reperfusion (IR) group, Pc before prolonged ischemia (Pc + IR) decreased LDH release [(380 +/- 55) vs (559 +/- 49) U.L-1, P < 0.05], attenuated intestinal edema [wet weight/dry weight (WW/DW), 5.6 +/- 0.6 vs 6.34 +/- 0.29, P < 0.05], ameliorated intestinal histological damage (grading scale, 3.4 vs 5.7, P < 0.01), and improved reperfusion-induced hypotension. These effects of Pc were mimicked by Cro [LDH, (298 +/- 40) vs (559 +/- 49) U.L-1, P < 0.05; WW/DW, 5.6 +/- 0.4 vs 6.34 +/- 0.29, P < 0.05; grading scale, 3.6 vs 5.7, P < 0.01] and abolished in the presence of Gli [LDH, (624 +/- 44) vs (559 +/- 49) U.L-1; WW/DW, 6.6 +/- 0.6 vs 6.34 +/- 0.29; grading scale, 5.7 vs 5.7; P > 0.05] compared with IR group, respectively.

Conclusion: Ischemic preconditioning on the rat small intestine is mediated by activation of KATP channels.

Aim: To study the effect of captopril (Cap) on hypoxia-induced proliferation and collagen synthesis in vascular smooth muscle cells (VSMC).

Methods: VSMC were isolated from rabbit pulmonary artery. Cultured VSMC were evaluated by incorporation of [3H]thymidine and [3H]proline, cell number, and intracellular calcium concentration ([Ca2+]i).

Results: Pretreatment of pulmonary VSMC with Cap 1 mumol.L-1 blocked hypoxia-induced increase in cell number and incorporation of [3H]proline and [3H]thymidine, which were decreased 25%, 21%, and 36%, respectively, as compared with hypoxic control. It also inhibited the increase of intracellular Ca2+ concentration under hypoxic condition. Addition of nifedipine inhibited hypoxia-stimulated increase in the collagen, DNA synthesis, and [Ca2+]i. Bay-K-8644 increased cell number (35%), DNA (55%), collagen synthesis (36%), and [Ca2+]i (33%) in pulmonary VSMC, that was completely abolished by Cap 1 mumol.L-1.

Conclusion: Cap inhibited hypoxia-induced proliferation and collagen synthesis in VSMC.

Aim: To study immunoinhibitory effects and preliminary mechanism of IL-10 and trichosanthin.

Methods: Surface molecule expression on antigen processing cells (APC) was stained with fluorescence and analyzed by FACScan. B7-1 mRNA expression was detected with nested RT-PCR.

Results: IL-10 2 mg.L-1 and trichosanthin 10 mg.L-1 inhibited B7-1 molecule expression. By contrast, they had not the same effects on ICAM-1. IL-10 and trichosanthin down-regulated LFA-1 expression, but had no regulatory effect on CD40. IL-10 and trichosanthin dramatically inhibited T-cell proliferation and IL-2 production. B7-1 mRNA expression was undetectable in APC treated with IL-10 and trichosanthin.

Conclusion: IL-10 and trichosanthin inhibit surface molecule expression on APC. They exert multiple immunoinhibitory effects.

Aim: To study the effects of berbamine (Ber) on intracellular calcium concentration ([Ca2+]i) mobilized by KCl depolarization, norepinephrine (NE), and caffeine.

Methods: [Ca2+]i was measured with fluorescent intensity (FI) by confocal microscope in single cultured cardiomyocytes of newborn rats loaded with Fluo 3-AM 2 mumol.L-1.

Results: FI value of [Ca2+]i in control level was 248 +/- 70 in the presence of extracellular calcium 1.5 mmol.L-1 and was not changed by Ber 3-30 mumol.L-1. KCl (60 mmol.L-1)- and NE (30 mumol.L-1)-induced [Ca2+]i mobilizations were inhibited (P < 0.01) by Ber 30 mumol.L-1, similar to that of verapamil (Ver). The inhibitory effect of Ber on [Ca2+]i induced by KCl was further increased (P < 0.05) in the presence of egtazic acid 3 mmol.L-1, but that on [Ca2+]i induced by NE was not changed. The [Ca2+]i mobilized by caffeine 80 and 160 mumol.L-1 in D-Hanks' solution was not affected (P > 0.05) by Ber and Ver.

Conclusion: Ber possessed the antagonistic effects on [Ca2+]i increases via voltage-dependent Ca2+ channel and receptor-operated Ca2+ channel in newborn rat cardiomyocytes, but without effect on intracellular Ca2+ release.

Aim: To study the effect of excitatory amino acid (EAA) and calcium channel blocker on neuronal calcium channels.

Methods: With path-clamp technique (whole-cell recording), the effects of Bay-K-8644, cesium glutamate, potassium aspartate, and nimodipine (Nim) on calcium currents (ICa) in cultured cortical neurons of neonatal rats were studied.

Results: ICa was raised obviously by Bay-K-8644 and glutamate. ICa was raised concentration-dependently by aspartate (0.5, 5, 50 mmol.L-1), with increasing rates 15% +/- 3%, 37% +/- 3%, and 53% +/- 6%, respectively. The inhibition of ICa was obvious while adding Nim in the bath solution. With Nim 10 mumol.L-1, the inhibitory rate was 46% +/- 4%.

Conclusion: EAA had increasing effects on neuronal calcium currents and Nim inhibited Ca2+ influx in neurons.

Aim: To establish the presence of the hypothalamic hormone protirelin (thyrotropin-releasing hormone, TRH) in human thyroid and to investigate whether the concentration of this peptide in the thyroid gland is sensitive to thyroid status.

Methods: A procedure has been developed for the determination of TRH in the thyroid gland, distinct from TRH-like peptides which also react with TRH-antibody.

Results: Human thyroid was shown to contain both authentic TRH and TRH-like peptides, a similar pattern was seen in a range of animal thyroids. The concentrations of TRH in non-active goiter thyroids were substantial (41.6-248 pmol.g-1); in contrast the thyroids from hyperthyroid patients contained very little TRH (0.01-2.52 pmol.g-1).

Conclusion: The physiologic role of TRH in the thyroid is not known but the large difference between the concentrations of this hormone in non-active and hyperactive thyroids suggests that thyroidal TRH may be involved in the regulation of thyroid status.