急性氰戊菊酯中毒大鼠BALF和血清免疫生化反应的时间效应

本文报道大鼠经气管染毒4.66mg/kg氰戊菊酯后,不同时间BALF与血清免疫生化反应。4h时,BALA中LDH、MDH、Tpr、ALb、IgA、IgG和IgM含量均显著升高,血清仅IgM升高,而TPr和ALb显著下降。这些反应的达峰时间一般在34～96h。4～1:d,各参数值渐恢复至正常水平。结果提示,4.66mg/kg氰戊菊酯可诱导急性肺损伤,抑制或破坏肝细胞的蛋白质合成功能。     

急性氰戊菊酯中毒大鼠肺泡细胞形态的动态变化

用扫描电镜观察氰戊菊酯(Fen)经气管染毒大鼠肺灌洗液(BALF)中肺泡细胞形态的动态变化,结果0.19 mg/kg染毒未诱发肺损伤,0.93 mg/kg仅引起轻度肺泡炎,4.7 mg/kg和(或)23.3 mg/kg导致肺实质损伤。肺泡巨噬细胞(PAM)表面呈现不同形状的凹窝、空洞及表面皱褶(或胞浆指状突起)的不规则样变,以至肺泡细胞大量裂解死亡。中性白细胞(PMN)、单核细胞(Mc)、淋巴细胞(Lc)、Ⅱ型肺泡上皮细胞(EPⅡ)、纤毛细胞(CC)及红细胞(RBC)显著增多,并出现多个细胞的聚集。上述反应发生于染毒后30 min,4～24 h达高峰,4 d后恢复正常。本研究为探讨Fen对肺的毒性、毒理和制订用药卫生标准提供了细胞形态学依据。     

IL-1ra-Fcε融合基因在大鼠体内表达条件优化及免疫原性分析

目的探索基因治疗载体pCI-neo-IL-1ra-Fcε在大鼠体内的最适表达条件及免疫原性。方法采用气道滴注方式将pCI-neo-IL-1ra-Fcε载体滴注至大鼠肺部,利用RT-PCR及Westernblot方法检测不同剂量(0.25、0.5、2.5mg.kg-1)载体在不同时间(d4、d7、d20)的表达量,并采用免疫组化方法进行验证。间接ELISA法检测滴注后IL-1ra-Fcε蛋白IgG抗体变化,并对IgG抗体亚型IgG2a和IgG1进行分析。结果3种不同剂量载体在滴注后d20均可检测到目的蛋白表达,2.5mg·kg-1组蛋白表达量明显高于另外2组;以0.25mg·kg-1剂量滴注载体,目的基因d4时未见表达,d7时表达量增加,d20时达到最大值;免疫组化结果显示IL-1ra-Fcε基因在大鼠肺组织中得到有效表达。结论成功建立pCI-neo-Ira-Feε载体在大鼠体内最适表达条件,此载体可诱导机体产生Th1型免疫应答。     

Antianginal effects of FK409, a new spontaneous NO releaser.

1. The aim of this study was to compare antianginal effects of (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409), a new spontaneous nitric oxide releaser, with those of isosorbide dinitrate (ISDN). We used two types of rat angina model; methacholine- and arginine vasopressin (AVP)-induced coronary vasospasm models. 2. In the in vitro study, FK409 showed 80 times more potent vasorelaxant effect in dog isolated coronary artery than ISDN (EC50 = 16.7 +/- 4.8 and 1340 +/- 320 nM, respectively). 3. In the rat methacholine-induced coronary vasospasm model, FK409 suppressed the elevation of ST segment dose-dependently and significantly at 0.1 mg kg-1, i.d. On the other hand, ISDN suppressed it significantly at 3.2 mg kg-1, i.d. In addition, the efficacy of 3.2 mg kg-1 ISDN in the model was almost the same as that of 0.1 mg kg-1 FK409. 4. In the above experiments, FK409 and ISDN decreased mean blood pressure significantly at the maximum dose tested (1.0 mg kg-1, i.d. and 3.2 mg kg-1, i.d., respectively) but did not change heart rate at these doses. Therefore, the hypotensive effect of FK409 was 10 times weaker than the antianginal effect of the compound, while those of ISDN were almost the same. 5. In the rat AVP-induced coronary vasospasm model, 32 mg kg-1 FK409 significantly inhibited the depression of ST segment 60 min after oral administration. On the other hand, 32 mg kg-1 ISDN did not inhibit it at 60 and 120 min after oral administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo comet assay of multi‐walled carbon nanotubes using lung cells of rats intratracheally instilled

The genotoxicity of multi‐walled carbon nanotubes (MWCNTs) was evaluated in vivo with comet assays using the lung cells of rats given MWCNTs. The MWCNTs were intratracheally instilled as a single dose at 0.2 or 1.0 mg kg^–1 or a repeated dose at 0.04 or 0.2 mg kg^–1, once a week for 5 weeks, to male rats. The rats were sacrificed 3 or 24 h after the single instillation and were sacrificed 3 h after the last instillation in the repeated instillation groups. Histopathological examinations of the lungs revealed that MWCNTs caused inflammatory changes including the infiltration of macrophages and neutrophils after a single instillation and repeated instillation at both doses. In comet assays using rat lung cells, no changes in % Tail DNA were found in any group given MWCNTs. These findings indicate that MWCNTs do not have the potential to cause DNA damage in comet assays using the lung cells of rats given MWCNTs at doses causing inflammatory responses. Copyright © 2012 John Wiley & Sons, Ltd.     

The role of vagal adrenergic activity in the mechanism of gastric acid secretion after pylorus-ligation in the rat

The role of the vagus nerve and adrenoceptor stimulation in acid secretion after pylorus-ligation in the rat has been examined. All drugs were administered intraperitoneally. Atropine (5 mg kg-1) depressed the H+ output (111 mumols +/- 33.8 vs 412.5 mumols +/- 62.2, mean +/- s.e.m., n = 10, P less than 0.001); cimetidine (40 mg kg-1) did not enhance this action, while vagotomy was more effective than atropine (32.7 mumols +/- 4.9, mean +/- s.e.m., n = 10, P less than 0.05). Atropine (10 mg kg-1) produced a similar depression to the 5 mg kg-1 dose. Cimetidine (100 mg kg-1) depressed the H+ output (248.5 mumols +/- 46.8, mean +/- s.e.m., n = 10, P less than 0.05). Propranolol (5-20 mg kg-1) had no significant effect on the H+ output but dose-dependent inhibition was produced by phenoxybenzamine or phentolamine; an inhibition similar to that achieved by vagotomy was seen with the 20 mg kg-1 dose. Both these drugs (5 or 10 mg kg-1) had no significant effect on the H+ output when given with atropine (5 mg kg-1) but the H+ output was significantly lower than that produced by either drug at the same dose given alone. Atropine (5 mg kg-1) with phenoxybenzamine or phentolamine (20 mg kg-1) produced H+ output not significantly different from that with vagotomy or either alpha-adrenoceptor given alone at 20 mg kg-1, but the result was significantly (P less than 0.05) lower than the H+ output with atropine (5 mg kg-1) alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary retention of [14C]benzo[a]pyrene in rats as influenced by the amount instilled

Studies on the pulmonary retention of benzo[a]pyrene after inhalation have shown that clearance is biphasic, with one component clearing with a half-time greater than 1 day and another with a half-time less than 1 day. In the work reported here we demonstrated that the amount of benzo[a]pyrene instilled in the lungs can affect the rate at which the benzo[a]pyrene is cleared into the blood. Fischer-344 rats were given 16, 90 or 6400 ng of [14C]benzo[a]-pyrene/rat by intratracheal instillation. Rats were sacrificed at various times up to 7 days after instillation. Individual lung lobes and trachea were removed, digested, and analyzed by liquid scintillation spectrometry. At 24 h after instillation the amount of 14C covalently bound to lung macromolecules was determined in some rats. Benzo[a]pyrene equivalents remaining in the lungs was expressed as a percentage of the instilled dose as a function of time. A two-component negative exponential function was fit to the data. With increasing dose (16-6400 ng/rat), an increasing percent (89-99.76%) was cleared with a half-time less than 1 day and a decreasing percent (11.3-0.24%) was cleared with a half-time greater than 1 day, suggesting that the mechanism by which the slower clearances occurred had been saturated at higher doses. At 24 h after instillation, from 1 to 2 pmol of [14C]benzo[a]-pyrene equivalents/lung were covalently bound to lung macromolecules. There was no difference in the amount of covalently bound 14C over the range of instillation doses used, suggesting that a small amount of benzo[a]-pyrene equivalents was bound in the lungs regardless of the amount instilled. These results suggested that linear extrapolation from high dose studies to environmental concentrations might underestimate lung burdens of benzo[a]pyrene.     

Changes in salicylate serum concentration and metabolism during chronic dosing in normal volunteers

Steady-state serum salicylic acid (SA) concentrations and the formation rates of salicyluric acid (SU), salicylphenolic glucuronide (SPG), salicylacyl glucuronide (SAG), and gentistic acid (GA), and the excretion rate of unchanged SA were determined in three normal subjects following the administration of a single oral dose of acetylsalicylic acid (ASA) 37 mg kg-1 and during multiple dosing with ASA 56 mg kg-1 day-1. Steady-state SA concentrations fell 23 per cent during the 4-week study period (mean +/- SD: 239 +/- 35 to 183 +/- 23 micrograms ml-1; p less than 0.05). Absorption of drug did not decrease during this time. Significant increases in the Vmax for SU and SPG formation occurred between baseline and during multiple dosing. Mean Vmax SU increased from 0.93 to 1.68 mg kg-1 h-1 (p less than 0.05) and mean Vmax SPG increased from 0.09 to 0.19 mg kg-1 h-1 (p less than 0.05). First-order rate constants for the formation of SAG and GA and for the excretion of unchanged SA did not change significantly between baseline and multiple dosing. The mechanism for the decline in CpssSA with time during high-dose SA therapy is most likely due to the induction of the formation rates of the major metabolites of SA, namely SU and SPG.     

Amelioration of cisplatin-induced acute renal failure with 8-cyclopentyl-1,3-dipropylxanthine.

1. The effect of the selective adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), on the development of cisplatin-induced acute renal failure was investigated in the rat. 2. CPX at doses of 0.03, 0.1 and 0.3 mg kg-1, i.v. caused increasing degrees of antagonism of adenosine-induced bradycardia in anaesthetized rats. The magnitude of antagonism was not directly proportional to the increment in dose, but for each dose, it was similar in rats injected with either saline or cisplatin. CPX at a dose of 0.03 mg kg-1 significantly antagonized adenosine-induced bradycardia for up to 2.5 h, while doses of 0.1 and 0.3 mg kg-1 produced significant blockade for periods longer than 5 h. 3. Administration of cisplatin (6 mg kg-1, i.v.) caused acute renal failure characterized by decreased inulin and p-aminohippurate clearances, increased urine volume but decreased excretion of Na+, K+ and Cl- ions and by increased plasma levels of urea and creatinine. Kidney weight was increased in cisplatin-treated rats and renal tubule necrosis occurred. 4. Administration of CPX (0.03 mg kg-1, i.v.; twice daily for two days) to rats given cisplatin did not reduce the severity of the resultant renal failure. However, treatment with 0.1 mg kg-1 CPX attenuated the increases in plasma creatinine/urea levels observed in rats on days 3 and 7 after induction of renal failure. In addition, this dose significantly reduced renal tubule damage and increased inulin and p-aminohippurate clearances. A similar pattern of protection was noted with CPX at a dose of 0.3 mg kg-1 although the increase in inulin clearance was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypotensive effect of 13-hydroxylinoleic acid in the rat: mediation via the release of a CGRP-like mediator from capsaicin-sensitive nerves.

1. The effect of 13-hydroxylinoleic acid (13-HODE) on changes in blood pressure in the rat was measured. 2. 13-HODE (0.1 - 100 micrograms kg-1) had no direct effect on blood pressure in the rat and had no effect on histamine (0.1 - 1000 micrograms kg-1)-induced changes in blood pressure. In contrast, it was found that 13-HODE itself induced a decrease in diastolic arterial blood pressure when it was injected intravenously after either a single dose of histamine (10, 100 or 1000 micrograms kg-1) or after a dose-response curve of histamine (0.1 - 1000 micrograms kg-1). 3. This hypotensive effect of 13-HODE was not observed after administration of the endothelium-dependent vasodilator, acetylcholine (0.1 - 10 micrograms kg-1), the endothelium-independent vasodilator, sodium nitroprusside (0.1 - 100 micrograms kg-1) or the inflammatory mediator, leukotriene B4 (0.1 - 300 micrograms kg-1). However, prior injection of bradykinin (0.1 - 100 micrograms kg-1) allowed a dose-dependent hypotensive effect of 13-HODE to be revealed. 4. The hypotensive effect of 13-HODE after histamine and bradykinin could be inhibited by neonatal capsaicin treatment of the rats (50 mg kg-1, s.c. on day 1 and 2 after birth). 5. Ruthenium red (120 micrograms kg-1 min-1), an inhibitor of excitatory effects on sensory nerves, and the CGRP antagonist, CGRP8-37 (1-3 micrograms kg-1 min-1) also inhibited the hypotensive effect of 13-HODE.(ABSTRACT TRUNCATED AT 250 WORDS)