Effects of the endothelin-1 receptor antagonist tezosentan on renal blood flow and diuresis during prolonged increased intra-abdominal pressure

BACKGROUND: It has earlier been shown that increased intra-abdominal pressure (IAP) reduces renal blood circulation and urine output both clinically and experimentally. The aim of this study was to investigate the effect of endothelin-1 inhibition by the endothelin-1 receptor antagonist tezosentan on renal blood circulation and diuresis in pigs subjected to prolonged increased intra-abdominal pressure. MATERIAL AND METHODS: The IAP in domestic pigs was maintained at 30 mmHg for 3 h. One group of 10 animals was pre-treated with the endothelin-1 receptor antagonist tezosentan, and then received continuous infusion of tezosentan throughout the experiment. Another group of 10 animals served as control. We measured renal cortex blood flow, plasma renin activity, blood concentrations of endothelin-1 and aldosterone, and diuresis. RESULTS: The administration of tezosentan to pigs with an IAP of 30 mmHg was followed by reduced arterial pressure, reduced renal cortex blood flow, and reduced diuresis. The plasma renin activity increased markedly, but neither renal vascular resistance nor blood concentration of aldosterone did change significantly. CONCLUSION: Tezosentan reduced the arterial blood pressure, which resulted in decreased renal cortex blood flow, and aggravation of the oliguria usually observed under increased IAP. The plasma renin activity increased, but this was not followed by changes in renal vascular resistance, or blood concentration of aldosterone. The results indicate that drugs, which reduce the arterial pressure, may be harmful to the kidneys under increased IAP.     

不饱和脂肪酸对豚鼠胃窦环行肌细胞毒蕈碱电流的影响

目的：研究外源性不饱和脂肪酸对豚鼠胃窦平滑肌细胞素毒蕈碱电流的影响及其作用机制。方法：利用膜片箝技术的全细胞记录法在急性分离的胃窦环行肌细胞上记录毒蕈碱电流。结果：在细胞外灌流液中给予花生四烯酸（arachidonic acid,AA）明显抑制I_cch,并具有量效关系：当AA的浓度在1。3和μmo1/L时,分别抑制I_cch至46%±8%,23%±5%和3.8%±0.9%;另一种不饱和脂肪酸,亚麻酸（linoleic acid,LA）也抑制I_cch,在1,5和10μmo1/L浓度分别抑制I_cch至3.8%±0.9%,35%±5%和67%±9%;用H-7（蛋白激酶C抑制剂）100μmo1/L预处理10-15分钟以后,AA分别抑制I_cch至5.5%±0.7%和3.0%±1.0%。结论：不饱和脂肪酸直抑制毒蕈碱电流,且抑制程度与不饱和脂肪酸链中的双键数目有关。     

Intravenous pyruvic acid application in minipigs partially protects acetylcholine-esteratic but not butyrylcholine-esteratic activity in plasma from inhibition by paraoxon

Intoxications with organophosphorus compounds such as paraoxon (POX) are frequent. Oximes are the only enzyme reactivators clinically available. In vitro and in vivo studies have shown that l-lactate reduces the inhibition of plasma acetylcholine-esteratic activity (AChEA) (in vitro and in vivo) and plasma butyrylcholine-esteratic activity (BChEA) (at least in vitro and possibly in vivo) by POX. However, a short infusion of 10 g of lactate was unable to elevate the plasma lactate level for >3 h. In this study we tested a substance related to l-lactate, i.e. pyruvic acid. The purpose of this animal experimental study (female minipigs with historical control group) was to determine in vivo whether intravenous (i.v.) pyruvic acid application under normoxic/normocapnic/normohydrogenaemic conditions is able to elevate blood lactate levels and whether it is able to protect AChEA and BChEA from POX inhibition. Animals were anaesthetized, intubated and mechanically ventilated. Each received 1 mg kg(-1) body wt. of POX in 50 ml of saline over 50 min and 10 g (ca. 0.5 g kg(-1) body wt.) of i.v. pyruvic acid in 50 ml of saline over 50 min. They were compared with a historical control group of six animals that received only 1 mg kg(-1) body wt. of POX in 50 ml of saline over 50 min. In central venous blood measurements of plasma AChEA and BChEA, the measurements were performed before (baseline), immediately after POX (50 min after start) and 110, 170, 230, 290, 530 and 1010 min after the start of infusion. A 10 g aliquot of i.v. pyruvic acid had a statistically significant protective effect in vivo on AChEA but not on BChE activity. Further study of the in vivo effects of pyruvic acid and l-lactate after paraoxon intoxication and a formal comparison with standard oxime therapy seems warranted. Also, a combination therapy with l-lactate and pyruvic acid in vivo should be investigated.     

Plasma cytokines do not reflect expression of pro- and anti-inflammatory cytokine mRNA at organ level after cardiopulmonary bypass in neonatal pigs

BACKGROUND: Plasma concentrations of inflammatory markers are increased in response to the trauma of cardiac surgery and cardiopulmonary bypass (CPB). It is, however, unknown whether the plasma cytokine levels and cytokine mRNA expression at organ level reflect each other. METHODS: Twenty-six piglets (17-19 days) were allocated to the sham-group (sternotomy only, n = 13) or to the CPB-group (sternotomy, 120 min CPB procedure with 60-min aortic cross-clamp, n = 13). The pigs were observed for 0.5 h or 4 h post-CPB. Plasma levels of IL-1beta, IL-6, IL-8 and IL-10 and mRNA expression of TNF-alpha, IL-1beta, IL-6, IL-8, IL-10 and iNOS in organs were registered with concomitant changes in oxygenation index (OI) and expiratory nitric oxide (NO). RESULTS: In pigs killed 0.5 h post-CPB there was a significant increase in IL-10 mRNA in the lungs and kidneys compared with the sham-group. IL-1beta mRNA was detectable in the kidneys and lungs of the CPB-pigs, while IL-6 mRNA was up regulated only in lungs. In pigs killed 4 h post-CPB a significantly higher IL-6 mRNA was found in heart tissue and a lower IL-10 mRNA was found in lungs of CPB pigs compared with the sham-group. There was a concomitant significant increase in OI and increased plasma IL-8 and IL-10 concentrations in the CPB-pigs compared with the sham-pigs. CONCLUSION: The cytokine mRNA expression pattern was very different for the pigs killed already 0.5 h after the CPB procedure compared with the pigs killed 4 h post-CPB. The plasma cytokine levels poorly reflected mRNA expression of the pro- and anti-inflammatory cytokines.     

Hypoglycaemic effect of Opuntia lindheimeri Englem in a diabetic pig model

The hypoglycaemic activity of Opuntia lindheimeri Englem. was investigated in non-diabetic (control pigs) and streptozotocin-induced diabetic pigs using an enteral (oral) route of administration. Following the administration of O. lindheimeri extract (0, 250 or 500 mg/kg body weight), blood glucose concentrations in control pigs fluctuated around initial baseline concentrations, but were not consistently affected by either the dose of O. lindheimeri or by the time following administration. In contrast, administration of O. lindheimeri extract to STZ-treated pigs resulted in both a dose- (p < 0.001) and time-dependent (p < 0.001) decrease in blood glucose concentrations. The hypoglycaemic effect of the extract was apparent within 1 h of administration, with maximal effects occurring at 4 h after administration. These results confirm the hypoglycaemic effect of O. lindheimeri extract in a diabetic pig model. In addition, given the physiological similarities of the pig to humans, this model will be of tremendous use in assessing the long-term effects of Opuntia administration on the secondary problems associated with diabetes.     

Hypothermia reduces sulphur mustard toxicity

The effect of temperature on the development of sulphur mustard (HD)-induced toxicity was investigated in first passage cultures of human skin keratinocytes and on hairless guinea pig skin. When cells exposed to HD were incubated at 37 degrees C, a concentration-dependent decline in viability was observed that was maximal by 2 days. In contrast, no significant HD-induced toxicity was evident up to 4 days posttreatment when the cells were incubated at 25 degrees C. However, these protective effects were lost by 24 h when the cells were switched back to 37 degrees C. The protective effects of hypothermia were also demonstrated when apoptotic endpoints were examined. The HD concentration-dependent induction of fragmented DNA (as quantitated using soluble DNA and the TUNEL reaction), morphology, and p53 expression were all significantly depressed when cell cultures were incubated at 25 degrees C compared to 37 degrees C. When animals were exposed to HD vapour for 2, 4, and 6 min and left at room temperature, lesions were produced whose severity was dependent on exposure time and that were maximal by 72 h posttreatment. Moderate cooling (5-10 degrees C) of HD exposure sites posttreatment (4-6 h) significantly reduced the severity of the resultant lesions. However, in contrast to the in vitro results, these effects were permanent. It appears that the early and noninvasive act of cooling HD-exposed skin may provide a facile means of reducing the severity of HD-induced cutaneous lesions.     

Long-term,low-level exposure of guinea pigs and marmosets to sarin vapor in air: lowest observable effect level

Realistic scenarios for low-level exposure to nerve agents will often involve exposures over several hours to extremely low doses of agent. In order to expose animals to the lowest controllable concentrations of agent and to increase exposure times until a lowest observable effect level (LOEL) becomes measurable, a validated system was developed for exposing conscious animals to 0.05-1.0 microg/m(3) (8-160 ppt) of sarin and other nerve agents. Based on cold trapping of sarin from the exposure air, the concentration could be measured semicontinuously, at 4-min time intervals by means of gas chromatography. We found that the LOEL upon a 5-h whole body exposure of guinea pigs and marmosets to sarin vapor corresponds with the measurement of an internal dose by means of fluoride-induced regeneration of sarin from phosphylated binding sites in plasma, mostly BuChE. For guinea pigs the LOEL was observed at Ct = 0.010 +/- 0.002 mg/min/m(3), whereas a Ct of 0.04 +/- 0.01 mg/min/m(3) was established for the LOEL in marmosets. These levels are several orders of magnitude lower than those based on classical measurement of depressed cholinesterase activities. At low exposure levels of guinea pigs and marmosets (< or =1 microg/m(3)), a reasonable linearity was observed between exposure dose and internal dose. The data were addressed in the light of the recently recommended occupational exposure limits to sarin for workers without respiratory protection, which suggests that the exposure limits should be reconsidered if the slightest inhibition of cholinesterases should be prevented.     

Large Porous Particles for Sustained Protection from Carbachol-Induced Bronchoconstriction in Guinea Pigs

Purpose. To determine whether a new formulated albuterol aerosol could sustain inhibition to bronchoconstriction for approximately one day in guinea pigs challenged with carbachol. Methods. Large and porous particles, comprising a combination of endogenous or PDA-approved excipients and albuterol sulfate, were prepared by spray drying using a NIRO portable spray drier. The anesthetized animals inhaled 5 mg of large porous or small nonporous particles by forced ventilation via cannulae inserted in the lumen of their exposed tracheae. At regular intervals over a period of 36 hours after drug delivery, airway resistance was determined in response to carbachol challenge dose. Results. Whereas inhalation of small nonporous albuterol particles protected from the carbachol-induced bronchoconstriction for up to 5 hours, inhalation of large porous albuterol particles produced a significant inhibition of carbachol-induced bronchoconstriction for at least 16 hours. Conclusions. The absence of substantial side effects, verified over a period of 24 hours by evaluating cardio-respiratory parameters as well as pulmonary inflammation, supports the utility of large porous albuterol particles for sustained therapies in asthma and other types of lung disease.Dr. Ben-Jebria is also affiliated with     

我国实验用豚鼠面神经核的立体定位坐标值

目的：确定我国实验用豚鼠面神经核（ＦＮ）中心的立体定位坐标值．方法：Ｎｉｓｓｌ染色、ＨＲＰ逆行追踪方法及立体定位仪确定ＦＮ立体定位坐标值;利用Ｎｉｓｓｌ染色在连续切片上确定豚鼠面神经核的外径．结果：体重３００ｇ～６５０ｇ豚鼠的ＦＮ中心坐标值为Ｐ：（２．４±０．１）ｍｍ,ＬＬ／ＲＬ：（２．０±０．０７）ｍｍ,Ｈ：（－１．９±０．０８）ｍｍ;ＦＮ的前后径：（１．５±０．０９）ｍｍ,左右径：（１．３±０．０７）ｍｍ,上下径：（１．４±０．０６）ｍｍ结论：确定了我国实验用豚鼠ＦＮ的立体定位坐标值,为面神经的研究提供了便利条件．