l‐Carnitine Attenuates Cardiac Remodelling rather than Vascular Remodelling in Deoxycorticosterone Acetate‐Salt Hypertensive Rats

Abstract: l ‐Carnitine is an important co‐factor in fatty acid metabolism by mitochondria. This study has determined whether oral administration of l ‐carnitine prevents remodelling and the development of impaired cardiovascular function in deoxycorticosterone acetate (DOCA)‐salt hypertensive rats (n = 6–12; #p < 0.05 versus DOCA‐salt). Uninephrectomized rats administered DOCA (25 mg every 4th day s.c.) and 1% NaCl in drinking water for 28 days developed cardiovascular remodelling shown as systolic hypertension, left ventricular hypertrophy, increased thoracic aortic and left ventricular wall thickness, increased left ventricular inflammatory cell infiltration together with increased interstitial collagen and increased passive diastolic stiffness and vascular dysfunction with increased plasma malondialdehyde concentrations. Treatment with l ‐carnitine (1.2% in food; 0.9 mg/g/day in DOCA‐salt rats) decreased blood pressure (DOCA‐salt 169 ± 2; + l ‐carnitine 148 ± 6# mmHg), decreased left ventricular wet weights (DOCA‐salt 3.02 ± 0.07; + l ‐carnitine 2.72 ± 0.06# mg/g body‐wt), decreased inflammatory cells in the replacement fibrotic areas, reduced left ventricular interstitial collagen content (DOCA‐salt 14.4 ± 0.2; + l ‐carnitine 8.7 ± 0.5# % area), reduced diastolic stiffness constant (DOCA‐salt 26.9 ± 0.5; + l ‐carnitine 23.8 ± 0.5# dimensionless) and decreased plasma malondialdehyde concentrations (DOCA‐salt 26.9 ± 0.8; + l ‐carnitine 21.2 ± 0.4# μmol/l) without preventing endothelial dysfunction. l ‐carnitine attenuated the cardiac remodelling and improved cardiac function in DOCA‐salt hypertension but produced minimal changes in aortic wall thickness and vascular function. This study suggests that the mitochondrial respiratory chain is a significant source of reactive oxygen species in the heart but less so in the vasculature in DOCA‐salt rats, underlying the relatively selective cardiac responses to l ‐carnitine treatment.     

The Effects of l‐Carnitine Against Cyclophosphamide‐Induced Injuries in Mouse Testis

In order to explore the possibility of l ‐carnitine (LC) as a protector of male fertility in chemotherapy, we observed the damage of cyclophosphamide (CTX) to Sertoli cells and the protective effect of LC on the testis Sertoli cells from such damage in this study. Healthy adult male mice were divided into three groups: chemotherapy group were injected intraperitoneally with the CTX; protective agent group were injected both LC and CTX; control group mice were injected only with isochoric physiological saline; all once a day for 5 days. After 5 days, the mice were, respectively, killed at 24 hr after the last injection. The testis and epididymis were removed. Epididymis was for sperm analysis immediately, and immunohistochemistry, RT‐PCR and Western blot for the assessments of occludin, glial cell‐derived neurotrophic factor (GDNF) and TGF‐β3 mRNA and protein expression. The sperm analysis of epididymis showed that CTX can significantly decrease sperm count and motility; and administration of LC resulted in significant recovery of the sperm count and sperm motility. Compared with control group, the expressions of occludin and GDNF decreased and the expression of TGF‐β3 increased significantly (p < 0.05) in the CTX group. In the LC + CTX group, the expressions of occludin and GDNF were higher than those of the CTX group and similar to those of the control group; the TGF‐β3 expression was lower (p < 0.05) than that of the CTX group and similar to that of the control group. The results of this study showed that CTX could damage the spermatogenesis and reduce the expression of occludin and GDNF, and increase the expression of TGF‐β3 in testis of mouse, which indicates CTX's damage or efficacy to testis Sertoli cells. LC could protect the Sertoli cells of testis from these damages caused by CTX, and promote or protect the spermatogenesis. In conclusion, this study provides meaningful information about the possible damage to male fertility by chemotherapeutics and potential of LC in the protection of male fertility during chemotherapy.     

Nebivolol Ameliorates Cisplatin‐Induced Nephrotoxicity in Rats

Treatment with cisplatin is associated with dose‐limiting side effects, mainly nephrotoxicity. On the other hand, nebivolol, a β₁‐adrenoceptor antagonist, exhibits vasodilatory and antioxidative properties. This study aimed to determine whether nebivolol possesses a protective effect against cisplatin nephrotoxicity and explore many mechanisms underlying this potential effect. Nephrotoxicity was induced in Wistar rats by a single intraperitoneal injection of cisplatin (6 mg/kg) on day 2. Nebivolol (10 mg/kg) was administered orally for 7 consecutive days. Nebivolol showed a nephroprotective effect as demonstrated by the significant reduction in the elevated levels of serum creatinine and urea as well as renal levels of malondialdehyde, nitric oxide products (nitrite/nitrate), inducible nitric oxide synthase, tumour necrosis factor‐alpha, caspase‐3, angiotensin II and endothelin‐1 with a concurrent increase in renal levels of reduced glutathione and endothelial nitric oxide synthase compared to untreated rats. Histopathological examination confirmed the nephroprotective effect of nebivolol. Pre‐treatment with N_ω‐nitro‐L‐arginine methyl ester, the non‐specific nitric oxide synthase inhibitor, partially altered the protection afforded by nebivolol. In conclusion, nebivolol protects rats against cisplatin‐induced nephrotoxicity that is most likely through its antioxidant, anti‐inflammatory and antiapoptotic effects as well as by abrogation of the augmented angiotensin II and endothelin‐1 levels.     

Pharmacological Evaluation of a β‐Hydroxyphosphonate Analogue of l‐Carnitine in Obese Zucker fa/fa Rats

In this study, we evaluated the effect of an analogue of l ‐carnitine on parameters involved with Metabolic Syndrome in obese Zucker rats. Twenty‐four rats were treated for 5 weeks with l ‐carnitine (300 mg/kg) and its analogue at two concentrations (100 and 250 mg/kg) to assess their impact on glucose, triglycerides and cholesterol in liver and blood samples, as well as the amount of liver glycogen. Liver slices were also analysed. The analogue reduced the levels of glucose, triglycerides and cholesterol in liver and the level of triglycerides in serum. At 100 mg/kg, the analogue proved more effective than l ‐carnitine in improving the biochemical alterations present in liver. The amount of liver glycogen content was higher in obese animals treated with both l ‐carnitine and the analogue. No changes on insulin and leptin were observed in animals treated. l ‐carnitine and its analogue reduced the microvesicular fatty infiltration in liver. This study demonstrated that the analogue tested is more potent and efficient than l ‐carnitine and improves the pharmacological profile of l ‐carnitine.     

l‐Carnitine protects against 1,4‐benzoquinone‐induced apoptosis and DNA damage by suppressing oxidative stress and promoting fatty acid oxidation in K562 cells

Widespread occupational and environmental exposure to benzene is unavoidable and poses a public health threat. Studies of potential interventions to prevent or relieve benzene toxicity are, thus, essential. Research has shown l ‐carnitine (LC) has beneficial effects against various pathological processes and diseases. LC possesses antioxidant activities and participates in fatty acid oxidation (FAO). In this study, we investigated whether 1,4‐benzoquinone (1,4‐BQ) affects LC levels and the FAO pathway, as well as analyzed the influence of LC on the cytotoxic effects of 1,4‐BQ. We found that 1,4‐BQ significantly decreased LC levels and downregulated Cpt1a, Cpt2, Crat, Hadha, Acaa2, and Acadvl mRNA expression in K562 cells. Subsequent assays confirmed that 1,4‐BQ decreased cell viability and increased apoptosis and caspase‐3, ‐8, and ‐9 activities. It also induced obvious oxidative stress and DNA damage, including an increase in the levels of reactive oxygen species and malondialdehyde, tail DNA%, and olive tail moment. Additionally, the mitochondrial membrane potential was significantly reduced. Cotreatment with LC (500 μmol/L) relieved these alterations by reducing oxidative stress and increasing the protein expression levels of Cpt1a and Hadha, particularly in the 20 μmol/L 1,4‐BQ group. Thus, our results demonstrate that 1,4‐BQ causes cytotoxicity, reduces LC levels, and downregulates the FAO genes. In contrast, LC exhibits protective effects against 1,4‐BQ‐induced apoptosis and DNA damage by decreasing oxidative stress and promoting the FAO pathway.     

Renoprotective Effects of Gamma‐Aminobutyric Acid on Cisplatin‐induced Acute Renal Injury in Rats

To investigate the effect of gamma‐aminobutyric acid (GABA) on acute renal injury (ARI), we used here a rat model of acute tubular necrosis induced by the anticancer drug cisplatin (CP). GABA was given orally (100 or 500 mg/kg/day for ten consecutive days), and on the 6th day, some of the treated rats were also injected intraperitoneally with either saline or CP (6 mg/kg). Four days after CP treatment, urine was collected from all rats, which were then anaesthetized for blood pressure and renal blood flow monitoring. This was followed by intravenous injection of norepinephrine for the assessment of renal vasoconstrictor responses. Thereafter, blood and kidneys were collected for measurement of several functional, biochemical and structural parameters. GABA treatment (at 500 but not 100 mg/kg) significantly mitigated all the measured physiological and biochemical indices. Sections from saline‐ and GABA‐treated rats showed apparently normal proximal tubules. However, kidneys of CP‐treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with GABA (500 mg/kg). The concentration of platinum in the cortical tissues was not significantly altered by GABA treatment. The results suggested that GABA can ameliorate CP nephrotoxicity in rats. Pending further pharmacological and toxicological studies, GABA may be considered a potentially useful nephroprotective agent in CP‐induced ARI.     

乌司他汀对大鼠急性胰腺炎的实验治疗研究

研究了国产乌司他汀对大鼠急性胰腺炎的治疗作用。以胰蛋白酶溶液直接注入大鼠胰导管制备急性胰腺炎模型。模型制备后60min静脉分别给予不同剂量的国产或进口对照品鸟司他汀，观察其对急性胰腺炎大鼠生存率、血清淀粉酶及胰腺病理组织学的影响。结果表明，国产乌司他汀与进口品均可明显提高胰蛋白酶致急性胰腺炎大鼠的生存率，生存率自20％提高至70％（10×104g／kg），显著抑制血清淀粉酶活性升高，改善胰腺病理组织学变化，给药组存活动物胰腺呈轻度急性胰腺炎病变，提示乌司他汀具有细胞保护作用。     

Docosahexaenoic acid and l‐Carnitine prevent ATP loss in SH‐SY5Y neuroblastoma cells after exposure to silver nanoparticles

Silver nanoparticles (AgNPs) are among the most commonly used nanomaterials, but thus far, little is known about ways to mitigate against potential toxic effects of exposure. In this study, we examined the potential effects of AgNPs on mitochondrial function and cellular ATP levels, and whether these could be prevented by treatment with docosahexaenoic acid (DHA) and l ‐carnitine (LC). Acute exposure of AgNPs for 1 h to SH‐SY5Y cells resulted in decreased mitochondrial membrane potential, and decreased ATP and ADP levels, indicating mitochondrial damage and reduced production of ATP. Incubation of cells with DHA partially reduced, while treatment with LC and DHA completely abolished the AgNP induced decreases in ATP and ADP levels. This could be due to a LC‐facilitated entry of DHA to mitochondria, for repair of damaged phospholipids. It is postulated that DHA and LC may be useful for treatment of accidental environmental exposure to AgNPs. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 224–232, 2016.     

Ivabradine reversed nondipping heart rate in rats with l‐NAME‐induced hypertension

We hypothesized that decreasing elevated night‐time heart rate (HR) in hypertension by administering a bradycardic agent (ivabradine) at bedtime could bring cardiovascular benefit. Since rats are nocturnal animals, they exhibit circadian rhythms phase‐shifted relative to humans. Sixty‐six Wistar rats were divided into non‐diseased controls and rats with l ‐NAME‐induced hypertension to compare the haemodynamic effects of daytime‐dosed and night‐time‐dosed ivabradine. l ‐NAME‐induced hypertension inverted the physiological 5.6% night‐to‐day HR dip to an undesirable HR rise by 11.1%. Ivabradine dosed at daytime (the rat's resting phase) reverted a night‐to‐day HR rise to HR dip by 14.2%. These results suggest a cardiovascular benefit of ivabradine dosed at the human's resting phase (night‐time) for hypertensive patients with nondipping HR.     

西维来司钠对大鼠重症急性胰腺炎后急性肝损伤的保护作用

目的:探讨西维来司钠对大鼠重症急性胰腺炎(SAP)后急性肝损伤的治疗价值。方法:SD大鼠54只随机分为3组,A组为对照组,仅开腹,轻翻动胰腺,B组采用经十二指肠乳头逆行胆胰管注射3.5%牛磺胆酸钠的方法制备大鼠SAP模型,C组为西维来司钠药物治疗组,在制备SAP大鼠模型后微量泵持续静脉滴注西维来司钠;各组又分为3h、6h、12h3个亚组,每时间点6只。检测血浆白介素-6(IL-6)、中性粒细胞弹性蛋白酶(NE)、淀粉酶(AMY)及肝组织匀浆中超氧化物歧化酶(SOD)、丙二醛(MDA)的水平并观察肝、胰病理变化。结果(:1)B组IL-6、NE、AMY、MDA较A组明显升高(P<0.05),SOD明显降低(P<0.05),镜下可见胰腺水肿、炎细胞浸润、坏死,肝脏肝窦充血、细胞浊肿及坏死,且损伤程度随时限延长而加重。(2)C组较B组血浆IL-6、NE、AMY(12h)及肝组织匀浆中MDA水平下降(P<0.05),SOD升高(P<0.05),胰、肝病理损害程度减轻。结论:西维来司钠通过抑制NE的活性及在肝组织中的表达,抑制SAP急性期炎症反应及有效提高机体对氧自由基的清除能力,减轻SAP致肝损伤的程度。     

MitoKATP通道开放对重症急性胰腺炎大鼠心肌保护的实验研究

目的：探讨线粒体ATP敏感性钾通道（MitoKATP通道）开放对重症急性胰腺炎（SAP）心肌的保护作用及机制。方法：清洁级雄性SD大鼠36只随机分为4组：K组假手术;M组建立SAP大鼠模型;D组和H组分别给予连续腹腔注射二氮嗪(DZ)、DZ+5-羟基葵酸盐（5-HD）3d后建立SAP大鼠模型。观察4组大鼠术后24 h血清肌酸激酶同工酶（CK-MB）、乳酸脱氢酶（LDH）水平;分光光度法测定心肌组织Na+-K+-ATPase活性;流式细胞仪检测心肌细胞线粒体线粒体膜电位(?ψm)变化;原位末端标记（TUNEL）法检测心肌细胞凋亡情况;留取部分心脏、胰腺组织行病理学检查。结果：M组CK-MB、LDH水平、心脏病理评分及凋亡指数较D组升高,Na+-K+ -ATPase活性及?ψm较D组降低,差异均有统计学意义（P < 0.01）,但M组上述指标与H组比较差异均无统计学意义（P > 0.05）。结论：MitoKATP通道开放对SAP引起的心肌损伤有保护作用。     

乌司他丁不同给药途径对重症急性胰腺炎模型大鼠治疗作用的研究

目的:探讨乌司他丁经2种给药途径对重症急性胰腺炎(SAP)模型大鼠的治疗作用及机制。方法:50只♂SD大鼠随机分成假手术组(自由饮水)、SAP模型组、阳性对照药萘莫思他组和乌司他丁外周静脉、腹腔动脉给药组共5组,后4组建立SAP模型后分组给药,12h后观察肺、胰腺大体病理及组织学并评分,检测血清淀粉酶、肿瘤坏死因子(TNF-α)、血栓素B2(TXB2)和肺、胰腺组织中髓过氧化物酶(MPO)水平。结果:与SAP模型组比较,各药物组的淀粉酶、TNF-α、TXB2和肺、胰腺组织的MPO及组织学Hughes评分均明显降低(P<0.05);乌司他丁腹腔动脉给药组与其静脉给药组比较,除肺组织的MPO水平更高外(P<0.05),其余各项指标均明显降低(P<0.05)。结论:乌司他丁经腹腔动脉给药比经外周静脉给药对SAP治疗作用更明显,其作用机制可能与其抑制淀粉酶活性、抑制TNF-α、TXB等炎症介质释放以及肺、胰腺组织中的中性粒细胞的浸润及其活化程度有关。     

Ghrelin对急性胰腺炎大鼠肠运动功能的影响

目的：探讨Ghrelin能否通过影响肠运动功能对大鼠急性胰腺炎（AP）起到保护治疗作用.方法：Wistar大鼠30只,雌雄不限,随机分为假手术对照组,模型组（非治疗组）、Ghrelin治疗组,每组10只,各组予相应的造模手术或假手术处理,并于术后6 h处死,留取标本.从心脏取血,测定血清肿瘤坏死固子-α（TNF-α）、淀粉酶水平;留取小肠组织标本,检测小肠组织含水量,进行小肠病理评分.结果：Ghrelin治疗组TNF-α、淀粉酶水平较模型组降低（P＜0.05）,肠运动系数较模型组升高（P＜0.05）,而小肠病理及小肠含水量与模型组之间差异无统计学意义.结论：Ghrelin对AP大鼠肠运动功能具有促进作用,这可能是Ghrelin对大鼠急性胰腺炎保护作用的机制之一.     

急性胰腺炎相关性肺损伤模型的建立

目的采用5%牛磺胆酸钠逆行胰胆管注射建立急性出血坏死性胰腺炎(AHNP)大鼠模型,动态观察肺组织损伤情况,以评价能否建立有效的急性胰腺炎相关性肺损伤(APALI)动物实验模型。方法SD大鼠随机分成假手术对照组和AHNP模型组,动态观察3,6,12和24h四个时相点的血清淀粉酶、胰腺和肺病理组织学改变、肺组织湿干重比和髓过氧化物酶活性,伊文氏蓝法观察1.5,3和6h三个时相点肺血管通透性。结果血清淀粉酶、肺组织湿干重比和髓过氧化物酶活性在5%牛磺胆酸钠诱导后3h明显增高,并持续到24h,肺组织病理检查发现,牛磺胆酸钠诱导后肺组织就出现了明显的充血、出血、炎症细胞浸润、组织结构破坏等肺组织损伤的病理表现,AHNP大鼠1.5h肺血管通透性就显著增高,且随时间呈显著性增加,各指标与假手术组比较差异有显著性(P<0.05)。结论应用5%牛磺胆酸钠能够成功建立APALI大鼠模型,为进一步研究对APALI的防治作用奠定了基础。     

Tephrosia purpurea Ameliorates N‐Diethylnitrosamine and Potassium Bromate‐Mediated Renal Oxidative Stress and Toxicity in Wistar Rats

Abstract: In an earlier communication, we have shown that Tephrosia purpurea ameliorates benzoyl peroxide‐induced oxidative stress in murine skin (Saleem et al. 1999). The present study was designed to investigate a chemopreventive efficacy of T. purpurea against N‐diethylnitrosamine‐initiated and potassium bromate‐mediated oxidative stress and toxicity in rat kidney. A single intraperitoneal dose of N‐diethylnitrosamine (200 mg/kg body weight) one hr prior to the dose of KBrO₃ (125 mg/kg body weight) increases microsomal lipid peroxidation and the activity of xanthine oxidase and decreases the activities of renal antioxidant enzymes viz., catalase, glutathione peroxidase, glutathione reductase and glucose‐6‐phosphate dehydrogenase, phase II metabolizing enzymes such as glutathione‐S‐transferase and quinone reductase and causes depletion in the level of renal glutathione content. A sharp increase in blood urea nitrogen and serum creatinine has also been observed. Prophylactic treatment of rats with T. purpurea at doses of 5 mg/kg body weight and 10 mg/kg body weight prevented N‐diethylnitrosamine‐initiated and KBrO₃ promoted renal oxidative stress and toxicity. The susceptibility of renal microsomal membrane for iron ascorbate‐induced lipid peroxidation and xanthine oxidase activities were significantly reduced (P<0.01). The depleted levels of glutathione, the inhibited activities of antioxidant enzymes, phase II metabolizing enzymes and the enhanced levels of serum creatinine and blood urea nitrogen were recovered to a significant level (P<0.01). All the antioxidant enzymes were recovered dose‐dependently. Our data indicate that T. purpurea besides a skin antioxidant can be a potent chemopreventive agent against renal oxidative stress and carcinogenesis induced by N‐diethylnitrosamine and KBrO₃.     

MitoKATP通道开放对重症急性胰腺炎大鼠心肌的保护作用

目的:探讨线粒体ATP敏感性钾(MitoKATP)通道开放对重症急性胰腺炎(SAP)心肌的保护作用及机制.方法:清洁级雄性SD大鼠36只随机分为4组,K组假手术;M组建立SAP大鼠模型;D组和H组分别给予连续腹腔注射二氮嗪(DZ)、DZ+5-羟基葵酸盐(5-HD)3 d后建立SAP大鼠模型.检测4组大鼠术后24h血清肌酸激酶同工酶(CK-MB)、乳酸脱氢酶(LDH)水平;分光光度法测定心肌组织Na+-K+-ATPase活性;流式细胞仪检测心肌细胞线粒体膜电位(△ψm)变化;原位末端标记(TUNEL)法检测心肌细胞凋亡情况;留取部分心脏、胰腺组织行病理学检查.结果:M组CK-MB、LDH水平、心脏病理评分及凋亡指数较D组升高,Na+-K+-ATPase活性及△ψm较D组降低,差异均有统计学意义(P＜0.01),但M组上述指标与H组比较差异均无统计学意义(P＞0.05).结论:MitoKATP通道开放对SAP引起的心肌损伤有保护作用,且上述作用可被该通道阻滞剂阻断.     

Pharmacokinetics of the Experimental Non‐Nucleosidic DNA Methyl Transferase Inhibitor N‐Phthalyl‐l‐Tryptophan (RG 108) in Rats

DNA methyl transferase (DNMT) inhibitors can re‐establish the expression of tumour suppressor genes in malignant diseases, but might also be useful in other diseases. Inhibitors in clinical use are nucleosidic cytotoxic agents that need to be integrated into the DNA of dividing cells. Here, we assessed the in vivo kinetics of a non‐nucleosidic inhibitor that is potentially free of cytotoxic effects and does not require cell division. The non‐specific DNMT inhibitor N‐phthalyl‐l ‐tryptophan (RG 108) was injected subcutaneously in rats. Blood was drawn 0, 0.5, 1, 2, 4, 6, 8 and 24 hr after injection and RG 108 in plasma was measured by high‐performance liquid chromatography coupled to mass spectrometry. Trough levels and area under the curve (AUC) were significantly higher with multiple‐dose administration and cytochrome inhibition. In this group, time to maximal plasma concentration (t_max, mean ± S.D.) was 37.5 ± 15 min., terminal plasma half‐life was approximately 3.7 h (60% CI: 2.1–15.6 h), maximal plasma concentration (C_max) was 61.3 ± 7.6 μM, and AUC was 200 ± 54 μmol·h/l. RG 108 peak levels were not influenced by cytochrome inhibition or multiple‐dose administration regimens. Maximal tissue levels (C_max in μmol/kg) were 6.9 ± 6.7, 1.6 ± 0.4 and 3.4 ± 1.1 in liver, skeletal and heart muscle, respectively. We conclude that despite its high lipophilicity, RG 108 can be used for in vivo experiments, appears safe and yields plasma and tissue levels in the range of the described 50% inhibitory concentration of around 1 to 5 μM. RG 108 can therefore be a useful tool for in vivo DNMT inhibition.     

重组牛胰蛋白酶抑制剂对大鼠急性胰腺炎的治疗作用

目的：观察重组牛胰蛋白酶抑制剂（rBPTI）对大鼠急性坏死性胰腺炎（ANP）的治疗作用。方法：取大鼠60只，随机分成6组：假手术组、模型组、rBPTI的3个剂量组、抑肽酶组。注射牛磺胆酸钠建立大鼠ANP模型，股静脉注射给药48h后，测定专鼠血清和组织淀粉酶和脂肪酶含量，观察胰腺组织病理变化。结果：rBPTI治疗组可明显降低血清和组织淀粉酶、脂肪酶的浓度，与模型组比较差异有统计学意义（P〈0．05，P〈0．01），且使胰腺的病理变化减轻。结论：rBPTI对牛磺胆酸钠诱导大鼠ANP具有治疗作用，作用效果同天然BPTI相当。     

Naloxone Antagonizes Soman‐induced Central Respiratory Depression in Rats

The influence of naloxone on respiration impaired by the highly toxic organophosphate nerve agent soman in anaesthetized rats was investigated. Soman, administered in a dose that was ineffective in blocking the electrically induced contractions of the phrenic nerve‐diaphragm preparation in situ, induced a complete block of the spontaneous respiratory movements of the diaphragm, indicating the domination of central over the peripheral effects. Naloxone dose‐dependently antagonized the soman‐induced respiratory blockade. Atropine, at a dose that was per se ineffective in counteracting soman‐induced respiratory depression, potentiated the protective effects of naloxone and completely restored respiration. Naloxone remained completely ineffective in antagonizing respiratory depression induced by the muscarinic receptor agonist the oxotremorine. It is assumed that naloxone antagonizes soman‐induced respiratory inhibition by blocking endogenous opioidergic respiratory control pathways that are independent of the stimulation of muscarinic receptors.     

Rutin Ameliorates Cyclophosphamide-induced Reproductive Toxicity in Male Rats

Cyclophosphamide (CYC) as an anticancer alkylating agent has been known as a male reproductive toxicant. This study was aimed to evaluate the protective effect of rutin (RUT) on CYC-induced reproductive toxicity. Sexually mature Wistar rats (weighing 199 ± 10 g with five animals in each group) were given CYC (15 mg/kg) and/or RUT (30 mg/kg) twice a week via gavage for 4 weeks. The sperm counts, sperm motility, sperm morphology, daily sperm production (DSP), testicular, and epididymal antioxidant systems: superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), glutathione reductase (GR), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), and testicular steroidogenic enzymes (3β-hydroxysteroid dehydrogenase and 17β-HSD and spermatogenesis marker enzymes (lactate dehydrogenase (LDH), sorbitol dehydrogenase (SDH), alkaline phosphatase (ALP), acid phosphatase (ACP) in the testes, epididymis and seminal vesicles were investigated at the end of the fourth week. By the end of the fourth week, RUT prevented lower sperm counts, sperm motility, DSP, and higher abnormal sperm numbers induced by CYC. In testes, RUT decreased SOD, LDH, and SDH and increased CAT, 3β-HSD, 17β-HSD, ALP, and ACP induced by CYC. In epididymis, RUT increased SOD, CAT, GSH, GSH-Px, GR, GST SDH, ALP and ACP and decreased MDA and LDH induced by CYC. In seminal vesicles, marker enzymes were unchanged in rats given CYC alone or in combination with RUT. It appears that RUT ameliorates CYC reproductive toxicity at the investigated dose.