Attenuation of the extract from Moringa oleifera on monocrotaline-induced pulmonary hypertension in rats

The purpose of this study was to determine the effects of an extract from Moringa oleifera (MO) on the development of monocrotaline (MCT)-induced pulmonary hypertension (PH) in Wistar rats. An ethanol extraction was performed on dried MO leaves, and HPLC analysis identified niaziridin and niazirin in the extract. PH was induced with a single subcutaneous injection of MCT (60 mg/kg) which resulted in increases in pulmonary arterial blood pressure (Ppa) and in thickening of the pulmonary arterial medial layer in the rats. Three weeks after induction, acute administration of the MO extract to the rats decreased Ppa in a dose-dependent manner that reached statistical significance at a dose of 4.5 mg of freeze-dried extract per kg body weight. The reduction in Ppa suggested that the extract directly relaxed the pulmonary arteries. To assay the effects of chronic administration of the MO extract on PH, control, MCT and MCT+MO groups were designated. Rats in the control group received a saline injection; the MCT and MCT+MO groups received MCT to induce PH. During the third week after MCT treatment, the MCT+MO group received daily i.p. injections of the MO extract (4.5 mg of freeze-dried extract/kg of body weight). Compared to the control group, the MCT group had higher Ppa and thicker medial layers in the pulmonary arteries. Chronic treatments with the MO extract reversed the MCT-induced changes. Additionally, the MCT group had a significant elevation in superoxide dismutase activity when normalized by the MO extract treatments. In conclusion, the MO extract successfully attenuated the development of PH via direct vasodilatation and a potential increase in antioxidant activity.     

Effects of 2-azafluorenones on phosphatidyl-inositol specific phospholipase C activation in c6 glioma cells

The purpose of this study was to determine the effects of an extract from Moringa oleifera (MO) on the development of monocrotaline (MCT)-induced pulmonary hypertension (PH) in Wistar rats. An ethanol extraction was performed on dried MO leaves, and HPLC analysis identified niaziridin and niazirin in the extract. PH was induced with a single subcutaneous injection of MCT (60 mg/kg) which resulted in increases in pulmonary arterial blood pressure (Ppa) and in thickening of the pulmonary arterial medial layer in the rats. Three weeks after induction, acute administration of the MO extract to the rats decreased Ppa in a dose-dependent manner that reached statistical significance at a dose of 4.5 mg of freeze-dried extract per kg body weight. The reduction in Ppa suggested that the extract directly relaxed the pulmonary arteries. To assay the effects of chronic administration of the MO extract on PH, control, MCT and MCT+MO groups were designated. Rats in the control group received a saline injection; the MCT and MCT+MO groups received MCT to induce PH. During the third week after MCT treatment, the MCT+MO group received daily i.p. injections of the MO extract (4.5 mg of freeze-dried extract/kg of body weight). Compared to the control group, the MCT group had higher Ppa and thicker medial layers in the pulmonary arteries. Chronic treatments with the MO extract reversed the MCT-induced changes. Additionally, the MCT group had a significant elevation in superoxide dismutase activity when normalized by the MO extract treatments. In conclusion, the MO extract successfully attenuated the development of PH via direct vasodilatation and a potential increase in antioxidant activity.     

Losartan, a nonpeptide angiotensin II (Ang II) receptor antagonist, inhibits neointima formation following balloon injury to rat carotid arteries.

Angiotensin-converting enzyme inhibitors have been shown to inhibit intimal thickening following balloon catheterization of rat carotid arteries. To assess the role of the renin-angiotensin pathway and the angiotensin type-I (AT1) receptor in this effect, the nonpeptide Ang II antagonist losartan (DuP 753) or vehicle was infused continuously i.v. in rats from two days before to two weeks after balloon injury to the left common carotid artery; drug effects upon intimal thickening were examined histologically. Losartan produced a dose-dependent reduction in cross-sectional area of intimal lesions determined two weeks post balloon injury. At 5 mg/kg/day a nonsignificant 23% reduction of intimal area was observed. At the higher dose of 15 mg/kg/day, losartan produced a 48% reduction in intimal area (P less than 0.05) compared to the vehicle-infused group. The cellular density of the neointima was not affected by losartan, indicating a probable effect of the drug upon migration and/or proliferation of smooth muscle cells. In separate groups of non-ballooned rats, losartan infusions of 5 and 15 mg/kg/day produced significant rightward shifts (averaging 6.4- and 55-fold, respectively) in curves relating increases in blood pressure to intravenous Ang II in pithed rats determined between 2 and 16 days following initiation of losartan infusion. Mean arterial blood pressure (determined under alpha-chloralose anesthesia) was reduced following continuous losartan infusion for 6 days from 128 +/- 8 mm Hg (vehicle) to 105 +/- 8 mm Hg at 5 mg/kg/day (P less than 0.05), and 106 +/- 4 mm Hg at 15 mg/kg/day (P less than 0.05). Thus, losartan attenuated the vascular response to balloon catheter injury, and this effect was associated with functional block of vascular AT1 receptors. The results support a role for Ang II, acting via AT1 receptors, in myointimal thickening subsequent to balloon injury of rat carotid arteries.     

PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation

Pulmonary hypertension frequently complicates interstitial lung disease, where it is associated with a high mortality. Patients with this dual diagnosis often fare worse than those with pulmonary arterial hypertension (PAH) alone and respond poorly to standard PAH therapy, often dying of right ventricular (RV) failure. We hypothesize that nitric oxide synthase (NOS) uncoupling is important in the pathogenesis of interstitial lung disease-associated pulmonary hypertension, and this process can be abrogated by phosphodiesterase type 5 (PDE5) inhibition to improve pulmonary vascular remodeling and right ventricular function. Intratracheal bleomycin (4 U/kg) or saline control was administered to C57/BL6 mice after anesthesia. After recovery, animals were fed a diet of sildenafil (100 mg.kg(-1).day(-1)) or vehicle for 2 wk when they underwent hemodynamic measurements, and tissues were harvested. Survival was reduced in animals treated with bleomycin compared with controls and was improved with sildenafil (100.0 vs. 73.7 vs. 84.2%, P < 0.05). RV/LV+S ratio was higher in bleomycin-alone mice with improvement in ratio when sildenafil was administered (33.00 +/- 0.01% vs. 20.98 +/- 0.01% P < 0.05). Histology showed less pulmonary vascular and RV fibrosis in the group cotreated with sildenafil. Bleomycin was associated with a marked increase in superoxide generation by DHE histological staining and luminol activity in both heart and lung. Treatment with sildenafil resulted in a concomitant reduction in superoxide levels in both heart and lung. These data demonstrate that PDE5 inhibition ameliorates RV hypertrophy and pulmonary fibrosis associated with intratracheal bleomycin in a manner that is associated with improved NOS coupling and a reduction in reactive oxygen species signaling.     

Respiratory and cardiovascular effects of thyrotropin-releasing hormone as modified by isoflurane, enflurane, pentobarbital and ketamine

Thyrotropin-releasing hormone (TRH) possesses significant arousing and cardio-respiratory stimulant actions. The effects of a 2 mg/kg i.v. bolus dose of TRH on respiration and systemic hemodynamics were compared in conscious, freely-moving rats and during anesthesia with 4 different anesthetics. Fifty-four male Sprague-Dawley rats weighing 285 +/- 4 g (mean +/- S.E.M.) were divided into 5 groups: conscious, enflurane (2%), isoflurane (1.4%), pentobarbital (8 mg/kg/h i.v.), and ketamine (60 mg/kg/h i.v.). Anesthetized rats were intubated and breathed oxygen or anesthetic/oxygen spontaneously. Aortic blood pressure, heart rate, cardiac output, respiratory rate, arterial blood pH, blood gases, lactate and glucose were measured, and data were collected over a 20 min baseline period and for 130 min post-TRH. TRH increased respiratory rate in all groups; concomitant changes in arterial PCO2 indicated increased minute ventilation in the inhalation agent groups but not in the i.v. anesthetic groups or in the awake group. Significant respiratory depression in the enflurane group was rapidly reversed by TRH. The respiratory stimulant and arousing effects of TRH were smallest with ketamine anesthesia. The hemodynamic responses to TRH were consistent with a pattern of sympathoadrenalmedullary activation and were relatively uniform across groups despite anesthetic-induced alterations in baseline values. TRH or its analogues may prove useful as an analeptic in clinical anesthesia.     

Role of thromboxane A2 and platelet activating factor in early haemodynamic response to lipopolysaccharide in rats.

The mechanism of early pulmonary and systemic haemodynamic response to intravenous infusion of LPS from Escherichia coli was investigated in anesthetised Wistar rats. 10 mg of LPS given at a rate of 4 mg/kg/min but not at a rate of 1 mg/kg/min induced an increase in pulmonary arterial pressure (PAP) and a fall in systemic arterial pressure (SAP). Pretreatment with a PAF receptor antagonist; WEB 2170 (5 and 25 mg/kg) inhibited both PAP and SAP responses to LPS (4 mg/kg/min) while an inhibitor of thromboxane synthesis; Camonagrel (10 and 20 mg/kg) abolished PAP response without a major effect on SAP response to LPS. In conclusion, both PAF and TXA2 mediate LPS induced rise in pulmonary arterial pressure while LPS-induced fall in systemic arterial pressure is mediated by PAF.     

脂肪干细胞移植对野百合碱诱发的肺动脉高压大鼠肺动脉压的量效和时效作用

目的探索脂肪干细胞（ADSC）移植治疗野百合碱（MCT）诱导的肺动脉高压（PAH）大鼠的适宜细胞数和干预时间。 方法（1）MCT的建模时效和量效：雄性SD大鼠48只分为正常对照组,20 mg/kg、30 mg/kg、40 mg/kg MCT组分别予腹腔注射生理盐水、MCT 20 mg/kg、30 mg/kg、40 mg/kg,4和8周后,右心室插管法检测平均肺动脉压（mPAP）,称重法计算右心室肥厚指数（RVHI）。（2）ADSC的治疗量效作用：雄性SD大鼠分别予腹腔注射MCT（30只）和生理盐水（30只）,1周后通过颈静脉注射分别移植0.5×10⁶、1.0×10⁶、3.0×10⁶、5.0×10⁶ADSC,其他组予等量生理盐水。移植3周后检测mPAP和RVHI。（3）ADSC的治疗时效作用：雄性SD大鼠30只,分别注射40 mg/kg MCT（24只）和生理盐水（6只）。MCT腹腔注射1 d,1、2周后分别移植1.0×10⁶个ADSC。MCT注射4周后检测mPAP和RVHI。多组间比较采用单因素或双因素方差分析,两两比较采用LSD检验。 结果（1）腹腔注射4周后,30 mg/ kg或40 mg/kg MCT组mPAP和RVHI均升高[mPAP值（24.89±3.31）mmHg,（27.19±2.11）mmHg比（15.80±0.42）mmHg,差异有统计学意义（P均< 0.05）;RVHI值0.42±0.06,0.47±0.04比0.25±0.02,差异有统计学意义（P均< 0.05）]。8周后,20 mg/kg或30 mg/ kg MCT组mPAP和RVHI均恢复正常,而40 mg/kg MCT组大鼠全部死亡。（2）40 mg/ kg MCT诱导的PAH大鼠mPAP和RVHI均升高。移植1.0×10⁶个ADSC可降低PAH大鼠的mPAP[（17.24±0.66）mmHg比（27.19±1.73）mmHg,P < 0.05]。移植0.5×10⁶、3.0×10⁶、5.0× 10⁶个ADSC不能降低PAH大鼠的mPAP和RVHI。（3）MCT腹腔注射1周和2周后,移植1.0×10⁶个ADSC可降低PAH大鼠的mPAP。 结论40 mg/kg MCT造模4周可建立稳定的PAH大鼠模型;造模1或2周后移植1.0×10⁶个ADSC能有效降低PAH大鼠的mPAP。     

Halofuginone does not reduce fibrosis in bleomycin-induced lung injury

Halofuginone, a coccidiostatic alkaloid, has anti-fibrotic properties, and may be useful as a therapeutic agent in lung fibrosis. To test this hypothesis we investigated the effect of halofuginone on bleomycin-induced lung fibrosis in Sprague-Dawley rats. Treatment groups included: (1) a single intratracheal (IT) instillation of 1.2U bleomycin, and intraperitoneal (IP) injection of halofuginone (0.5 mg/dose), every other day; (2) IT 1.2U bleomycin and IP distilled water (D.W.), every other day; (3) IT 0.8U bleomycin and daily IP halofuginone (0.5 mg/dose); (4) IT 0.8U bleomycin and daily IP D.W.; (5) IT saline and IP halofuginone, every other day; (6) IT saline and daily IP D.W.; (7) IT 0.625U bleomycin and oral halofuginone (10 mg/kg rodent lab chow); (8) IT 0.625U bleomycin and standard lab chow. Animals were studied 14 days after IT instillation. Lung injury was evaluated by total and differential cell count in bronchoalveolar lavage fluid, by a semi-quantitative morphological index of lung injury, and by biochemical analysis of lung hydroxyproline content. Overt signs of lung injury were apparent in bleomycin-treated rats by all measures. These changes were not affected by treatment with halofuginone, irrespective of the treatment regimen used. This study does not support the use of halofuginone to prevent or ameliorate lung fibrosis.     

Bronchial circulation and cyclooxygenase products in acute lung injury

The role of cyclooxygenase products in the response of the bronchial circulation to acute lung injury was examined in 30 dogs. By use of an open-chest preparation the left lower lobe (LLL) pulmonary circulation was isolated, continuously weighed, and perfused in situ. The anastomotic bronchial blood flow [Qbr(s-p)] was measured as the rate of increase in the volume of the LLL-perfusion circuit. Four groups of dogs were studied. In group A, six dogs received cyclooxygenase inhibition (COI) with either indomethacin (2 mg/kg) or ibuprofen (10 mg/kg). In group B (n = 10) lung injury caused by airway instillation of glucose (15 mg) with glucose oxidase (500 micrograms/kg) (G/GO) or LLL pulmonary arterial infusion of alpha-napthyl thiourea (ANTU, 2 mg/kg). Group C (n = 10) received COI, and 30 min later injury was induced as above with either ANTU or G/GO. Group D (n = 4) received COI immediately after anesthesia; then, 30 min after completion of the surgical preparation, injury was induced with ANTU or G/GO. After COI, Qbr(s-p) decreased to 35 +/- 9% of the basal values (P less than 0.05). After administration of ANTU or G/GO, Qbr(s-p) increased irrespective of whether COI was present. 6-Ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2) were measured by radioimmunoassay in the LLL pulmonary artery and systemic venous blood, demonstrating an increase in 6-keto-PGF1 alpha due to surgical preparation and confirming complete COI in those animals receiving COI immediately after anesthesia. These findings demonstrate that 1) the bronchial circulation is capable of a sevenfold increase in flow in response to acute lung injury.(ABSTRACT TRUNCATED AT 250 WORDS)     

Is MutaMouse insensitive to clastogens?

Several studies suggest that MutaMouse is insensitive to clastogens, including the accompanying paper by Mahabir et al., which describes a study with bleomycin, camptothecin, m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide) and its ortho-analogue, o-AMSA (4'-(9-acridinylamino)-methanesulfon-o-anisidide). Only camptothecin was clastogenic in MutaMouse and none of these four compounds induced mutations at the lacZ locus. However, to improve exposure, dose range-finding studies were performed in CD2F1 mice, the parental strain of MutaMouse. Male CD2F1 mice (n=3) were treated with bleomycin (25-100 mg/kg bw, p.o. and i.p.), camptothecin (1-10 mg/kg bw p.o.) and m-AMSA (10-50mg/kg bw p.o. and 1-5 mg/kg bw i.p.) for 5 days and blood was sampled on day 3 and/or day 6 for analysis by flow cytometry to determine % MN-RETs. Camptothecin (1 mg/kg bw, day 6) induced a 3.6-fold increase in % MN-RET (P<0.05) but was toxic at higher doses. All day-3 camptothecin samples were positive (P<0.05). Bleomycin was negative when administered p.o. but positive at all doses on both days when given i.p. (P<0.05) whereas m-AMSA was negative when given i.p. or orally. Based on these results, male MutaMouse mice (5 per group) were dosed daily with bleomycin (50 mg/kg bw) for 5 days or with camptothecin (5 mg/kg bw) for 2 days. Peripheral blood was sampled 24 h after the final dose in each group and tissues were sampled 37 days later. Both compounds induced significant increases in % MN-RET, but only bleomycin induced a significant increase in MF (6-fold in liver, 4.5-fold in kidney and 2-fold in lung) compared with the untreated control. These studies support the view that MutaMouse is insensitive to compounds where the genotoxic mechanism of action is predominantly clastogenesis, but demonstrates that the peripheral blood micronucleus test is a useful adjunct to the transgenic gene-mutation assay.     

Age related toxic effects of endosulfan on certain enzymes of rat erythrocytes

The effect of oral administration of endosulfan (12.5 mg/kg body weight), daily for 4 days was investigated on erythrocytes of female rats of 4 different age groups i.e. 15, 30, 70 and 365 days old. Erythrocyte membrane Na+, K(+)-ATPase and Mg2(+)-ATPase activities were significantly inhibited in all the age groups of rats. However, percent inhibition was maximum in the youngest animals. A significant decrease in the activity of erythrocyte glutathione reductase was observed in 30 and 70 days old rats whereas a significant increase in the activity of glucose-6-phosphate dehydrogenase (G-6-PD) was observed in these groups. The increase in G-6-PD activity may be a physiological response to compensate for decrease in the reduced glutathione level which results from decrease in the activity of glutathione reductase.     

降钙素基因相关肽对肺纤维化大鼠肺组织eIF3a、p27表达的影响

目的：观察降钙素基因相关肽（CGRP）对肺纤维化大鼠肺组织真核翻译起始因子3a （eIF3a）、p27表达的影响,探讨CGRP在肺纤维化中的作用及机制。方法：雄性SD大鼠,体重180~220 g,随机分为3组（n=8）：对照组、博莱霉素组、博莱霉素+辣椒素组。采用气管内注射博莱霉素（5 mg/kg）诱导肺纤维化大鼠模型。造模前4 d大鼠皮下注射辣椒素（Capsaicin）（50 mg/kg·d）,造模后第28天处死动物,颈动脉采血ELISA法测定血浆CGRP含量。细胞实验分6组（n=9）：Control组,转化生长因子-β1（TGF-β1）组,CGRP （1、10、100 nmol/L）组,CGRP8-37 1 μmol/L和CGRP 100 nmol/L组。细胞用CGRP和（或） CGRP8-37预处理1 h,再用TGF-β1（5 ng/ml）处理48 h。5-溴脱氧尿嘧啶核苷（BrdU）法检测细胞增殖。免疫组化、real-time PCR和（或） Western blot检测eIF3a、p27、α-平滑肌肌动蛋白（α-SMA）、collagen Ⅰ mRNA及蛋白表达。结果：博莱霉素诱发肺纤维化动物肺组织eIF3a、α-SMA及Ⅰ胶原表达增高,CGRP及p27的表达明显降低。外源性CGRP可剂量依赖性的抑制TGF-β1诱导的肺成纤维细胞增殖,明显抑制eIF3a、α-SMA、Ⅰ胶原的表达,上调p27的表达,这些作用可以被CGRP阻断剂CGRP8-37所取消。结论：CGRP在博莱霉素诱导的肺纤维化中起着重要作用,可能通过抑制eIF3a、上调p27的表达而抑制肺成纤维细胞的增殖,进而抑制肺纤维化的形成与发展。     

Direct injury to the bronchial vasculature in anesthetized sheep.

Injury to the bronchial vasculature may contribute to liquid and solute leakage into the lung during noncardiac pulmonary edema. The purpose of this study was to measure changes in hemodynamics, pulmonary mechanics, extravascular lung water, and lung morphometry after selectively injuring the bronchial vasculature in anesthetized sheep. In two groups of seven sheep, we injected oleic acid (0.1 ml/kg) or normal saline directly into the bronchoesophageal artery. We measured systemic and pulmonary arterial pressures, cardiac output, oxygen saturation, pulmonary resistance and compliance, and lung volumes before and 1 and 4 h after injection. The lungs were removed for measurement of extravascular water, histology, and morphometry. Four hours after injection of oleic acid, cardiac output decreased but pulmonary arterial pressure did not change. In addition, pulmonary resistance increased and dynamic compliance and vital capacity decreased. Extravascular lung water was slightly but significantly greater in the oleic acid group. Histological examination showed interstitial edema and leukocytes in airway walls and sloughing of bronchial epithelium but little or no alveolar edema. Morphometric analysis showed significant thickening of airway walls. We conclude that direct injury to the bronchial vasculature increases lung resistance, decreases dynamic compliance, and increases extravascular lung water by the accumulation of an inflammatory infiltrate in airway walls.     

Monocrotaline-induced cardiopulmonary damage in rats: amelioration by the angiotensin-converting enzyme inhibitor CL242817

Pulmonary injury induced by the plant alkaloid monocrotaline is partially prevented by the angiotensin-converting enzyme (ACE) inhibitor captopril. CL242817 [(S-[R*,S*])-1-([3-acetylthio]-3-benzoyl-2-methyl-propionyl)- L-proline] is a new orally active ACE inhibitor under evaluation as an antihypertensive agent. To determine whether CL242817 also can modify monocrotaline-induced pulmonary injury, male rats were divided into four groups: control; CL242817 (60 mg/kg/day, po); monocrotaline (2.4 mg/kg/day, po); or monocrotaline plus CL242817, and were sacrificed after 6 weeks of continuous treatment. Rats receiving monocrotaline alone exhibited occlusive medial thickening of the pulmonary arteries, cardiomegaly, and right ventricular hypertrophy. Electron micrographs of monocrotaline-treated lung revealed degeneration of both endothelial and Type I epithelial cells, as well as marked interstitial hypercellularity and fibrosis. Hydroxyproline (collagen) content of monocrotaline-treated lung also increased significantly, confirming the fibrosis observed in the electron micrographs. These structural changes were accompanied by decreased lung ACE and plasminogen activator (PLA) activities, indicative of pulmonary endothelial dysfunction. Concomitant CL242817 treatment ameliorated all anatomic manifestations of monocrotaline injury, particularly the right ventricular hypertrophy, pulmonary arterial occlusion, epithelial degeneration, and interstitial fibrosis. CL242817 also significantly prevented the monocrotaline-induced increase in lung hydroxyproline content. In contrast, concomitant CL242817 did not significantly influence the suppressed lung ACE and PLA activities in monocrotaline-treated rats. CL242817 alone produced retarded weight gain, decreased heart weight relative to body weight, decreased lung hydroxyproline content and ACE activity, and increased serum ACE activity and plasma AII concentration. Thus CL242817 resembles captopril, both in its ability to ameliorate monocrotaline-induced pulmonary injury in rats, and in many of its side effects.     

Investigation of the effects of α-tocopherol on the levels of Fe,Cu, Zn,Mn, and carbonic anhydrase in rats with bleomycin-induced pulmonary fibrosis

This study was designed to examine the effects of vitamin E on the levels of Zn, Mn, Cu, Fe, and carbonic anhydrase in rats with bleomycin-induced pulmonary fibrosis. Twenty-one male Wistar albino rats were randomly divided into three groups: bleomycin alone, bleomycin+vitamin E, and saline alone (control group). The bleomycin group was given 7.5 mg/kg body weight (single dose) bleomycin hydrochloride intratracheally. The bleomycin+vitamin E group was also instilled with bleomycin hydrochloride but received injections of α-tocopherol twice a week. The control group was treated with saline alone. Animals were sacrified 14 d after intratracheal instillation of bleomycin. Tissue Zn, Mn, Cu, Fe, and carbonic anhydrase activities were measured in the lung and liver. Lung Cu, Fe, and carbonic anhydrase activity increase in both experimental groups. Zn and Mn levels decreased, except for the Mn level in the bleomycin group. Liver Zn, Mn, and Cu levels decreased in both experimental groups compared to the control group, whereas Fe and carbonic anhydrase activity increased in comparison to the control group. However, the liver tissue Fe level decreased compared to the control group. In the histopathologic assesment of lung sections in the bleomycin+vitamin E group, partial fibrotic lesions were observed, but the histopathologic changes were much less severe compared to the bleomycin-treated group.     

肺纤维化初期肺动脉高压大鼠肺动脉反应性的变化

目的：观察肺纤维化初期肺动脉高压大鼠肺动脉血管反应性的变化。方法：66只雄性SD大鼠,随机分为博莱霉素（BLM）组和手术对照（Sham）组。BLM组为气管内一次性滴注BLM（5 mg/kg）;Sham组为气管内滴注等容量的生理盐水（NS）。应用离体血管张力检测技术测定大鼠肺动脉血管反应性变化;用HE显示肺动脉壁病理形态学变化;Masson染色检测肺纤维化程度;右心漂浮导管技术测定大鼠平均肺动脉压。结果：①BLM组大鼠的肺动脉血管（保留内皮和去内皮）对苯肾上腺素（PE）的收缩反应均弱于Sham组（P均〈0.05）。②BLM组大鼠肺动脉血管（保留内皮）对氯化乙酰胆碱（Ach）的舒张反应明显弱于Sham组（P〈0.01）。③Sham组有内皮的肺动脉血管对L-NAME和PE联合作用的收缩反应明显强于PE单独作用（P〈0.01）,而BLM组有内皮肺动脉血管对L-NAME和PE联合作用的收缩反应与对PE单独作用比,其差异无统计学意义（P〉0.05）。④BLM组肺动脉内皮细胞脱落。⑤BLM组大鼠肺组织呈现纤维增生初期的病理特征,且大鼠的平均肺动脉压明显高于Sham组（P〈0.05）。结论：肺纤维化形成初期肺动脉高压大鼠肺动脉血管反应性出现异常。     

Role of platelet-activating factor in the ovine heparin-protamine reaction.

Platelet-activating factor (PAF) infusion into sheep, as well as protamine reversal of heparin anticoagulation, causes thromboxane release into plasma, pulmonary hypertension, hypoxemia, and leukopenia. We investigated the possible role of PAF in the heparin-protamine reaction. Intravenous protamine was administered to neutralize heparin anticoagulation in five awake sheep and caused an increase of mean pulmonary arterial pressure from 16.6 +/- 1 (SE) mmHg at base-line to 47 +/- 9 mmHg at 1 min after protamine injection (P < 0.01) because of a 4.5-fold increase of pulmonary vascular resistance. This neutralization reaction induced a 25% reduction of circulating leukocyte count and arterial PO2. Undetectable blood levels of PAF were measured by bioassay and high-performance liquid chromatography during these heparin-protamine reactions. Infusion of BN 52021 (20 mg/kg), a PAF receptor antagonist, before rechallenging the same sheep with heparin and then protamine did not reduce the level of peak pulmonary hypertension or the degree of hypoxemia and leukopenia. We conclude that the leukopenia and thromboxane-mediated pulmonary vasoconstriction occurring after rapid intravascular formation of heparin-protamine complexes in sheep are not due to the release of PAF.     

Physiological,pharmacokinetic and liver metabolism comparisons between 3-, 6-, 12- and 18-month-old male Sprague Dawley rats under ketamine-xylazine anesthesia

The main objective of this study was to compare the physiological changes (withdrawal and corneal reflexes, respiratory and cardiac frequency, blood oxygen saturation, and rectal temperature) following intraperitoneal administration of ketamine (80 mg/kg) and xylazine (10 mg/kg) to 3-, 6-, 12- and 18-month-old male Sprague Dawley rats (n=6/age group). Plasma pharmacokinetics, liver metabolism, and blood biochemistry were examined for a limited number of animals to better explain anesthetic drug effects. Selected organs were collected for histopathology. The results for the withdrawal and corneal reflexes suggest a shorter duration and decreased depth of anesthesia with aging. Significant cardiac and respiratory depression, as well as decreased blood oxygen saturation, occurred in all age groups however, cardiac frequency was the most affected parameter with aging, since the 6-, 12-, and 18-month-old animals did not recuperate to normal values during recovery from anesthesia. Pharmacokinetic parameters (T_1/2 and AUC) increased and drug clearance decreased with aging, which strongly suggests that drug exposure is associated with the physiological results. The findings for liver S9 fractions of 18-month-old rats compared with the other age groups suggest that following a normal ketamine anesthetic dose (80 mg/kg), drug metabolism is impaired, leading to a significant increase of drug exposure. In conclusion, age and related factors have a substantial effect on ketamine and xylazine availability, which is reflected by significant changes in pharmacokinetics and liver metabolism of these drugs, and this translates into shorter and less effective anesthesia with increasing age.     

Assessment of chronic administration of aloe vera gel on haematology, plasma biochemistry, lipid profiles and erythrocyte osmotic resistance in wistar rats

The study was designed to investigate the effects of chronic administration of Aloe vera gel extract on markers of hepatic damage, lipid profiles and erythrocyte osmotic fragility using the Wistar rats. Forty male Wistar rats divided into four groups of ten rats per group were used in the study. Group I which served as the control received 0.9% physiological saline while those in groups II, III and IV received Aloe vera gel (100, 250 and 500mg/kg), respectively, for four weeks. There was significant increase in the haemoglobin concentration while the PCV, RBC count, MCH and MCHC though showed some marginal increases but the increases were not significant in all the treated rats. No significant change was also observed in the erythrocyte osmotic fragility. However, there were significant reductions in plasma ALT, AST and ALP levels in animals that received the gel compared with the control while the plasma albumin and total protein values were higher than those of the control. All the animals that received the gel also showed significant reduction in plasma total cholesterol, triglycerides and LDL-cholesterol ratio compared with the control. In a similar manner, those animals that were administered with 500mg/kg gel had significantly higher HDL-cholesterol ratio than those of the control. This study showed that, chronic administration of Aloe vera gel extract had no significant effects on the haematological parameters of the rats and did not affect erythrocyte osmotic resistance. It however showed some cholesterol lowering action.keywords: Aloe vera, Haematology, Osmotic fragility, Plasma biochemistry.     

Oxygen radicals and substance P in perinatal hypoxia-exaggerated, monocrotaline-induced pulmonary hypertension

Perinatal hypoxia has been observed to cause more aggressive pulmonary hypertension in human. Several mediators such as reactive oxygen species (ROS) and substance P are believed to be crucial in the mechanism of inducing pulmonary hypertension. This study was designed to test whether substance P and ROS play a role in perinatal hypoxia-exaggerated, monocrotaline (MCT)-induced pulmonary hypertension. Normoxic Wistar rats (weighing 258 ± 9 g, n = 31) were divided into two groups: control (n = 16) and MCT (n = 15). Perinatal hypoxia Wistar rats (weighing 260 ± 19 g, n = 49) were divided into six groups: Hypoxia (n = 8), Hypoxia+MCT (n = 8), Hypoxia+capsaicin (CP)+MCT (n = 7), Hypoxia+MCT+1,3-dimethyl-2-thiourea (DMTU)E (n = 10), Hypoxia+MCT+DMTUL (n = 9), and Hypoxia+MCT+ hexa(sulfobutyl) fullerenes (HSF) (n = 7). Rats in the control group received saline injections. MCT (60 mg/kg, s.c.) was given three weeks prior to the functional examination. Chronic capsaicin pretreatment was performed to deplete substance P. Hydroxyl radical scavenger DMTU (500 mg/kg) was intraperitoneally (i.p.) injected early (DMTUE ) or late (DMTUL ) after MCT. Antioxidant HSF (10 mg/kg, i.p.) was given once daily for three weeks following MCT. MCT treatment caused significant increases in pulmonary arterial pressure (Ppa) and substance P level in lung tissue in normoxic rats. The MCT-induced increase in pulmonary arterial blood pressure was exaggerated by perinatal hypoxia, but this exaggeration was attenuated by either capsaicin pretreatment or antioxidant administrations. These results suggest that both ROS and substance P are involved in perinatal hypoxia-augmented, MCT-induced pulmonary hypertension.