A selective thromboxane synthetase inhibitor,OKY-046, fails to improve blood rheology in endotoxin-shocked rabbits

Effects of a selective thromboxane synthetase inhibitor, (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate (OKY-046), were studied hemorheologically in endotoxin shocked-rabbits. The animals were intravenously administrated with 0.1mg of endotoxin 3 times at intervals of 3 days. At 7 days after the last endotoxin injection, endotoxin (0.2mg·kg^–1) was intravenously administrated to induce a shock. OKY-046 (30mg·kg^–1) was administrated after hypotension was developed by the endotoxin treatment and, then, it was continuously injected at 0.03mg·kg^–1·min^–1. Blood pressure remained unchanged and hypotensive was maintained during the treatment with OKY-046. Blood was sampled from the femoral artery 15 (before the administration of OKY-046), 45, and 120 minutes after the final administration of endotoxin. Pa_{O 2} increased, and Pa_{CO 2}, arterial pH, and base excess (BE) decreased during the endotoxin shock. The decrease of pH and BE was prevented by the administration of OKY-046. In the endotoxin-shocked animals, hematocrit, whole blood viscosity, erythrocyte deformability, plasma fluidity, and the ratio of hematocrit to whole blood viscosity showed no significant differences between the OKY-046 treated animals and non-treated ones. These data show that a selective thromboxane synthetase inhibitor (OKY-046) does not improve the blood rheology during endotoxin shock, although it seems to prevent the acidosis in some extent.(Kato T, Hayashi K, Takamizawa K, et al.: A selective thromboxane synthetase inhibitor, OKY-046, fails to improve blood rheology in exdotoxin-shocked rabbits. J Anesth 5: 247–254, 1991)     

Effect of diltiazem and thromboxane A2 synthetase inhibitor (OKY-046) on vessels following experimental subarachnoid hemorrhage

In order to examine the functional changes in the vascular smooth muscle, the effects of a thromboxane A2 synthetase inhibitor (OKY-046) and a calcium channel blocker (diltiazem) on vessels following subarachnoid hemorrhage, and the contractile activity of cerebral vessels with various vasoactive agents, were investigated by studying isometric tension recordings in rings of cat basilar artery. The maximum contractile activities of the vessels in response to noradrenalin and adrenaline during the course of subarachnoid hemorrhage were significantly less than those in the control group. On the other hand, the maximum contractile activity of the vessels in response to prostaglandin F2 alpha on the seventh day following subarachnoid hemorrhage was significantly augmented compared with that in the control group. A significant decline in the relaxation of responsiveness to diltiazem during the course of subarachnoid hemorrhage was observed compared with that of diltiazem in the control group. This responsiveness to vasoactive agents was not influenced by the application of OKY-046. The present study reveals functional changes in vascular smooth muscle exposed to subarachnoid hemorrhage in response to vasoactive agents and a calcium entry blocker. Thromboxane A2 may not be a significantly influential factor in the present results. It is suggested that cerebral vasospasm may well be related to functional changes of the arterial wall, which appear to be associated with derangement of the mechanisms of smooth muscle constriction and dilatation based on organic changes.     

Effects of a selective thromboxane synthetase inhibitor OKY-046 on experimental diabetic nephropathy

To examine the effects of endogenous thromboxane A2 on the development of diabetic nephropathy, we administered OKY-046, an inhibitor of thromboxane synthesis, to streptozotocin-induced diabetic rats. Animals were divided into three groups; nondiabetic control, diabetic, and diabetic with OKY-046, and were sacrificed 16 weeks after experimental procedures. The chronic oral administration of OKY-046 to diabetic rats significantly decreased plasma and urinary thromboxane B2 levels. Urinary protein excretion and serum glucose levels were significantly lower in the OKY-046-treated diabetic rats than in the untreated diabetics (60.8 +/- 23.2 vs. 94.1 +/- 33.4 mg/day in the 16th week, p less than 0.05 and 424.4 +/- 93.3 vs. 614.4 +/- 102.3 mg/dl in the 16th week, p less than 0.01, respectively). Platelet aggregation was inhibited by OKY-046. Blood urea nitrogen was unaffected. Ultrastructural examination revealed that the thickness of glomerular basement membrane was markedly thinner in the OKY-046-treated diabetic rats than in the untreated diabetics (197.4 +/- 29.6 vs. 288.6 +/- 46.9 nm, p less than 0.01). These results suggest that thromboxane A2 may play an important role in the development and progression of diabetic nephropathy in rats.     

The effects of thromboxane A2 synthetase inhibitor (OKY-046) on complete hepatic ischemia in rats with obstructive jaundice

The effects of OKY-046, a thromboxane A₂ synthetase inhibitor, on hepatic dysfunction produced by liver cell ischemia were studied in an experimental model of rats with obstructive jaundice. The experiments were performed 7 days after the rats underwent bile duct ligation. Warm total ischemia of the liver was induced by Pringle's method over a 20-min period and the animals were divided into two groups according to whether or not OKY-046 was administered. The reperfusion time was 30 min in each group. OKY-046 was administered via the femoral vein at a rate of 100 g/kg per min from 15 min before the blockade to the end of the experiment. The level of ATP in the liver tissue of the OKY-046 group was elevated slightly, but not significantly, compared to that of the control group. The ratio TXB₂/6-keto PGF₁ in the liver tissue was lower in the OKY-046 group than in the control group, and significant differences were found between the two groups in the water content of the liver and the mitochondrial score as examined by transmission electron microscopy. Thus, it was observed that an improvement in the balance of TXA₂ and PGI₂ associated with OKY-046 administration protected the cellular structure of the mitochondria in the rat liver.     

Involvement of platelet activating factor and thromboxane A2 in the renal response to unilateral ureteral obstruction

Platelet activating factor (PAF) and thromboxane A2 (TxA2) are two vasoactive mediators which can decrease renal blood flow. Both are synthesized by various intrarenal cell types or by macrophages which may infiltrate the kidney during unilateral ureteral obstruction (UUO). In several experimental systems, PAF receptor activation is accompanied by TxA2 release; pharmacological modification of TxA2 synthesis or receptor activation modulates the response to PAF. The involvement of PAF in UUO has not been studied previously, and the role of TxA2 has not been clearly defined by previous investigations. The hemodynamic response to acute UUO is characterized by decreases in renal blood flow (RBF) and glomerular filtration rate and an acute increase in ureteral pressure. In the present experiments, the involvement of either PAF or TxA2 in the acute response to UUO was studied by determining if blockade of either the TxA2 or PAF receptor would affect the renal hemodynamic response to UUO. In addition, the effect of blockade of the TxA2 receptor on the renal response to PAF was determined. Our results indicate that only a small portion of the renal response to PAF is mediated by TxA2, and that neither PAF nor TxA2 can be implicated in the acute hemodynamic response to UUO. TxA2 or PAF involvement in the chronic response to UUO still remains to be determined.     

The effect of partial unilateral ureteral obstruction release and allopurinol on the renal malondialdehyde and glutathione levels

PURPOSE: The aim of the present study was to evaluate whether relief of partial unilateral ureteral obstruction (PUUO) with or without antioxidant drug affect renal tissue malonedialdehyde (MDA) and glutathion (GSH) levels. MATERIALS AND METHODS: A total of 25 rats were used in this PUUO study. Partial unilateral ureteral obstruction was created by the burial of the upper one-third of the left ureter in the psoas muscle. The rats were sacrificed on 28th day following PUUO. Relief of the obstruction was performed twenty minutes before sacrifice by cutting the proximal ureter in reperfusion group. 50 mg/kg intraperitoneal allopurinol was administered 20 minutes before relief of obstruction in the antioxidant group. Renal tissue MDA and GSH levels were measured in both kidneys. RESULTS: At the end of the study 5, 7 and 7 rats could only be interpreted in sham, reperfusion and antioxidant groups, respectively. While the mean left and right renal MDA and GSH levels were statistically different from each other in reperfusion group (P < 0.001), there were no significant differences in the sham (P > 0.05) and antioxidant (P > 0.05) group. Both the mean sham group left and right renal tissue MDA or GSH levels were significantly different from reperfusion group, but only the mean sham group left renal tissue MDA and right renal tissue GSH levels were not statistically different from antioxidant group (P < 0.05). The mean left or right renal MDA and GSH tissue levels of the antioxidant group were statistically different from reperfusion group (P < 0.05) except for the right renal tissue GSH level (P > 0.05). CONCLUSION: Partial unilateral ureteral obstruction leads to oxidative injury by relief of obstruction in both kidneys. The antioxidant allopurinol has a beneficial effect on renal MDA and GSH levels in both kidneys.     

输尿管膀胱再植术对患侧肾功能的影响

目的：探讨输尿管膀胱再植术对患侧肾功能的影响。方法：回顾性筛选分析手术前后分别行ECT肾小球滤过率（GFR）测定，对侧肾输尿管正常，膀胱或肾无其他病变的输尿管膀胱再植术患者临床资料。结果：在33例符合筛选条件患者中，Cohen-Ahmed术式26例，Politano-Ledbetter术式5例，Lich-Gregoir术式2例，21例（63．6％）GFR术后近期较术前降低（平均5．3％），结论：大部分输尿管膀胱再植术病例，术后近期，患肾功能轻度受损。     

Atorvastatin preserves renal function in chronic complete unilateral ureteral obstruction

PURPOSE: The pleiotropic effects of hMG-CoA (3-hydroxy-3-metylglutaryl coenzyme A) reductase inhibitors may provide renal protection in chronic kidney disease. We examined whether atorvastatin administration preserved renal function in rats with chronic unilateral ureteral obstruction. MATERIALS AND METHODS: Renal clearance experiments were performed in sham operated rats and rats subjected to 3 or 12-day unilateral ureteral obstruction. Hemodynamics parameters and urinary microalbumin levels from the obstructed kidney were also measured. The rats were maintained on a regular diet or the same diet but supplemented with atorvastatin (50 mg/kg daily). RESULTS: Atorvastatin administration did not alter plasma total cholesterol but it significantly decreased triglyceride levels. In sham operated and 3-day unilateral ureteral obstruction rats atorvastatin treatment did not have effects on the glomerular filtration rate or effective renal plasma flow and it also did not affect urinary microalbumin levels. In rats with 12-day unilateral ureteral obstruction the glomerular filtration rate but not effective renal plasma flow was significantly higher and urinary microalbumin was significantly lower in atorvastatin treated rats than in those without atorvastatin treatment. CONCLUSIONS: Atorvastatin treatment decreased microalbuminuria and helped preserve filtration function in chronic unilateral ureteral obstruction without altering plasma cholesterol levels, suggesting that pleiotropic renal protection is offered by this statin.     

Effect of thromboxane inhibition on renal blood flow in dogs with complete unilateral ureteral obstruction

The effect of the thromboxane synthetase inhibitor OKY-046 on renal blood flow and ureteral pressure in awake dogs during 18 hours of complete unilateral ureteral obstruction was studied. OKY-046 was infused continuously throughout the period of obstruction and post-release. Renal blood flow and ureteral pressure were constantly monitored during the study. Urinary thromboxane B2 and prostaglandin E2 excretion served as markers for inhibition of renal thromboxane A2 synthesis. The triphasic relationship between ipsilateral renal blood flow and ureteral pressure previously found following unilateral ureteral obstruction was observed despite OKY-046 infusion. Inhibition of ipsilateral urinary thromboxane B2 excretion was greater than 90% compared to control while ipsilateral urinary prostaglandin E2 excretion was not consistently decreased showing specific thromboxane inhibition. These results suggest that urinary thromboxane B2 may serve as a useful marker for determining the effects of inhibition on renal thromboxane A2 production. At the level of inhibition of thromboxane synthesis achieved we did not observe any change in the late decrease in renal blood flow which is typically seen with chronic unilateral ureteral obstruction.     

Recovery of renal function after prolonged unilateral ureteral obstruction.

Concepts of renal counterbalance and animal experiments have long supported nephrectomy for prolonged complete unilateral ureteral obstruction. The situation in humans has been clarified by only a few reported cases. Herein we report 3 cases with relief of obstruction after at least 28, 28 and 150 days. Evidence is presented to support renal preservation in similar cases.     

γ-干扰素对梗阻性积水肾间质纤维化的治疗作用

目的 探讨γ干扰素(IFN-γ)对梗阻性肾积水肾间质纤维化的抑制作用及其可能的机制.方法 将65只雄性SD大鼠随机分成4组:治疗组(20只)、模型组(20只)、药物对照组(20只)、假手术组(5只).在建模和给药后的第3、7、14、21、28天,每组各随机处死动物4只(假手术组1只).采用苏木素-伊红(HE)和Masson染色观察病变肾脏间质纤维化的情况;采用聚合酶链反应(RT-PCR)技术检测肾组织中转化生长因子-β1(TGF-β1)、α-平滑肌肌动蛋白(α-SMA)和Ⅰ型胶原(Col-Ⅰ)的mRNA表达情况;免疫组织化学法观察以上三种蛋白的变化.结果 模型组大鼠术后肾间质逐渐出现纤维化改变,并随梗阻时间的延长逐渐加重,TGF-β1、α-SMA和Col-Ⅰ的mRNA和蛋白表达亦逐渐升高.第14天,模型组TGF-β1和α-SMA的表达量达到高峰,28 d时各指标的表达均达到最高,TGF-β1、α-SMA和Col-Ⅰ分别为51.84%、72.59%和68.73%.治疗组各指标在不同时间点均低于模型组,第28天时,三项指标依次为33.84%、32.59%和48.73%,与模型组比较P＜0.05.Banff评分显示治疗组间质纤维化程度明显减轻(P＜0.01).其余两组未见肾间质纤维化改变.结论 IFN-γ具有减轻积水后肾间质纤维化程度的作用,该作用与其下调TGF-β1的表达、抑制肌成纤维细胞(MyoF)激活和减少Col-Ⅰ生成有关.     

Long-term effects of 24-hr unilateral ureteral obstruction on renal function in the rat

To characterize the pattern of recovery following release of unilateral ureteral obstruction of 24-hr duration, rats were studied with whole kidney clearance techniques, 3 hrs, 8, 14, and 60 days after release. The single nephron glomerular filtration rate (SNGFR) of superficial and juxtamedullary nephrons was estimated with a modification of Hanssen's technique in rats studied 8 and 60 days after ureteral release. The whole kidney glomerular filtration rates (GFR) were decreased markedly 3 hrs after relief of obstruction, but gradually increased and by 14 days, the GFR of the postobstructed kidney (POK) and the contralateral kidney (CK) were comparable. This recovery of GFR was not a consequence of a homogeneous improvement in SNGFR. At 8 days, more than 15% of superficial and juxtamedullary nephrons were not filtering in the POK. This decrease in the percent of filtering nephrons persisted to 60 days post release, indicating a permanent loss of nephron units. The SNGFR of the residual nephrons of the POK was significantly greater than that of the CK at 8 and 60 days following ureteral release. Thus, acute unilateral ureteral obstruction results in a permanent loss of filtering nephrons, which is offset by hyperfiltration of those remaining. Abnormalities in renal tubule function persisted beyond the time (14 days) when whole kidney GFR had returned to normal. These abnormalities were in distal tubule function. Urine osmolality was consistently lower at all time intervals post release, as was net acid excretion. The results of the present study suggest that these abnormalities are a consequence of the reduction in the number of filtering juxtamedullary nephrons and/or to abnormalities in collecting duct function.     

The effects of pentoxifylline on renal function and free radical production in unilateral ureteral obstruction

There is an ongoing discussion about ureteral obstruction-related renal dysfunction. In this study, we aimed to test the effect of pentoxifylline (PTX) on both kidneys in unilateral ureteral obstruction (UUO), and to determine its interaction of with prostaglandin E₂ (PGE₂), and diclofenac sodium (DIS). A sham operation was performed in group 1. Placebo, PTX, DIS, and PTX+DIS were administrated to groups 2, 3, 4 and 5, respectively. The left ureter was ligated in all groups except group 1. At 24 h, technetium 99m diethylenetriamine penta-acetic acid scintigraphy was performed to determine renal function. Additionally, the tissue levels of thiobarbituric acid reactive substances (TBARS) and PGE₂ in both kidneys were measured to determine cytotoxic and cytoprotective mechanisms. When the ipsilateral kidneys were evaluated: (1) UUO significantly reduced DTPA uptake and none of the medications used prevented the reduction, (2) UUO significantly increased TBARS production, and only PTX prevented the increase, (3) UUO caused a significant increase in PGE₂ production, and only DIS significantly decreased this. When the contralateral kidneys were evaluated: (1) UUO significantly increased DTPA uptake but DIS and PTX+DIS prevented this, (2) UUO significantly elevated TBARS levels and DIS and PTX+DIS caused an additional elevation, (3) UUO significantly increased PGE₂ production, and only DIS prevented this. In conclusion, UUO caused ipsilateral renal hypofunction and contralateral hyperfunction, which are related to increased TBARS and PGE₂ levels. PTX markedly decreased free radical activity in the ipsilateral kidney. While PTX showed a placebo effect, DIS prevented the compensatory contralateral renal response through increased TBARS and decreased PGE₂ levels. The beneficial effect of PTX on the ipsilateral kidney, and the hazardous effect of DIS on the contralateral kidney may be explained by more complex interactions among TBARS, PGE₂, PTX, DIS and UUO-related renal dysfunction.     

脉血康对单侧输尿管梗阻大鼠肾保护作用及机制探讨

目的观察脉血康对单侧输尿管梗阻(unilateral ureteral obstruction,UUO)大鼠肾脏保护作用并探讨其可能作用机制。方法建立UUO大鼠模型,大鼠随机分为假手术组、模型组及脉血康组3组,各组给予相应干预,各组大鼠于术后14 d处死,抽取血清并留取肾组织标本,检测各组大鼠血肌酐(SCr)、尿素氮(BUN)、胆固醇(total cholesterol,TC)、三酰甘油(triglyceride,TG)情况,并观察各组肾脏病理改变情况,采用免疫组化方法观察肾组织中组织型纤溶酶原激活物(tissue type plasminogen activator,t-PA)、尿激酶型纤溶酶原激活物(urokinase type plasminogen activator,u-PA)、纤溶酶原激活物抑制剂1(plasminogen activator inhibitor-1,PAI-1)在各组的表达情况。结果①3组肾脏形态学变化有差异,假手术组双肾大小及体积无改变,颜色红润,模型组及脉血康组术侧肾脏体积明显增大,术侧肾盂肾盏及输尿管结扎段以上全程扩张。模型组肾实质颜色变浅,剖面肾皮质变薄,皮髓质分界不清,脉血康组肾脏颜色稍红润,肾脏皮髓质分界较清。②假手术组肾脏病理未见明显改变,与假手术组比较,模型组及脉血康组肾小管损伤及肾间质纤维化程度显著(P0.01);与模型组比较,脉血康组肾小管损伤及肾间质纤维化程度明显减轻(P0.05)。③与假手术组相比,模型组SCr、BUN、TC、TG水平均升高(P0.05),与模型组相比,脉血康组SCr、BUN、TC、TG水平均下降(P0.05)。④假手术组PAI-1、t-PA、u-PA表达于肾小管上皮细胞及肾小球系膜细胞胞浆,肾间质表达极少;与假手术组比较,模型组及脉血康组PAI-1明显增多(P0.05),而t-PA、u-PA表达明显减少(P0.05),与模型组相比,脉血康组PAI--1表达明显减少,t-PA表达明显增多(P0.05),u-PA无明显差别(P0.05)。结论脉血康可能通过调节脂质代谢下调肾脏PAI-1的表达,上调t-PA的表达从而促进肾脏细胞外基质降解,对UUO大鼠肾间质纤维化及肾功能具有保护作用。