Impaired glucose tolerance in cyclosporine-prednisolone-treated renal graft recipients

In 33 renal transplant patients, an intravenous glucose tolerance test (IVGTT) was performed, and fasting plasma C-peptide concentrations analyzed. Nineteen of the patients were on treatment with cyclosporine-prednisolone (CsA-Po), and 14 were treated with azathioprine-prednisolone (Aza-Po). In the Aza-Po group, the K-values at IVGTT were normal in 13/14, but in the CsA-Po group they were only normal in 9/19 (P = 0.02). The fasting C-peptide levels were significantly higher in the CsA-Po group (P less than 0.001). within this group, there was no correlation between C-peptide level and serum-creatinine concentration, i.e. retention of C-peptide due to decreased renal function as judged by serum creatinine level was not suspected. Intrinsic prednisolone clearance was determined in the CsA-Po patients and was found to be lower than that previously described in Aza-Po patients. However, between those CsA-Po-treated patients with a pathologic K-value at IVGTT and those with a normal K-value there was no difference in prednisolone clearance, fasting C-peptide levels, CsA dose, or serum-creatinine concentrations. The pathophysiology of the cyclosporine-induced glucose intolerance is uncertain, and increased insulin resistance is possible.     

Repeated dosing with oral allosteric modulator of adenosine A1 receptor produces tolerance in rats with neuropathic pain

BACKGROUND: The positive allosteric adenosine receptor modulator, T62 (2-amino-3-(4-chlorobenzoyl)-5,6,7,8-tetrahydrobenzothiophene), has been shown to reduce mechanical allodynia in a rat model of neuropathic pain. However, whether chronic oral T62 retains efficacy in this pain model has not been examined. Therefore, the authors studied antiallodynic effects of chronic oral T62 in spinal nerved-ligated rats, as well as motor and sedative behavioral effects. METHODS: Oral T62, 100 mg/kg, or oral oil was applied daily to spinal nerve-ligated rats for 4 weeks, with rat weights examined daily. Sedation, placing and ambulation scores, and withdrawal threshold were observed for 3 h daily for the first 2 weeks and then once a week. At the end of observation, the animals were killed, and the spinal tissues were collected for radioligand binding. In addition, withdrawal thresholds were also observed in rats with 5 days of treatment with 50 mg/kg oral T62. Furthermore, the effects of intrathecal adenosine on rats with oral T62 or oil treatment were compared. RESULTS: Chronic oral T62, at 100 mg/kg, initially returned the withdrawal threshold to mechanical testing to preinjury levels, with minor or no sedative or motor effects. Tolerance was observed, with a 60% loss of most possible effects in antiallodynia within 5 days of daily administration. Similarly, tolerance also occurred with chronic oral T62 at 50 mg/kg but did not alter the effect of intrathecal adenosine. Furthermore, 4 weeks of exposure to 100 mg/kg T62 resulted in a small reduction in spinal cord A1 receptor number. CONCLUSION: The results imply that chronically administered A1 adenosine modulators lose efficacy over time, partly as a result of receptor down-regulation.     

Impaired angiotensin II type 1 receptor signaling contributes to sepsis-induced acute kidney injury

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Impaired fracture healing in the absence of TNF-alpha signaling: the role of TNF-alpha in endochondral cartilage resorption.

TNF-alpha is a major inflammatory factor that is induced in response to injury, and it contributes to the normal regulatory processes of bone resorption. The role of TNF-alpha during fracture healing was examined in wild-type and TNF-alpha receptor (p55(-/-)/p75(-/-))-deficient mice. The results show that TNF-alpha plays an important regulatory role in postnatal endochondral bone formation. INTRODUCTION: TNF-alpha is a major inflammatory factor that is induced as part of the innate immune response to injury, and it contributes to the normal regulatory processes of bone resorption. METHODS: The role of TNF-alpha was examined in a model of simple closed fracture repair in wild-type and TNF-alpha receptor (p55(-/-)/p75(-/-))-deficient mice. Histomorphometric measurements of the cartilage and bone and apoptotic cell counts in hypertrophic cartilage were carried out at multiple time points over 28 days of fracture healing (n = 5 animals per time point). The expression of multiple mRNAs for various cellular functions including extracellular matrix formation, bone resorption, and apoptosis were assessed (triplicate polls of mRNAs). RESULTS AND CONCLUSIONS: In the absence of TNF-alpha signaling, chondrogenic differentiation was delayed by 2-4 days but subsequently proceeded at an elevated rate. Endochondral tissue resorption was delayed 2-3 weeks in the TNF-alpha receptor (p55(-/-)/p75(-/-))-deficient mice compared with the wild-type animals. Functional studies of the mechanisms underlying the delay in endochondral resorption indicated that TNF-alpha mediated both chondrocyte apoptosis and the expression of proresorptive cytokines that control endochondral tissue remodeling by osteoclasts. While the TNF-alpha receptor ablated animals show no overt developmental alterations of their skeletons, the results illustrate the primary roles that TNF-alpha function contributes to in promoting postnatal fracture repair as well as suggest that processes of skeletal tissue development and postnatal repair are controlled in part by differing mechanisms. In summary, these results show that TNF-alpha participates at several functional levels, including the recruitment of mesenchymal stem, apoptosis of hypertrophic chondrocytes, and the recruitment of osteoclasts function during the postnatal endochondral repair of fracture healing.     

Neuroanesthesia and Intensive Care Isoflurane tolerance against focal cerebral ischemia is attenuated by adenosine A1 receptor antagonists

PURPOSE: To investigate the role of the adenosine A1 receptor in the rapid tolerance to cerebral ischemia induced by isoflurane preconditioning. METHODS: Seventy-five rats were randomly assigned into five groups (n = 15 each): Control, 8-cyclopentyl-1,3-dipropulxanthine (DPCPX), Isoflurane, DPCPX+Isoflurane and Vehicle+Isoflurane groups. All animals underwent right middle cerebral artery occlusion (MCAO) for two hours. Isoflurane preconditioning was conducted one hour before MCAO in Isoflurane, DPCPX+Isoflurane and Vehicle+Isoflurane groups by exposing the animals to 1.5% isoflurane in 98% oxygen for one hour. In the Control and DPCPX groups, animals were exposed to 98% oxygen one hour before MCAO for one hour. A selective adenosine A1 receptor antagonist, DPCPX, was administered (0.1 mg x kg(-1)) 15 min before isoflurane/oxygen exposure in the DPCPX and DPCPX+Isoflurane groups to evaluate the effect of adenosine A1 receptor antagonist on isoflurane preconditioning. Dimethyl sulfoxide, the solvent of DPCPX, was administered (1 mL x kg(-1)) 15 min before isoflurane exposure in the Vehicle+Isoflurane group. Neurological deficit scores and brain infarct volumes were evaluated 24 hr after reperfusion. RESULTS: Animals in the Isoflurane and Vehicle+Isoflurane groups developed lower neurological deficit scores and smaller brain infarct volumes than the Control group (P < 0.01). Animals in the DPCPX+Isoflurane group developed higher neurological deficit scores and larger brain infarct volumes than the Isoflurane and Vehicle+Isoflurane groups (P < 0.01). CONCLUSION: The present study demonstrates that preconditioning with isoflurane reduces focal cerebral ischemic injury in rats, and the adenosine A1 receptor antagonist (DPCPX) attenuates the neuroprotection induced by isoflurane preconditioning.     

腺苷A1受体在全身麻醉中的作用研究进展

背景 由于腺苷在睡眠方面的作用与全身麻醉所产生的作用非常相似,近年来关于腺苷及其受体在全身麻醉过程作用的研究越来越多,但其机制尚无定论.目的 综述腺苷A1受体与全身麻醉的关系及在全身麻醉过程中可能的作用机制.内容 简述全身麻醉与腺苷A1受体在睡眠方面的相似之处以及全身麻醉相关的重要受体γ-氨基丁酸A型(γ-amino butyric acid A,GABAA)受体、N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)受体与腺苷A1受体的关系,总结目前腺苷A1受体在全身麻醉中作用的研究结果.趋向 腺苷A1受体在全身麻醉中的作用机制尚不完全清楚,有待进一步的研究证实,研究腺苷A1受体和全身麻醉之间的关系对于临床麻醉工作及药物的研究应用有一定的指导意义.     

Pharmacologic stimulation of adenosine A2 receptor supplants ischemic preconditioning in providing ischemic tolerance in rat livers

BACKGROUND: Ischemic preconditioning (IPC) is a promising strategy for conferring ischemic tolerance. We confirmed the acquisition of ischemic tolerance in the liver immediately after IPC and the role of adenosine kinetics in this process. METHODS: Male Lewis rats were used. IPC was administered with a 10-minute ischemia followed by a 10-minute reperfusion. Ischemic tolerance was tested with a 45-minute ischemia. Changes in the adenosine concentrations in liver tissue were evaluated, and the effects of adenosine A1 or A2 receptor agonists or antagonists were examined either in place of or against IPC. RESULTS: The 7-day animal survival was significantly better in the IPC group than in the control group (87% vs 53%; n = 15, P < .05). The release of liver-related enzymes during reperfusion was suppressed better in the IPC group (P < .01). Recovery of adenosine triphosphate levels was faster in the IPC group (P < .01). After IPC, adenosine concentrations in liver tissue immediately increased to 1555 +/- 299 pmol/g wet tissue and were maintained at that level during a subsequent 45-minute ischemia. The ischemic tolerance generated by IPC was mimicked by the administration of adenosine A2 receptor agonist and opposed by adenosine A2 receptor antagonist. CONCLUSIONS: The ischemic tolerance of the liver immediately after IPC can be supplanted by selective pharmacologic stimulation of adenosine A2 receptors.     

Impaired sperm function after spinal cord injury in the rat is associated with altered cyclic adenosine monophosphate signaling

Our previous observations of changes in the expression of cAMP-dependent genes and the cAMP-responsive element modulator (CREM) in rat testicular cells after spinal cord injury (SCI) implied abnormal cAMP signaling as one of the mechanisms underlying the effects of SCI on spermatogenesis. It was postulated that such effects might contribute to abnormal sperm function after SCI. In this study, we examined this possibility. In spinal cord-contused (SCC) and -transected (SCX) rats, impaired sperm motility was accompanied by an increase in sperm cAMP content. Treatment of SCX rats with exogenous testosterone or follicle-stimulating hormone resulted in a further decrease in sperm motility, whereas sperm cAMP either increased or remained unchanged. These effects differed from those in sham control rats that received identical treatments. Results of these experiments also demonstrated that impaired sperm motility in SCC and SCX rats was accompanied by decreases in sperm viability and mitochondrial potential, thus suggesting a possible link between these changes. We concluded that impaired sperm motility after SCI was associated with decreases in sperm viability and mitochondrial potential. These effects occurred in the face of elevated sperm cAMP content and changes in its regulation, suggesting that altered cAMP signaling events might contribute to impairment of sperm motility and perhaps other sperm functions after SCI.     

Improvement of glucose tolerance and hepatic insulin sensitivity by oligofructose requires a functional glucagon-like peptide 1 receptor

Nondigestible fermentable dietary fibers such as oligofructose (OFS) exert an antidiabetic effect and increase the secretion of glucagon-like peptide 1 (GLP-1). To determine the importance of GLP-1 receptor-dependent mechanisms for the actions of OFS, we studied high-fat-fed diabetic mice treated with OFS for 4 weeks in the presence or absence of the GLP-1 receptor antagonist exendin 9-39 (Ex-9). OFS improved glucose tolerance, fasting blood glucose, glucose-stimulated insulin secretion, and insulin-sensitive hepatic glucose production and reduced body weight gain. Ex-9 totally prevented the beneficial effects of OFS. Furthermore, GLP-1 receptor knockout mice (GLP-1R(-/-)) were completely insensitive to the antidiabetic actions of OFS. At the molecular level, the effects of OFS on endogenous glucose production correlated with changes of hepatic IRS (insulin receptor substrate)-2 and Akt phosphorylation in an Ex-9-dependent manner. As inflammation is associated with diabetes and obesity, we quantified nuclear factor-kappaB and inhibitor of kappaB kinase beta in the liver. The activity of both intracellular inflammatory effectors was reduced by OFS but, importantly, this effect could not be reverted by Ex-9. In summary, our data show that the antidiabetic actions of OFS require a functional GLP-1 receptor. These findings highlight the therapeutic potential of enhancing endogenous GLP-1 secretion for the treatment of type 2 diabetes.     

腺苷A1受体敲除小鼠癫痫点燃过程中神经损伤的研究

目的 观察腺苷A1受体(A1R)敲除小鼠癫痫点燃过程中神经超微病理损伤,探讨腺苷A1受体的脑保护作用.方法 动物分为野生型、纯合子及敲除组3组,选择皮层、小脑、海马、脑干4个部位,采用透射电镜技术观察动物对戊四氮点燃的潜伏期及点燃癫痫过程中不同时间点(2 h、7 d、1 m)神经细胞的超微结构改变.结果 纯合子组点燃癫痫潜伏期平均值为(2.38±1.66)d,与野生型比较差异有统计学意义(P<0.01),结果显示纯合子组在点燃后2 h即出现广泛超微结构异常,主要为线粒体改变,随时间延长逐渐加重,而野生型组点燃后7 d才出现海马、颞叶为主的线粒体损伤,晚期时仍局限于海马.结论 腺苷A1受体有较强的脑保护作用,可减少戊四氮点燃过程中的细胞的超微结构损伤.     

腺苷A1受体系统对兔脑缺血损伤的保护效应

目的　探讨腺苷A1 受体系统对兔脑缺血的保护作用。方法　家兔 2 4只随机分为对照组 (Ⅰ组 ,n =8)、缺血组 (Ⅱ组 ,n =8)和腺苷A1 受体激动药 +缺血组 (Ⅲ组 ,n =8) ,股动脉抽血至平均动脉压 35～ 40mmHg时 ,阻断双侧颈总动脉诱导脑缺血。观察术后第 3天海马CA1 区神经元密度。结果　 (1 )Ⅱ组神经元密度为 (76 50± 1 5 2 6)个 /毫米 ,显著低于Ⅰ组神经元密度 (2 0 8 1 3±1 1 0 8)个 /毫米 (P <0 0 5) ;而Ⅲ组神经元密度 [(1 30 78± 1 8 0 7)个 /毫米 ]明显高于Ⅱ组 (P <0 0 5)。结论　激活腺苷A1 受体系统能减轻脑缺血性损害     

Renal tubule necrosis and apoptosis modulation by A1 adenosine receptor expression

We have shown that A1 adenosine receptors (A1ARs) are cytoprotective against renal tubular necrosis and apoptosis both in vivo and in vitro. To study the role of A1AR numbers on renal epithelial cell survival, we stably overexpressed the human A1 receptor in a porcine renal tubule cell line and utilized primary cultures of proximal tubules obtained from A1AR knockout mice. Receptor-overexpressing cells were protected against peroxide-induced necrosis and tumor necrosis factor-alpha/cycloheximide-induced apoptosis. Conversely, cultured proximal tubule cells from receptor knockout mice showed more necrotic and apoptotic cell loss than corresponding cells from wild-type mice. Overexpression of the receptor resulted in a significantly higher baseline expression of both total and phosphorylated heat-shock protein (HSP)27; the latter due to A1 receptor enhancement of p38 and AP2 mitogen-activated protein kinase activities. The resistance to cell death in the porcine cells was reversed by selective A1 receptor antagonism and by a selective inhibitor of HSP synthesis. Receptor activation in wild-type mice in vivo led to increased total and phosphorylated HSP27, whereas receptor knockout mice showed decreased baseline and adenosine-mediated HSP phosphorylation. These studies show that endogenous A1AR activation produces cytoprotective effects in renal proximal tubules by modulating HSP27 signaling pathways.     

超氧化物歧化酶介导腺苷延迟预处理的研究

目的 探讨以腺苷介导延迟预处理与锰-超氧化物歧化酶(Mn-SOD)的关系。方法大鼠随机分 6组,B组以腺苷 A1受体激动剂 CCPA预处理,24 h后制成离体心脏,低温缺血 3 h,复灌1h。观测心功能、SOD等。A组为缺血对照;C、E、F组在预处理前分别静注Mn-SOD反义、意义、错配寡核苷酸(ODN)。结果 B、C组左室压力上升最大速率恢复率(％)分别为 72.62±16.28,50.00±17.02、Mn-SOD活性(IU/mg.prot)分别为67.81±19.12,35.70±15.02,B组都高于C组,差异有显著性(P<0.05)。结论 Mn-SOD参与腺苷 A1受体介导的延迟预处理。     

The effect of an adenosine A1 receptor agonist in the treatment of experimental subarachnoid hemorrhage-induced cerebrovasospasm

Summary Background. Adenosine is a potent vasodilator and an important modulator of cardiovascular function. It has been postulated that nitric oxide (NO) is involved in adenosine-induced vasodilation. This study was designed to examine the effect of an adenosine A₁ agonist, N⁶-cyclopentyladenosine (CPA), in the prevention of subarachnoid haemorrhage (SAH)-induced vasospasm. Method. Experimental SAH was induced in Sprague-Dawley rats by injecting 0.3 mL autogenous blood into the cisterna magna. Intraperitoneal injections of CPA (0.003 mg/kg), or vehicle were administered 5 min and 24 hours after induction of SAH. The degree of vasospasm was determined by averaging the cross sectional areas of the basilar artery 2 days after SAH. Expressions of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) in basilar artery were evaluated. Findings. There were no significant differences among the control and treated groups in physiological parameters recorded before sacrifice. When compared with animals in the control group, cross-sectional area of basilar arteries areas in the SAH only, SAH plus vehicle and SAH plus CPA groups were reduced by 19% (p < 0.01), 22% (p < 0.01), and 9% (p = 0.133), respectively. The cross-sectional areas of the CPA-treated group differed significantly from those of the SAH only and SAH plus vehicle group (p < 0.05). Induction of iNOS-mRNA and protein in basilar artery by SAH was not significantly diminished by CPA. The SAH-induced suppression of eNOS-mRNA and protein were relieved by CPA treatment. Conclusions. This is the first evidence to show an adenosine A₁ receptor agonist is effective in partially preventing SAH-induced vasospasm without significant cardiovascular complications. The mechanisms of adenosine A₁ receptor agonists in attenuating SAH-induced vasospasm may be, in part, related to preserve the normal eNOS expression after SAH. Inability in reversing the increased iNOS expression after SAH may lead to the incomplete anti-spastic effect of CPA.     

Natriuretic and diuretic actions of a highly selective adenosine A1 receptor antagonist

The natriuretic and diuretic action of a highly selective adenosine A1 receptor (A1AdoR) antagonist, 1,3-dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine (CVT-124), was investigated in anesthetized rats. CVT-124 (0.1 to 1 mg/kg) caused dose-dependent increases in urine flow and fractional and absolute sodium excretion of by six- to 10-fold and, at 0.1 mg/kg, increased the GFR (1.6+/-0.1 to 2.5+/-0.2 ml/min; P<0.01). There were no changes in BP or heart rate. CVT-124 reduced absolute proximal reabsorption (26+/-3 to 20+/-2 nl/min; P<0.05) despite unchanged proximally measured, single-nephron GFR (SNGFR) (42+/-5 to 44+/-4 nl/min; NS) and thereby decreased fractional proximal reabsorption (60+/-3 to 46+/-4%; P<0.05). Despite increasing distal tubular fluid flow rate (5.4+/-0.7 to 9.7+/-0.9 nl/min; P<0.001), it reduced the proximal-distal difference in SNGFR (before: 9.4+/-1.0 versus during CVT-124: 4.6+/-1.5 nl/min; P<0.01), suggesting that it had blunted the effects of the macula densa on SNGFR. Direct measurements of maximal tubuloglomerular feedback (TGF) responses were made from proximal stop flow pressure (PSF) during orthograde loop perfusion from the proximal tubule with artificial tubular fluid at 40 nl/min. TGF was blunted by intravenous CVT-124 (0.5 mg/kg; deltaPSF with vehicle: 8.3+/-0.6 versus CVT-124: 6.5+/-0.3 mm Hg; n = 9; P<0.01). In conclusion, A1AdoR blockade reduces proximal reabsorption and uncouples it from glomerular filtration. It increases distal delivery of fluid yet does not activate a macula densa-dependent fall in SNGFR because it blunts the TGF response. Natriuresis accompanied by blockade of proximal glomerulotubular balance and TGF characterizes a new class of diuretic drugs.     

AT1 receptor downregulation: A mechanism for improving glucose homeostasis

There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations of angiotensin-Ⅱ enable chronic activation of the AT1 receptor, promoting sustained vasoconstriction and the consequent development of high blood pressure. Furthermore, the chronic activation of the AT1 receptor has been associated with the development of insulin resistance. From a m...