Renal eicosanoids as determinants of renal function in liver disease

The available data suggest that alterations in renal prostaglandin metabolism participate in the pathogenesis of at least two prominent renal complications of liver disease: (a) sodium retention and (b) HRS. Although the data are highly suggestive, additional studies, including experimental manipulations that augment vasodilatory prostaglandins while diminishing vasoconstrictor metabolites of arachidonic acid, will be required to establish the role of prostaglandins or other arachidonic acid metabolites in mediating these renal abnormalities. The clinical caveat emerging from these observations is that every attempt should be made to avoid prescribing drugs which possess cyclooxygenase inhibitory activity to patients with decompensated liver disease who are sodium-avid.     

Role of angiotensin II in the neural control of renal function

The aim of the present study was to distinguish between the direct effects of the renal nerves on renal function and indirect effects via neurally mediated increased systemic angiotensin II. We applied low-level electrical stimulation (1 Hz) to the left renal nerves in pentobarbitone-anesthetized rabbits for 180 minutes and measured renal blood flow, sodium excretion, and urine flow rate from both the stimulated and the nonstimulated contralateral kidney in the presence and the absence of ACE inhibition (enalaprilat). Stimulation resulted in an angiotensin II-mediated rise in arterial pressure and decreases in renal blood flow, urine flow rate, and sodium excretion on the stimulated side. On the nonstimulated denervated side, we found no change in renal blood flow, but found a decrease in urine flow rate. With ACE inhibition, renal stimulation no longer caused an increase in arterial pressure, the antidiuretic responses of the stimulated kidney were attenuated, and, importantly, the decrease in urine flow rate on the nonstimulated kidney was completely abolished. We therefore propose that although a direct effect of the renal nerves on sodium excretion is clearly present, the antidiuresis and antinatriuresis observed during renal activation is further supported by a neurally mediated increase in systemic angiotensin II.     

Influence of eicosanoids on renal function of DOCA-salt hypertensive rats

The present study examined the contribution of changes in the synthesis or degradation (or both) of renal eicosanoids to the alterations in renal hemodynamics observed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Renal blood flow and glomerular filtration rate were markedly reduced in DOCA-salt hypertensive rats compared with values observed in control rats given water or saline to drink. The abnormalities in renal hemodynamics in the hypertensive rats were associated with an increase in the excretion of thromboxane B2, an increase in the release of thromboxane B2 from renal cortical tissue slices, and a diminished release of prostaglandin E2 (PGE2) from renal medullary tissue. Additionally, the urinary excretion of PGE2 and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and the release of 6-keto-PGF1 alpha from renal cortical and medullary tissue were elevated in rats with DOCA-salt hypertension. Since the excretion of PGE2 and 6-keto-PGF1 alpha and the release of 6-keto-PGF1 alpha by medullary tissue were also elevated in normotensive rats given 1% NaCl solution to drink, these latter changes probably were related to an elevation of sodium intake rather than to the development of hypertension. The functional significance of the alterations in the renal production of thromboxane in DOCA-salt hypertensive rats was evaluated by comparing the effects of a thromboxane synthesis inhibitor and a receptor antagonist on renal function in normotensive and DOCA-salt hypertensive rats. The administration of the thromboxane synthetase inhibitor furegrelate and the thromboxane receptor blocker SQ 29548 had no effect on renal hemodynamics in either group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of nitric oxide in the control of renal function and salt sensitivity

Nitric oxide (NO) plays critical roles in the control of renal and glomerular hemodynamics, tubuloglomerular feedback response, release of renin and sympathetic transmitters, tubular ion transport, and renal water and sodium excretion. This paper explores the importance of NO in the control of renal water and sodium excretion and in the long-term control of arterial blood pressure. Synthesis of NO, characteristics of NO tissue redox forms, NO synthase activity, and NO synthase isoforms in the kidney are reviewed. To define the role of NO as a natriuretic and antihypertensive factor, the most supportive evidence is summarized, and some contradictory results are also noted. Given the evidence that high salt intake results in high NO concentrations and great NO synthase expression and activity selectively in the renal medulla of the kidney, as well as evidence of a deficiency of the NO synthase activity in Dahl salt-sensitive rats confined in the renal medulla, this report emphasizes the mechanisms by which the renal medullary L-arginine/NO system controls sodium excretion and arterial blood pressure. Other mechanisms for the action of NO on sodium homeostasis such as the action on glomerular filtration rate and the direct effect on tubules are also discussed. We conclude that there is strong evidence that under physiologic conditions, NO plays an important role in the regulation of renal blood flow to the renal medulla and in the tubular regulation of sodium excretion. It is thereby involved in the long-term control of arterial blood pressure, and inhibition or deficiency of NO snythase may result in a sustained hypertension.     

Role of eicosanoids in structural degradation in osteoarthritis

PURPOSE OF REVIEW: Osteoarthritis is characterized mainly by degenerative changes in joint cartilage, ultimately resulting in loss of cartilage, and alterations in the subchondral bone. Osteoarthritis osteoblasts show a number of metabolic alterations that may interfere with normal cell metabolism and signaling, possibly leading to altered extracellular matrix composition. This review examines the role of eicosanoids in this structural degradation. RECENT FINDINGS: Prostaglandins exert diverse modulatory roles in osteoarthritis, with prostaglandin E2 known to play an important role in inflammation. Prostaglandins and leukotriene B4 have been shown to regulate proinflammatory cytokine and interstitial collagenase synthesis in human osteoarthritis synovial membrane explants. Human osteoarthritis osteoblasts produce variable levels of prostaglandin E2 and leukotriene B4 compared with normal osteoblasts. Prostaglandin E2 levels can distinguish two types of patients with osteoarthritis: osteoblasts from one group produce low levels of prostaglandin E2 and interleukin-6, and the other shows an increase in production. In contrast, osteoarthritis osteoblasts that produce high levels of prostaglandin E2 produce low levels of leukotriene B4 and vice versa. This observation could be explained by the selective metabolism of arachidonic acid via the 5-lipoxygenase or cyclooxygenase pathways in osteoarthritis osteoblasts. SUMMARY: Prostaglandins play a significant role not only in joint physiology, but also in the pathogenesis of joint disorders. In addition, it has been identified that osteoarthritis subchondral osteoblasts can synthesize leukotriene B4, indicating a role of leukotrienes in bone remodeling associated with osteoarthritis. A therapeutic intervention that blocks lipoxygenase/cyclooxygenase pathways, thereby inhibiting production of prostaglandins and leukotrienes, may therefore be very attractive for the treatment of osteoarthritis patients.     

Role of eicosanoids in human and experimental colitis

Prostaglandins, thromboxanes, and leukotrienes (collectively called eicosanoids) are increased at sites of inflammation and contribute to the manifestations of inflammation, such as hyperemia, hyperalgesia, edema, and inflammatory cell infiltration. Inhibition of eicosanoid production is the basic mechanism of action of corticosteroids and of nonsteroidal antiinflammatory drugs. Eicosanoid synthesis is also increased in human and experimental inflammatory bowel disease. Leukotriene B₄ is the most potent proinflammatory eicosanoid, and in vivo production of this compound is the predominant eicosanoid in colitis. Recent experimental data demonstrate that selective inhibition of leukotrienes may be a therapeutic strategy to reduce inflammation in inflammatory bowel disease.     

Low serum creatinine levels in severe hepatic disease

For five years, eight patients had abnormally low serum concentrations of creatinine. All patients presented with severe hepatic failure, which was due to fulminant hepatitis in seven patients and to advanced primary biliary cirrhosis in one patients. The serum urate (as uric acid) concentration was also low in seven patients. Endogenous creatinine clearance was increased in all patients (2.38 to 14.75 mL/s [143 to 885 mL/min]). However, inulin clearance measured in four patients was reduced (25 to 32 mL/min) and the creatinine-to-inulin clearance ratio ranged from 4.5 to 9.9. This range can be explained largely by an increased tubular secretion of creatinine related to body fluid expansion caused by a large fluid infusion. Renal function would be extremely overestimated when assessed from serum concentrations or clearance of creatinine in such patients.     

Role of ethanol in the regulation of hepatic stellate cell function

INTRODUCTION Ethanol abuse is a leading cause for morbidity and mortality throughout the world. It affects many organ systems, most notably the liver causing both acute and chronic liver disease, and the central nervous system[1-3].Hepatic cirrhosis resul…     

Cardiac function in end-stage renal disease

To assess cardiac status in end-stage renal disease, we compared clinical, ECG, and echocardiographic data from 37 patients on maintenance hemodialysis with data from 42 patients with functioning renal transplants. Cardiovascular symptoms and abnormal cardiovascular findings were more common in dialysis-maintained patients than in those with transplants. Follow-up studies indicated that despite a high prevalence of cardiac symptoms, abnormal physical signs, and dilated left ventricles among patients with end-stage renal disease, systolic left ventricular function was generally well preserved irrespective of renal failure therapy. Compared with maintenance hemodialysis, however, successful renal transplantation is associated with an overall enhancement of cardiac status, the majority of which is probably secondary to transplant-associated improvement in hemoglobin level and control of intravascular volume.     

Role of eicosanoids in the pathogenesis of murine cerebral malaria.

Because microvascular damage is a common feature of cerebral malaria, we have examined the role eicosanoid metabolites (prostaglandins and leukotrienes) in experimental cerebral malaria. Eighty ICR mice were infected with Plasmodium berghei ANKA, with 40 uninfected mice as controls. Half of the infected mice were treated on days 4 and 5 with aspirin, a prostaglandin synthesis inhibitor. Infected mice started to die of cerebral malaria on day 6, and by day 17, all infected mice died. In contrast, all infected mice treated with aspirin died by day 12. Infected mice had increased phospholipase A2 mRNA expression in the spleen and cyclooxygenase 1 (COX1) and COX2 expression in the brain. At the peak of cerebral malaria, infected mice had higher serum leukotriene B4 levels than control mice, and aspirin-treated infected mice had higher serum leukotriene B4 levels than untreated infected mice. These results suggest that prostaglandins are protective whereas leukotrienes are detrimental in cerebral malaria.     

Role of cyclooxygenase-2 in the prolonged regulation of renal function

The role of cyclooxygenase-2 (COX-2) in the prolonged regulation of renal function was evaluated during changes in sodium intake and reduction of NO synthesis. It was evaluated in conscious dogs by administering a selective inhibitor (nimesulide) during 8 consecutive days. Nimesulide administration to dogs with normal or high sodium load did not modify glomerular filtration rate but reduced renal blood flow (16%; P<0.05). The vasoconstriction elicited by COX-2 inhibition was greater when NO production was inhibited because glomerular filtration rate decreased by >25% when nimesulide was administered to dogs with a reduced NO synthesis. During low sodium intake, COX-2 inhibition elicited a decrease (P<0.05) of both glomerular filtration rate (34%) and renal blood flow (31%). Sodium excretion only decreased (P<0.05) during the first day of COX-2 inhibition in dogs with normal or high sodium load. The increase in plasma potassium levels elicited by COX-2 inhibition was greater in dogs with low sodium intake and was enhanced when NO production was inhibited. This change in potassium was not secondary to a decrease in plasma aldosterone levels. The results of this study suggest that COX-2-derived metabolites (1) play a more important role in the long-term regulation of renal hemodynamic when sodium intake is low, (2) protect the renal vasculature from the vasoconstriction secondary to a reduction in NO, (3) are only acutely involved in regulating urinary sodium excretion, and (4) play a more important role in regulating plasma potassium concentration when NO synthesis is reduced.     

成人Still病与急性重度肝损害

目的 探讨成人Still病并发急性重度肝损害的发生、发展，提高临床医生对成人Still病急性重度肝损害的认识。方法 收集1990-2006年北京中日友好医院风湿免疫科诊治的104例（102例住院和2例门诊患者）成人Still病的患者资料，并对其临床表现、实验室检查，特别是10例并发急性重度肝损害的发生及发展情况进行了回顾性分析。结果 102例住院诊治的成人Still病有54例（52．9％）出现不同程度肝损害，其中8例（7．8％）在治疗过程中出现急性重度肝损害，加上2例门诊随诊的重度肝损害患者，丙氨酸转氨酶均≥1000U／L，总胆红素40～250mg／L。10例患者在患病初期均有轻度肝损害，因不同原因加用常规剂量抗生素或免疫抑制剂或非甾体抗炎药，而出现急性重度肝损害。3例重度肝损害发展到肝功能衰竭而死亡，7例经激素加量或大量激素、保肝等治疗，肝功能恢复正常。结论成人Still病伴发轻度肝损害较常见，治疗过程中可因机体对某种药物的过度免疫反应，发生急性重度肝损害，因此对伴有轻度肝损害者的Still病患者用药一定要慎重。发生重度肝损害积极激素加量治疗，可以改善预后。