[Experimental models of acute renal failure].
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Biomedical subjects
Publications and source records attributed to H Nihei.
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This study analyzes the changes induced by subarachnoid hemorrhage (SAH) on the serotonin (5-hydroxytryptamine, 5-HT) uptake and release evoked in rabbit basilar arteries by tyramine. Rabbits were injected with 5 ml of autologous arterial blood into the cisterna magna to produce SAH. Tritium accumulation in basilar arteries was measured after 30 minutes of incubation with 10(-7) M [3H]5-HT and a subsequent 120-minute superfusion (1 ml/min) period. The uptake of 5-HT by arteries 1, 2, 3, and 7 days after SAH was found to be 109%, 69%, 57% (P less than 0.05), and 67% (P less than 0.05) (n = 4, 4, 9, and 6; P less than 0.05) of control (n = 13; 16.8 +/- 1.2 X 10(2) dpm/mg tissue), respectively. The neuronal (cocaine-sensitive) uptake of 5-HT in the arteries 3 days after SAH decreased to approximately 38% of control, whereas the extraneuronal (cocaine-insensitive) uptake of both groups had almost the same absolute value (n = 6 and 6; 4.4 +/- 0.4 and 4.8 +/- 0.4 X 10(2) dpm/mg). Autoradiographic study disclosed that dense clusters of silver grains in the adventitia were not observed after treatment with cocaine (3 X 10(-5) M), although a diffuse distribution of grains was present throughout the vascular wall. The labeled arteries were stimulated by superfusion of tyramine, which is known to replace amines in the sympathetic nerve ending. Tyramine (10(-6) and 10(-4) M)-induced 3H efflux was significantly potentiated by SAH (n = 6) and was suppressed by treatment with cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)
Uremic patients often complain of fatigue and muscle weakness. In order to elucidate the abnormalities of energy metabolism in the muscles of such patients, we measured the concentrations of phosphocreatine (PCr), inorganic phosphate (Pi) and adenosine triphosphate (ATP) as well as the intracellular pH in skeletal muscles by 31P-NMR at rest, during aerobic and anaerobic exercise and during recovery in 15 uremic patients (7 non-dialyzed patients and 8 dialyzed patients) and 6 control subjects. At rest, there was no difference in intracellular pH between the uremic patients and controls, but the concentrations of PCr and ATP in the skeletal muscle were lower in the uremic patients. However, during aerobic exercise, the uremic patients showed a rapid decrease in intracellular pH and a delay in its recovery. They also revealed an increased PCr utilization during aerobic exercise and its delayed resynthesis during recovery. During anaerobic exercise, the uremic patients, especially non-dialyzed patients, displayed a slower decrease in pH than the controls and a delay in its recovery. An increased PCr utilization during anaerobic exercise and a delayed resynthesis during recovery were also demonstrated. These findings suggest that the aerobic and anaerobic energy productions in uremic patients are impaired and that the energy production of the muscle depends on anaerobic glycolysis during exercise. Hemodialysis apparently facilitates recovery of the inhibited enzyme activities of oxidative phosphorylation and glycolysis in uremic patients.
Ninety-five autopsy cases of chronic renal failure, which had or had not been treated by hemodialysis, were examined histologically and immunohistochemically for evidence of amyloid deposition in the intervertebral disks and posterior longitudinal ligaments of the spine. beta 2-Microglobulin (beta 2M) amyloid was not present in non-dialyzed patients with chronic renal failure. In cases showing beta 2M amyloid deposition, the shortest term of hemodialysis was 2 years and 5 months. The incidence of beta 2M amyloidosis tended to increase as the dialysis period was prolonged. An inverse correlation was present between dialysis period and age in 22 cases showing beta 2M amyloid deposition (correlation coefficient: -0.43, p less than 0.05), and beta 2M amyloidosis tended to occur earlier in elderly patients than in younger patients. This suggests that elderly patients are more susceptible to beta 2M amyloidosis. beta 2M amyloid was absent in all of 8 cases of systemic lupus erythematosus which were treated by dialysis for periods ranging from 2 days to 12 years. In these patients, beta 2M amyloidosis may have been prevented by steroids, which had been administered for long periods in all cases. Another amyloid of unknown composition was also frequently present in the intervertebral disks and posterior longitudinal ligaments not only in patients with chronic renal failure but also control patients without chronic renal failure. This amyloid was immunohistologically negative for beta 2M, amyloid A protein, light chain kappa or lambda, prealbumin, and apolipoprotein A-II.
The existence of uric acid in mammalian brain was recently reported, but it has not yet become a consensus. The mammalian brain has been thought to lack xanthine oxidase, which catalyzes hypoxanthine to xanthine and xanthine to uric acid as the last steps of ATP degradation in other tissue. Using high-performance liquid chromatography, we performed assays for hypoxanthine, xanthine, and uric acid in rat brain after cerebral ischemia. It was confirmed that all three substances showed significant augmentation in the removed brains and that the chronological order of those increases corresponded to the order in the metabolic pathway. Allopurinol, a specific inhibitor of xanthine oxidase, significantly suppressed the increases in uric acid and xanthine, and a compensatory accumulation of hypoxanthine was observed. From these results, it was concluded that uric acid does exist in the brain, increases after ischemia, and is possibly the end product of purine degradation in the brain. Furthermore, it is suggested that xanthine oxidase exists in the brain and catalyzes the reaction from hypoxanthine to xanthine and then to uric acid. These reactions catalyzed by xanthine oxidase are considered to be a source of free radicals and may play important roles in the pathogenesis of cerebral ischemic injury.
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Xanthine and uric acid, products of purine metabolism, were measured by reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection in rat forebrain following focal cerebral ischemia. Focal cerebral ischemia was induced in the rat by permanent occlusion of the left middle cerebral artery (MCA). Sprague-Dawley rats were anesthetized with halothane inhalation and left MCA was occluded via trans-retro-orbital approach. Normal and sham-operated rats were used as control animals. The animals were decapitated 2 (MCA = 5, Sham = 5), 4 (MCA = 7, Sham = 6), 8 (MCA = 5, Sham = 5), and 16 (MCA = 6, Sham = 6) hours or 1 (MCA = 5, Sham = 5), 2 (MCA = 6, Sham = 6), 7 (MCA = 7, Sham = 6), 14 (MCA = 6, Sham = 5), and 28 (MCA = 7, Sham = 5) days after the operation. The brains were removed and divided into right and left hemisphere. Each hemisphere was homogenized and centrifuged. The supernates were filtered with membrane filter. An aliquot of the filtrate was used for measurement of xanthine and uric acid in both of the ischemic and contralateral hemisphere by a HPLC system. In the normal group, xanthine and uric acid in the brain was 12.4 +/- 0.4 and 2.2 +/- 0.1 nmol/g tissue (mean +/- SEM), respectively. In the ischemic hemisphere, xanthine increased up to 57.7 +/- 5.2 nmol/g tissue 2 hours after MCA occlusion and reached a maximum value of 59.42 +/- 4.91 nmol/g tissue 4 hours following the induction of ischemia. Xanthine level was still high 8 hours after ischemia and then rapidly decreased to the normal value at day 2.(ABSTRACT TRUNCATED AT 250 WORDS)
Phase I and Phase II studies of recombinant human erythropoietin (rhEpo) were conducted in normal volunteers and in anemic patients with chronic renal failure on maintenance hemodialysis. Three hundred U/person of rhEpo was administered intravenously to healthy normal volunteers in the Phase I study, resulting in no subjective or objective changes. In the Phase II study, 66 patients with chronic renal failure on maintenance hemodialysis with less than 20% hematocrit values were treated with rhEpo in doses of 50 U/kg to 200 U/kg two or three times a week. Hematocrit values increased significantly during the 12 weeks, and the patients' conditions improved. Patients previously requiring blood transfusions became transfusion-independent during our study. There were no obvious side effects, thus indicating the safety and efficacy of rhEpo in the anemia of chronic renal failure.
Clinical effect and safety of recombinant human erythropoietin (r-HuEPO) were evaluated in 66 hemodialysis patients with intractable anemia. Initially, 50U/kg dry weight (DW) of r-HuEPO was administered intravenously at the end of every hemodialysis procedure for 4 weeks, then the dosage was increased to 100 and 200U/kg DW for poor responders. The patients' hematocrits rose from 19.8 +/- 2.3% (pretreatment) to 30.2 +/- 4.9% after 12 weeks. From 206 U of blood transfusion requirement in the 3-month period before the study, only 34 U were needed after treatment. Serum iron and ferritin levels fell significantly during the study, and iron storage was considered to be one of the decisive factors in the response to r-HuEPO. Blood pressure rose in the course of r-HuEPO administration, but uncontrollable hypertension was rarely observed. There was no significant adverse effect of r-HuEPO except for this mild hypertension. These results indicate that r-HuEPO is an excellent therapeutic aid for the anemia associated with chronic renal failure.
Cerebral hypoxanthine, xanthine, and uric acid levels were measured by high-performance liquid chromatography (HPLC) for up to 4 hours following focal cerebral ischemia in the rat. Fifty male Sprague-Dawley rats were subjected to occlusion of the left middle cerebral artery under halothane inhalation anesthesia. The animals were sacrificed with microwave at 30, 60, 120, and 240 minutes after surgery. The brains were removed and divided into right and left hemisphere. Each hemisphere was homogenized with perchloric acid and centrifuged. The supernates were filtrated with membrane filter. An aliquot of the filtrate was used for measurement of uric acid, xanthine, and hypoxanthine in both of the ischemic and contralateral hemisphere by a HPLC system. A HPLC with multiple ultraviolet spectroscopy was used for measuring hypoxanthine and xanthine. Identification of hypoxanthine and xanthine was made by parallel chromatography of standards, disappearance with xanthine oxidase, and the spectrum of UV absorption. Uric acid was measured by reversed-phase HPLC with electrochemical detection as reported previously. Hypoxanthine increased rapidly and arrived at a peak value at 60 minutes. Xanthine increased not so rapidly as hypoxanthine and showed the highest value at 120 minutes. Uric acid also increased significantly but very slowly and did not seem to reach the peak value during the observation period. Hypoxanthine is oxidized to xanthine and then xanthine is oxidized to uric acid at the terminal stage of purine degradation. The order of peak times of cerebral hypoxanthine, xanthine, and uric acid levels following cerebral ischemia corresponds to the order in purine metabolism. This result strongly suggests that hypoxanthine is degraded into uric acid in ischemic rat brain.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood sample were collected from both the arterial and venous lines of the patients undergoing hemodialysis using cuprophan membrane at several time intervals. Radioimmunoassay was then applied to measure the C3a and C5a levels. C3a levels from the arterial lines of patients undergoing uneventful hemodialysis were 463.2 +/- 51.3 ng/ml (mean +/- S.D.), 1112.9 +/- 109.9, 956.0 +/- 72.1, and 721.2 +/- 49.6 at 0, 15, 120 and 360 min, respectively. C5a levels did not change significantly during uneventful hemodialysis. C3a and C5a levels were significantly higher in the blood from the venous lines than those from the arterial lines, a finding indicating that complement activation via alternative pathway takes place in the dialyzer. C3a and C5a levels were markedly elevated in patients with anaphylactoid reaction. Reuses of dialyzers on the patients having a history of an anaphylactoid reaction during hemodialysis suppressed not only the rise of C3a levels, but also the recurrence of the reaction. From these findings, it is concluded that rises of C3a and C5a in the arterial lines of patients are causally related to the induction of anaphylactoid reaction during hemodialysis.
A pedigree of C1 inhibitor (C1 INH) deficiency associated with positive LE cell and an elevated titer of DNA antibodies and antinuclear factor (ANF) and nephropathy was presented. The proband of this family was diagnosed as having definite systemic lupus erythematosus (SLE) after a clinical course of several year since her first visit to our hospital and because of the lack of hemolytic activity of complement (CH50), in spite of the absence of idiopathic edema, C1 INH levels were 1.2 mg/dl (3.8% NHS) determined as antigen and 65 site forming unit (SFU) (5.8% NHS) determined by hemolytic assay in her blood. Her mother and brother had characteristic idiopathic edema of her face, larynx, hand and bowel and they had low levels of C1 INH of 1.8 mg/dl (5.8% NHS) and 4.8 mg/dl (15.5% NHS) respectively in their blood. On the basis of these findings, this family was diagnosed as having a pedigree of hereditary angioneurotic edema (HANE) which is supposedly an inherited autosomal positive trait. Actually, however, the proband's serological and hematological indices became positive and progressed year by year, which implies that SLE was absent for the first several years. It might be said that this interesting clinical course indicates that SLE appeared chronologically as a hereditary deficiency in one of the complement components in this case. In concurrence with the general observation that recurrent viral infections due to the deficiency of complement components are presumed to be responsible for SLE-like disease. Her levels of several kinds of anti-virus antibodies were high. Methylprednisolone helped normalize her level of C1 INH and ameliorate the clinical course.
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Pharmacokinetics of cefoperazone (CPZ) was examined in 5 patients with end-stage renal failure on maintenance intermittent peritoneal dialysis. Blood levels of CPZ given as a 1 g intravenous bolus injection were not different whether a patient was on or off peritoneal dialysis. Peritoneal clearance of CPZ was 1.6-1.9 ml/min. Blood CPZ levels reached the therapeutic level within 30-120 minutes after an intraperitoneal administration of 1 g CPZ, and remained at the level at least for 3-5 hours. Side effects of CPZ were not observed in any patient. These data indicate that the peritoneal dialysis does not affect blood CPZ levels given intravenously and that effective blood levels of CPZ can be maintained for several hours after an intraperitoneal injection of the drug. Thus, CPZ is considered useful in renal failure patients on peritoneal dialysis.
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