Relation between toxicity and carcinogenesis in the kidney: an heuristic hypothesis

Cellular toxicity and cellular carcinogenesis are closely linked. In the kidney, this relationship has been emphasized by the recent discovery of a number of putatively non-mutagenic chemicals that result in acute and chronic toxicity and ultimately in carcinogenesis, especially in the male rat. Many, but not all such compounds, result in renal PTE phagolysosomal overload. At the same time, known metabolites of other carcinogens, e.g., HCBD and FBPA, result in acute renal injury and/or necrosis, followed by chronic tubular disease, interstitial nephritis, and ultimately carcinogenesis. A series of cell mechanisms have been suggested that lead from acute cell injury to altered control of cell division. These mechanisms appear to involve ion deregulation, (especially [Ca2+]i) resulting from a variety of continued injuries, (e.g., oxidative stress from inflammatory cells) and ultimately leading to altered gene expression.     

Increase in the activities of plasma pseudocholinesterase dependent on the blood glucose level and its relation to the hypersensitivity to acetylcholine in striated muscles of KK-CAy mice with diabetes

Acetylcholinesterase activity and pseudocholinesterase activity were examined in plasma and in striated muscles (whole heart and diaphragm muscles) of diabetic KK-CAy mice. Both activities of acetylcholinesterase in heart muscle and pseudocholinesterase in plasma were significantly increased in diabetic KK-CAy mice compared to pre-diabetic KK-CAy mice. Both acetylcholinesterase and pseudocholinesterase activities in skeletal muscle were not changed by the diabetic state. The increases in activity of plasma pseudocholinesterase was significantly correlated to the increase in blood glucose level in alloxan-, streptozotocin (STZ)-diabetic ddY mice and diabetic KK-CAy mice. The increase was not correlated to the body weight in non-diabetic female-KK-CAy mice. Furthermore, the activity of heart acetylcholinesterase was significantly correlated with the activity of plasma pseudocholinesterase (r = 0.79, P less than 0.01). The activities of acetylcholinesterases in heart muscles from STZ- and alloxan-diabetic ddY mice also tended to increase. The hypersensitivity of the pulse rate to a low dose (1 mg/kg) of acetylcholine was correlated to the activity of plasma pseudocholinesterase (r = -0.51, P less than 0.05). These results demonstrate that the activities of plasma pseudocholinesterase were increased by the diabetic state being associated with the increasing alteration of cardiac sensitivity to acetylcholine in the whole body.     

Antihypertensive effect of beta blockade in renal transplant recipients with or without host kidneys

Host kidneys may contribute considerably to hypertension after renal transplantation. Their role in sustaining hypertension is more prominent if glomerulonephritis (GN) than if interstitial nephritis (IN) is the original renal disease. We compared the antihypertensive effect of beta-blockade in IN (n = 10) and GN (n = 19) hypertensive renal transplant recipients with host kidneys in situ with those who had undergone bilateral nephrectomy (BN, n = 10). Pretreatment blood pressures were comparable in BN, IN, and GN patients, being 165 +/- 6/108 +/- 3, 172 +/- 5/104 +/- 3, and 161 +/- 3/104 +/- 1, mmHg, respectively. Blood pressure did not change on beta-blockade in BN patients, whereas it decreased significantly more (P less than 0.001) in GN than in IN patients, changes of mean arterial pressure being -107 +/- 1.0, -14.9 +/- 1.3, and -6.8 +/- 1.6%, respectively. This failure to respond to beta-blockade in patients without host kidneys may be related to low activity of the renin-angiotensin system or to functional denervation of the grafted kidney. Further investigations of this phenomenon may clarify the mechanism of antihypertensive action of beta-blockade as well as the nature of hypertension after renal transplantation.     

A new and highly sensitive method for measuring 3-methoxytyramine using HPLC with electrochemical detection. Studies with drugs which alter dopamine metabolism in the brain

3-Methoxytyramine (3-MT) is a minor metabolite of dopamine which is suggested to reflect the turnover and utilization of dopamine. A novel, isocratic HPLC method has been developed which can be used to analyse 3-MT in homogenates of rat brain without the need for additional purification procedures. Furthermore, the coulometric electrochemical detection system is sensitive enough to measure 3 pg of 3-MT (equivalent to 0.6 ng/g tissue wet weight). 3-Methoxytyramine was measured in the striatum and n. accumbens after decapitation and rapid freezing, using 3-methoxy-4-hydroxybenzylamine as the internal standard. The effects of dopaminergic and other drugs on this metabolite were examined using this method. -Methyl-p-tyrosine (200 mg/kg i.v.) produced parallel linear decreases in dopamine and 3-MT in naive rats, but not those pretreated with tranylcypromine (5 mg/kg i.p.). Methamphetamine (0.3–10 mg/kg i.p.) and amphetamine (0.3–10 mg/kg i.p.) both dose-dependently increased 3-MT in naive and tranylcypromine-pretreated rats. In naive animals, 3-MT was not altered by intraperitoneal injection of the dopamine reuptake inhibitors, bupropion (10 mg/kg) and nomifensine (10 mg/kg) or by sibutramine HCl (3 mg/kg), amitriptyline (10 mg/kg), desipramine (10 mg/kg) and zimeldine (10 mg/kg). 3-Methoxy-tyramine was decreased by apomorphine (5 mg/kg i.p.) and also by large doses of the selective D₂ antagonist, BRL 34778 (5 mg/kg i.p.) or -DOPA (50 mg/kg i.p.). The selective D₁ antagonist, SCH 23390 (0.1 or 5 mg/kg i.p.) was without effect. In tranylcypromine-pretreated rats, 3-MT was dose-dependently reduced and increased by apomorphine (0.01–5 mg/kg i.p.) and BRL 34778 (0.1–5 mg/kg i.p.), respectively. The drug SCH 23390 (0.1–5 mg/kg i.p.) produced much smaller increases in 3-MT which were probably mediated through the striatonigral pathway. Overall, the data suggest that measurement of 3-MT, after inhibition of monoamine oxidase, is a useful index of the release and utilization of dopamine. However, after substantial and prolonged depletion of dopamine, levels of 3-MT in naive animals are a better index. Also, the formation of 3-MT in naive rats provides a sensitive method for distinguishing between dopamine releasing agents and reuptake inhibitors.     

Spinal imaging: will MRI replace myelography?

A retrospective study on the value of magnetic resonance imaging (MRI) in replacing contrast studies of the lumbar spine has been undertaken. Studying pre- and postoperative conditions, the authors attempted to answer the question, Will MRI replace myelography? In this retrospective study, comparison is made in 20 patients between MRI and myelography and with 12 intra-operative findings. The overall impression was that MRI is equally sensitive as the invasive myelogram in diagnosing both protruded lumbar discs and postoperative fibrosis. The practical conclusion was an almost complete abandonment of myelography.     

Deficiencies of Vitamins in CAPD Patients: The Effect of Supplementation

Concentrations of the vitamins B₁, B₂, B₆, B₁₂, C, folic acid,A, E and ß-carotene were determined in blood and 24-hdialysate in 44 CAPD patients. Twenty-five of these patientswere studied during chronic treatment (mean 313 days, range60–1034 days). Nineteen patients were studied during training.In a longitudinal study, 11 patients were analysed again after77–507 (mean 238) days. In both patient groups a considerable portion of patients (11%–64%)had blood concentrations indicative of a deficiency of the vitaminsB₁, B₆, C and folic acid. The average concentrations of thesevitamins were normal in both groups. The only abnormal findingwas the mean EGOT activity being deficient in patients on chronictreatment. Mean concentrations of vitamin A were above normalin both groups. In the longitudinal study a significant increaseof vitamin B₂ and a decrease of vitamin B₆ in blood was found. When compared to 24-h excretion in normal urine, loss with 24-hdialysate was low for vitamin B₁, normal to relatively highfor vitamin B₂ and B₆, but extremely high for vitamin C andfolic acid. The vitamins B₁₂, A, E and carotenoids were hardlydetectable in the dialysate. In ten other patients the effect of daily supplementation with2 mg vitamin B₆, 100mg vitamin C and 400 µg folic acidwas analysed during a 16-week period. In all patients a significantincrease in blood concentrations was obtained. It is concludedthat these dosages were sufficient to maintain a normal statusof these vitamins in CAPD patients.