Mesangial cells initiate compensatory tubular cell hypertrophy.

Unilateral nephrectomy results in compensatory renal growth, in which both the size and the functional capacity of the remaining kidney are increased. The functional adaptation to the removal of the contralateral kidney consists mostly of an increase in the glomerular filtration rate of the remaining kidney, and hypertrophy of cells comprising the nephron, mainly of the proximal tubular cells. Although the phenomenon of single kidney hypertrophy has been known for the past thousand years and despite intensive research over the past century, the mechanism of this process still remains unclear. The present article reviews the role of mesangial cells in compensatory renal hypertrophy.

Hyperbaric oxygen, oxidative stress, NO bioavailability and ulcer oxygenation in diabetic patients.

BACKGROUND: Hyperbaric oxygen therapy (HBO2) increases tissue oxygenation, thus serving as an adjunct therapy for diabetic wounds. However, in some patients there is insufficient increase in tissue O2. AIMS: To investigate the pathophysiology of insufficient HBO2 and the possible role of N-acetylcysteine (NAC). METHODS: Prospective, randomized, cross-over trial included 50 diabetic patients with non-healing ulcers. Each patient received two treatments with 100% oxygen/2ATA. NAC was administered i.v. at one of the two treatments. Basal and post-treatment peri-wound transcutaneous O2 (TcPO2) pressure, malondialdehyde (MDA), total anti-oxidant status (TAOS) and nitric oxide (NO) were assessed. An ulcer oxygenation increase above 200 mmHg was accepted as sufficient. RESULTS: During HBO2, 17 patients (34%) demonstrated insufficient increase in TcPO2. Concomitantly, their TAOS and NO decreased, while MDA increased. NAC administration attenuated these parameters, thus improving the HBO2 outcome. In those affected by NAC, the cure rate was 75%. By contrast, in 66% of patients with sufficient increase in TcPO2 TAOS was increased and MDA decreased irrespective of NAC administration. The cure rate in this subgroup was 82%. CONCLUSIONS: Insufficient increase of ulcer oxygenation during HBO2 results from exaggerated oxidative stress and decreased NO bioavailability. NAC administration-induced modulation of both parameters and may improve ulcer oxygenation during HBO2.

Gentamicin-induced ototoxicity in hemodialysis patients is ameliorated by N-acetylcysteine.

Aminoglycoside (AG) antibiotics are associated with several side effects, including a reversible nephrotoxicity and a permanent ototoxicity. Oxidative stress is thought to contribute to the pathophysiology of both conditions. We studied the possible protective effect of the antioxidant N-acetylcysteine (NAC) in gentamicin-induced hearing loss in hemodialysis patients. This study includes 53 hemodialysis patients scheduled to receive gentamicin for dialysis catheter-related bacteremia that were randomized to receive the antibiotic with or without NAC. Hearing function was assessed by the standard technique of pure-tone audiograms over a range of frequencies. Audiometric evaluations were performed at baseline, 1 week and at 6 weeks after the completion of gentamicin therapy. A total of 40 patients completed the study protocol with a mean duration of therapy of almost 15 days. At both 1 and 6 weeks after the completion of antibiotic therapy, there were significantly more patients exhibiting ototoxicity in the control group compared with the group receiving NAC. Additionally, significantly more patients in the control group had bilateral ototoxicity. The greatest otoprotective effect of NAC was noticed in the high audiometric tone frequencies. Taken together, our study suggests that NAC treatment may ameliorate gentamicin-induced ototoxicity in hemodialysis patients.

Total cellular calcium and magnesium content of cultured human peripheral blood mononuclear cells following exposure to antidiabetic drugs.

Drugs modulating the ATP-sensitive potassium (K(ATP)) channel activity are widely used for the treatment of diabetes mellitus, the target being pancreatic beta-cells. However, any cell type possessing K(ATP) channels might be concomitantly affected. We investigated the metabolic effect of glibenclamide, a K(ATP) channel closer, and/or diazoxide, a K(ATP) channel opener, on total intracellular content of calcium (Ca) and magnesium (Mg) of cultured peripheral blood mononuclear cells (PBMC). Metformin and rosiglitazone, acting via cellular mechanisms other than K(ATP) channels, were also tested. Ca and Mg were assessed in PBMC from healthy subjects following 72 h in vitro treatment with the respective drugs. Ca content increased significantly in PBMC treated with glibenclamide or rosiglitazone, however apparently via different intracellular pathways. Mg increased only following treatment with rosiglitazone. Metformin had no effect on intracellular Ca or Mg. Pretreatment with diazoxide resulted in a significant intracellular Ca and Mg loss in each experimental situation. If verified clinically, rosiglitazone-induced increase in Mg content of PBMC might prove beneficial beyond hypoglycaemic control. On the other hand, loss of intracellular Ca/Mg content following K(ATP) channel opening by diazoxide might eventually result in significant intracellular Ca and/or Mg depletion.

Dextran 40 (Rheomacrodex) or Polygeline (Haemaccel) as an epidural patch for post dural puncture headache: a neurotoxicity study in a rat model of Dextran 40 and Polygeline injected intrathecally.

BACKGROUND AND OBJECTIVE: Although an epidural autologous blood patch is considered the most effective treatment for post dural puncture headache, which sometimes occurs following spinal or inadvertent spinal anaesthesia, there remains a need for alternative materials for epidural patches. We investigated the potential neurotoxicity of Dextran 40 (Rheomacrodex) and Polygeline (Haemaccel) used for this purpose in a rat model. METHODS: Repeated boluses of 10% Dextran 40, 3.5% Polygeline or 0.9% saline were injected intrathecally over a period of 1 month in three groups of rats. RESULTS: No behavioural or clinical derangements were observed in any of the three groups during this period. After sacrifice of the animals at the end of the experiment, no significant differences in the histopathological appearances of the spinal cords in the three groups were observed. No toxic effects diminishing viability of spinal cord cells were evident. Similarly, viability of renal, hepatic and peripheral blood mononuclear cells remained unaffected (98% +/- 2%). CONCLUSIONS: No deleterious effects, clinical or cellular, were evident in this rat model when Dextran 40 or Polygeline were injected intrathecally. Thus, both substances can be considered as possible alternative materials for epidural patches.

The effect of sildenafil on gastric emptying in patients with end-stage renal failure and symptoms of gastroparesis.

BACKGROUND: Delayed gastric emptying is a common disorder among patients with end-stage renal failure (ESRF). Pyloric relaxation, a major determinant of gastric emptying, is a nitric oxide (NO)-mediated process. NO-induced smooth muscle relaxation is mediated through its second messenger cyclic guanosine monophosphate, which is broken by tissue phosphodiesterases (PDEs). Thus the inhibition of cyclic guanosine monophosphate breakdown by PDE inhibitors can potentiate NO-mediated responses and facilitate pyloric relaxation. In an animal model of diabetes mellitus, treatment with sildenafil (a PDE-5 inhibitor) restored NO-mediated pyloric relaxation and improved gastric emptying. The aim of our study was to examine the hypothesis that sildenafil may improve gastric emptying in patients with ESRF and symptoms of gastric paresis. METHODS: We studied 12 patients with ESRF (6 men; age range, 54-80 years; 5 with diabetic nephropathy; 4 +/- 1 years receiving long-term renal replacement therapy) after either placebo or a 25-mg tablet of sildenafil (Viagra; Pfizer Inc). Gastric emptying of a solid meal (one medium-sized fried egg mixed with 37 MBq [1 mCi] technetium Tc 99m phytate plus 1 slice of bread and 150 mL of water at the end of the meal) was assessed 1 hour after dosing by use of a single-headed camera. Images were acquired every 30 seconds for 90 minutes immediately after patients ate. RESULTS: The gastric emptying rate was decreased at baseline (after placebo), to 33% +/- 6% (normal, > or =50%). Treatment with sildenafil had no effect on gastric emptying rates after 90 minutes (from 33% +/- 6% after placebo to 30% +/- 6% after sildenafil, P =.9). CONCLUSIONS: Sildenafil did not improve gastric emptying in patients with ESRF and gastric paresis. Sildenafil may have opposing effects on gastric peristalsis (causing gastric relaxation) compared with its effects on pyloric relaxation. Studies combining sildenafil with prokinetic drugs are of interest.

Renal dysfunction in congestive heart failure, pathophysiological and prognostic significance.

AIMS: Many congestive heart failure (CHF) patients suffer from various comorbidities, which may aggravate CHF or independently increase mortality risk. Renal failure (RF) is one of them. We defined bedside clinical, laboratory and electrocardiographic parameters characterizing CHF patients with and without concomitant RF, and analyzed their impact on mortality. METHODS: We studied symptomatic unselected consecutive furosemide-treated CHF patients hospitalized for various acute conditions. On admission, history taking, physical examination, chest x-ray, ECG and routine laboratory tests were performed. Subsequently, patients were divided into 2 subgroups, those with serum creatinine > or = 1.5 mg/dl (RF) and those with lower values. Following discharge, information concerning mortality and circumstance of death was obtained from hospital records and outpatient death certificates. RESULTS: Included were 398 patients, 163 (40.9%) with RF and 235 free of RF. Prevailing in the RF subgroup were older age (mean age 75.5 vs 70.8, p < 0.001), male gender (p < 0.001), admission pulmonary edema (p = 0.007), cardiac arrhythmias (p = 0.05), cardiac conduction disturbances (p = 0.002), severe CHF (p = 0.005), lower ejection fraction (p = 0.03), anemia (p = 0.009), higher furosemide maintenance dosages (p < 0.001), insulin treatment (p = 0.03) and receiving less ACE inhibitors (p = 0.006). On median follow-up of 43 months, mortality was 54.9% in the RF vs 31.9% in the non-RF subgroup (p < 0.001), RF being the parameter most significantly associated with low survival (OR 1.97, p < 0.001). In the RF subgroup older age (p < 0.02), female gender (p < 0.003) and not using ACE inhibitors (p = 0.04) or drugs with antiarrhythmic effects (p < 0.005), emerged significantly associated with low survival, while diabetes mellitus (DM) and admission pulmonary edema tended to be so associated (p < 0.2). Using multivariate analysis in the RF subgroup, older age, female gender and DM proved most significantly associated with poorer survival (p = 0.004, OR 1.5, p = 0.03, OR 1.72, p = 0.04, OR 1.28, respectively). In the non-RF subgroup, only older age (p = 0.005) and DM (p = 0.05) were significantly associated with low survival. Sudden death occurred in 21 patients, 14 (8.6%) in the RF and 7 (3%) in the non-RF subgroup (p < 0.001). CONCLUSIONS: RF is a marker of severity in CHF. Its full-blown deleterious prognostic effect is already manifested at serum creatinine 1.5 mg/dl. Older age, DM and female gender most significantly heralded a shorter survival. Such patients require special care.

Copper and zinc blood levels among children with nonorganic failure to thrive.

BACKGROUND AND AIMS: Copper and zinc deficiency are commonly reported among children with organic failure to thrive. In contrast, reports on copper and zinc status in children with non-organic failure to thrive are scarce. The goal of this study was to evaluate copper and zinc blood levels and nutritional intake among children with non-organic failure to thrive. METHODS: A study group of 32 children with non-organic failure to thrive were investigated and compared with 32 healthy controls. Each child had copper and zinc blood level measurements. In addition, the study group underwent evaluation of thyroid function, immunoglobulins, endomesial antibodies and xylose test. A dietary questionnaire that included a diet history and a 24-h dietary recall was administered to parents by a dietician. Weight for height, height for age and mean daily intake of calories, protein, copper and zinc were calculated. RESULTS: There were no significant differences between the two groups in either socioeconomic status or caloric, copper or zinc intake. Protein intake was significantly lower in the study group (P<0.0001). Plasma copper levels were within the normal range in both groups (P=0.3). Zinc plasma levels were significantly higher in the study group as compared to controls (P=0.03); however, they remained within the normal range in both groups. CONCLUSIONS: Children with non-organic failure to thrive can maintain plasma copper and zinc levels within normal range and similar to normal controls.

Zn metabolism affects apoptosis rate and proliferative responsiveness of PBMC from patients on chronic hemodialysis.

Patients with end-stage renal failure suffer from severe plasma trace metal deficiency that is not corrected by dialysis. Trace metals, including Zn(2+), are critical for cell differentiation and replication. Zn(2+)also plays important role in cell apoptosis. Both processes are known to be impaired in uremia. The present study was undertaken to evaluate the effect of Zn(2+) supplementation on apoptosis of cultured peripheral blood mononuclear cells (PBMC) from patients on chronic hemodialysis versus those from healthy control subjects, concomitantly with assessment of mitogen-induced cell proliferation. The results showed that (1) basal total cell-associated Zn(2+) was elevated in uremic PBMC, compared to normal controls (23.9 +/- 5.64 v 10.5 +/- 2.64 micromol/L/mg protein). The gap persisted following incubation in Zn(2+)-enriched medium (63.3 +/- 26.12 v 81.6 +/- 13.4 micromol/L/mg protein, P <.005). (2) Basal proliferative response to phytohemagglutinin (PHA) was significantly decreased in uremic PBMC compared to normal controls (12,000 +/- 1,560 cpm v 16,600 +/- 1,460 cpm, P <.01). Incubation of uremic PBMC in Zn(2+)-enriched medium improved their proliferative response to PHA, yielding counts per minute significantly higher compared to their normal counterparts (37,000 +/- 7,500 cpm v 22,000 +/- 3,000 cpm, P <.001). (3) Basal apoptosis rate in uremic PBMC was significantly elevated compared to normal control cells (7.6% v 2.6%, P <.05). Following incubation in Zn(2+)-enriched medium, apoptosis was increased both in normal and uremic PBMC. Percent apoptosis of uremic PBMC remained significantly elevated compared to control cells (11.7% v 5.7%). We conclude that uremic PBMC are more responsive to exogenous Zn(2+) in culture than their normal counterparts. This, among other abnormalities, might reflect an abnormal regulation of Zn(2+) transport by uremic mononuclear cell membranes. The resultant increase in total cell-associated Zn(2+) content improves poor proliferative responsiveness of uremic PBMC. On the other hand, increased total cell-associated Zn(2+) stimulates enhanced apoptosis in uremic PBMC, which, probably by eliminating defective cells, contributes to the functional capability of the population as a whole. The net effect of the 2 processes is still augmentation of cell proliferation.

Intracellular Ca++/Mg++ homeostasis during postnatal growth of experimental rats. Multiple time-point study.

In most tissues, various cell membrane ion transporting systems are not fully developed and/or maximally active at the prenatal and early postnatal stage. Their progressive development and expression are a function of growth and maturity. We performed a multiple time-point study, in order to investigate the ability of a variety of tissues to maintain appropriate Ca++ and Mg++ homeostasis at different stages of postnatal development. Total intracellular Ca++ in one-week-old rat liver, brain and spinal cord tissues was significantly elevated, compared to mature animals. It increased further through the first three weeks of gestation. Intracellular Ca++ gradually and significantly declined in adult and mature animal groups. Alterations in total intracellular Mg++ of the same tissue samples, although not so profound, paralleled changes in total intracellular Ca++. We conclude that a developmental switch in intracellular Ca++ and Mg++ homeostasis occurs one to three weeks following birth. It might be related to the incomplete development of Ca++ and Mg++ transmembrane transporting systems, previously reported as being only partially expressed at the early postnatal stage. These developmental alterations in total intracellular Ca++ and Mg++ content might serve as a regulatory mechanism, adjusting cell activities to the physiological requirements of the growing and maturing animal.

The effect of Losartan on insulin resistance and beta cell function in chronic hemodialysis patients.

Insulin resistance (IR) is prevalent in hemodialysis patients. IR and hyperinsulinemia have an important role in the development of atherosclerosis, which is the most common cause of morbidity and mortality in hemodialysis patients. Thus, antihypertensive drugs that lower IR, may have an additional beneficial effect in the treatment of cardiovascular diseases in these patients. In this preliminary study we examined the effect of Losartan (an angiotensin II receptor antagonist) treatment on IR and beta cell function in five hypertensive non-diabetic chronic hemodialysis patients. All other known causes of IR in end stage renal failure were excluded. After a washout period of two weeks, Losartan 50 mg, was administered for 6 weeks. Fasting blood glucose (FBG) and insulin levels were measured before and after the treatment IR and beta cell function were calculated using the "homeostasis model assessment"-HOMA. Systolic and diastolic blood pressure (BP) have not changed significantly throughout the study. FBG increased significantly from 76 mg/dL +/- 1 to 89 mg/dL +/- 4 (p < 0.01), however, insulin levels have not changed significantly. Calculated IR values did not show a difference, but calculated beta cell function decreased significantly after Losartan treatment from 291% +/- 50 to 146% +/- 10, (p < 0.016). These preliminary results suggest that in chronic hemodialysis hypertensive non-diabetic patients short treatment with Losartan has deleterious effect on glucose homeostasis mediated via a decrease in beta cell function.

Red eye syndrome: clinical and experimental experience in a new aspect of diffuse eosinophilic infiltration?

Twenty-two of 24 hemodialysis patients dialyzed simultaneously with a new batch of cellulose acetate dialyzers promptly developed a spectrum of symptoms and physical signs including red eyes, hearing loss, tinnitus, and bone pain, previously described as red eye syndrome. We subsequently injected 4 rabbits with an eluate from a dialyzer of the same or a control batch. Six hours following exposure, the animals developed, in addition to red eyes, diffuse eosinophilic infiltration of various organs as well as myopathic changes and moderate brain edema. On the basis of these data, we suggest that it cannot be concluded whether the underlying pathophysiological mechanisms were toxic, allergic or both and that the occurrence of relevant symptomatology in 2 or more simultaneously dialyzed patients is a strong argument against unnecessary diagnostic or therapeutic procedures. Finally, a second exposure in a given patient should be avoided.

Intrathecal anaesthesia alters intracellular Ca2+/Mg2+ homeostasis in the spinal cord neurones of experimental rats.

BACKGROUND AND OBJECTIVE: The effect of anaesthesia induced by intrathecal injection of 6.3% MgSO4 or 4% lidocaine on intracellular electrolyte homeostasis in spinal cord neurones of a rat model was investigated. METHODS: Intracellular Ca2+, Mg2+, Na+ and K+ concentrations were determined at different times after intrathecal administration of NaCl (saline, a control group), MgSO4 or lidocaine. RESULTS: In both thoracic and lumbar spinal cord segments, Ca2+ concentrations rose significantly 30 min and 2 h after 6.3% MgSO4 injection, and after 24 h were still significantly increased compared with the values obtained from the control group which were subjected to sham 'anaesthesia' by saline injection (172, 121 and 108 ng mg-1 protein vs. control 23 ng mg-1 protein, respectively, in the thoracic segment and 222, 229 and 176 ng mg-1 protein vs. control 43 ng mg-1 protein, respectively, in the lumbar segment). Lidocaine injection also produced a significant increase in intracellular Ca2+ in the thoracic and lumbar spinal cord segments (69, 64 and 53 ng mg-1 protein vs. control 33.4 ng mg-1 protein and 26, 94 and 46 ng mg-1 protein vs. 23 ng mg-1 protein respectively). Only a modest rise in intracellular Mg2+ was observed after intrathecal MgSO4 or lidocaine injection (27 ng mg-1 protein vs. 23 ng mg-1 protein). Na+ and K+ concentrations decreased 24 h after MgSO4 and 1 h after lidocaine injection. CONCLUSION: Intrathecal anaesthesia by MgSO4 or lidocaine alters intracellular electrolyte homeostasis in spinal cord neurones of experimental rats. A possible common mechanism of action via Ca2+ ion channels is discussed.

Vitamin B(6) therapy does not improve hematocrit in hemodialysis patients supplemented with iron and erythropoietin.

BACKGROUND/AIM: Pyridoxine deficiency may be the cause of failure to respond appropriately to iron and erythropoietin (EPO) administration in hemodialysis patients. METHOD: We studied 36 patients on chronic hemodialysis amply supplemented with iron and EPO, who failed to raise hematocrit levels >33%. Patients were divided into three equal groups and evaluated for 6 months as follows: Group A -- no additional therapy; group B -- supplemented with oral pyridoxine 50 mg/day, and group C received 100 mg/day pyridoxine orally. RESULTS: In all our patients, erythrocyte pyridoxine levels were initially within reference range for a healthy population and did not vary significantly during the study period. Likewise, ferritin levels and iron saturation values remained normal and constant. Hemoglobin and/or hematocrit levels remained practically unchanged in all three groups. CONCLUSIONS: The results indicate that in hemodialysis patients with normal pyridoxine status who, despite appropriate supplementation of iron and EPO, fail to reach optimal hematocrit levels, additional pyridoxine treatment does not produce any hematocrit elevation.

Total cell-associated Zn2+ and Cu2+ and proliferative responsiveness of peripheral blood mononuclear cells from patients on chronic hemodialysis.

We investigated total copper (Cu2+) and zinc (Zn2+) content in plasma and peripheral blood mononuclear cells (PBMC) and its impact on proliferative ability of the latter in patients on chronic hemodialysis versus age- and sex-matched healthy volunteers. Plasma levels of Cu2+ and Zn2+ were significantly lower in dialysis patients compared with the control group (83.6 +/- 7.29 v 95.1 +/- 9.63 microg/dL, P <.03 for Cu2+; 71.1 +/- 7.64 v 89.7+/- 12.55 microg/dL, P <.005 for Zn2+). Basal total PBMC-associated Cu2+ content was significantly higher in uremic patients (19.3 +/- 3.59 v 14.6 +/- 2.72 micromol/mg protein, P <.005). Basal PBMC-associated Zn2+ concentration was also significantly elevated in hemodialysis patients compared with their healthy counterparts (23.9 +/- 5.64 v 10.5 +/- 2.64 micromol/mg protein, P <.005). In addition, we incubated PBMC of the uremic patients versus healthy control PBMC in a Zn2+ free versus Zn2+ enriched medium. After a 72-hour incubation, total cell-associated Zn2+ of both normal and uremic cell populations increased significantly compared with the respective baselines (34.6 +/- 22.49 v 4.3 +/- 1.42 and 20.3 +/- 10.71 v 5.8 +/- 2.22 micromol/mg protein, respectively). However, no statistically significant difference was evident between the 2 groups (34.6 +/- 22.49 v 20 +/- 10.7 micromol/mg protein). Total cell Zn2+ content, on the other hand, was significantly increased in uremic PBMC after 72 hours of incubation in Zn2+ enriched medium compared with the control group (63.3 +/- 26.12 v 18.6 +/- 13.42 micromol/mg protein, P <.005). A significant increase in PBMC proliferation evaluated by 3H-thymidine incorporation was evident in the Zn2+ enriched culture (35,559 +/- 4,136 counts per minute [CPM] v 20,497 +/- 7,263 CPM, P <.005). Cu2+ enrichment of the medium, while resulting in a modest elevation of cell-associated Cu2+, did not produce such a proliferative effect.

High insulin requirements and poor metabolic control do not modify the expression, regulation and PKC mediated activation of the p21ras pathway in PBMC from type II diabetic patients.

AIMS: To asses whether clinically severe insulin resistance and poor metabolic control in patients with type 11 diabetes are associated with aberrant expression or function of the p21ras pathway. METHODS: We examined the expression and function of the p21ras pathway in resting and activated PBMC from 10 insulin treated patients with type II diabetes characterized by high insulin requirements and poor metabolic control (IR group) and 10 age and sex matched well controlled patients treated by diet alone or oral hypoglycemic medications (WC group). RESULTS: Levels of p21ras and its regulatory elements: p21rasGAP and hSOS1, were comparable in the two groups. The induced activities of p21ras and its associated down-stream regulatory enzyme MAP-kinase following TPA stimulation were also comparable in the IR and WC patients. CONCLUSIONS: Taken together, these data indicate that clinically significant severe insulin resistance does not modify the expression, regulation and activation of p21ras pathway in PBMC of patients with type II diabetes.

Inactive systemic lupus erythematosus id associated with a normal stimulated Th(1)/Th(2) cytokine secretory pattern.

OBJECTIVES: To determine the Th(1)/Th(2)balance in systemic lupus erythematosus (SLE) patients with inactive disease. METHODS: A comprehensive analysis of peak secretion, overall cytokine production and secretory pattern of Th(1)and Th(2)cytokines from stimulated PBMC of 10 SLE patients with inactive disease and 10 age- and sex-matched controls. RESULTS: No significant differences were found in the peak and total secretion of all cytokines, as well as in the Th(1)and Th(2)secretory patterns and proliferative response between the two groups. CONCLUSION: Th(1)and Th(2) balance in inactive SLE is normal.

Proliferative responses of mesangial cells to growth factors during compensatory versus dietary hypertrophy.

While the bulk of renal hypertrophy induced by contralateral nephrectomy or a high-protein diet consists of tubular cell growth, there is some evidence suggesting that mesangial cells play a role in this phenomenon. Previous data suggest that this role of mesangial cells is associated with their proliferation. We, therefore, undertook this investigation to assess the proliferative responses of mesangial cells, originating from single remaining kidneys or from kidneys of rats fed a high-protein diet, to epinephrine, endothelin, arginine vasopressin, neo-synephrine, or epidermal growth factor (EGF). All agents significantly enhanced the proliferation of normal mesangial cells, though the responses to neo-synephrine and EGF were significantly lower as compared with the other growth promoters. The mitogenic effects of the first three agents on single kidney mesangial cells were significant, but blunted as compared with control cells. This blunting was not evident in the case of the latter two mitogens. A significant enhancement of proliferation of mesangial cells originating from protein-fed rats was produced by epinephrine, neo-synephrine, and EGF. These effects were statistically not different from those observed in normal mesangial cells. The proliferative response to each of the mitogens used in the study proved highly specific for each mitogen, since it was abolished by respective specific inhibitors. Mesangial cells may play a role in the activation and later in progressive inhibition of renal hypertrophy in vivo.

Substances used for local and general anaesthesia in major surgery suppress proliferative responsiveness of normal rat peripheral blood mononuclear cells in culture.

We studied the direct effect of intravenous anaesthetics, local anaesthetics and premedication drugs in common use for major surgery, on the spontaneous versus lectin induced proliferation of cultured normal rat peripheral blood mononuclear cells, not exposed to surgical or any other trauma prior to culture. Peripheral blood mononuclear cells were incubated in cell-culture medium in the presence or in the absence of propofol, ketamine, fentanyl, midazolam, thiopental sodium, lidocaine or etomidate. The cells proliferated either spontaneously or under stimulation with a lectin phytohaemagglutinine P for 72 h. The proliferation rate was evaluated by 2H-Thymidine incorporation. Fentanyl, thiopental sodium, lidocaine and etomidate significantly inhibited phytohaemagglutinine P induced 3H-Thymidine incorporation in cultured rat peripheral blood mononuclear cells. Counts per minute of the cultures treated with these drugs were 1667.80 +/- 745.72, 1614.1 +/- 615.00, 1688.0 +/- 615.0 and 1549 +/- 560.41, respectively, compared with the phytohaemagglutinine P stimulated positive control counts per minute, 13488 +/- 4305.6 (P < 0.001 in each comparison). Propofol, ketamine and midazolam inhibited the lectin-induced cell proliferation to levels not statistically different from the baseline. Counts per minute of these cultures were 1361.90 +/- 745.73; 1108.90 +/- 751.33 and 1518.10 +/- 848.88, respectively. Compared either with the baseline 972.57 +/- 356.73 counts per minute or to the positive control culture counts per minute, 13488 +/- 4305.6 the difference was statistically significant (P < 0.001) in each comparison. All the substances tested in this study proved capable of exerting direct inhibitory effect on circulating immunocompetent cells, because the latter were not subjected to any other immunosuppressive factor, be it operative trauma, blood transfusion, malnutrition, drug abuse, prior to culture. The possible theoretical and practical implications are discussed in this study.