Somatostatinoma syndrome. Biochemical, morphologic and clinical features.

Diabetes mellitus, steatorrhea, cholelithiasis and a tumor distorting the duodenum prompted a work-up for somatostatinoma in a 52-year-old man. The responses of pancreatic B-cells but not of A-cells to nutrient stimuli were inhibited, and growth-hormone release was suppressed, suggesting somatostatin resistance in some target tissues. Plasma somatostatin-like immunoreactivity ranged from 9000 to 13,000 pg per milliliter (normal: 88+/-8, mean +/- S.E.M.) and was distributed in four molecular forms, including free somatostatin. The primary tumor contained 5 microgram of somatostatin-like immunoreactivity per milligram of wet tissue, distributed in three of the molecular forms noted in plasma. Plasma calcitonin was also elevated (4650 pg per milliliter; normal: less than 120). Immunocytochemical studies showed that cells of the primary tumor contained somatostatin and calcitonin but no other peptide hormones. Only somatostatin was present in the metastases. Somatostatin was localized electron microscopically in all secretory granules, irrespective of size and shape, whereas calcitonin was present only within a single subpopulation of small granules in the same cells.     

Effects of furosemide,acetazolamide, and mannitol on medullary collecting-duct function in the rat kidney

The microcatheterization technique was used to study transport of fluid, sodium, and potassium in the medullary collecting duct in rats (232–357 g) before and during administration of diuretic drugs. Series I received furosemide (1.5 mg initial dose + 1.5 mg/h), Series II acetazolamide (0.75 mg +0.75 mg/h), and Series III and IV mannitol at 0.3 g+0.3 g/h, and 0.3 g+1.0 g/h, respectively. All diuretics caused diuresis, natriuresis, and kaliuresis. The renal response to furosemide and acetazolamide was associated with increased hematocrit and decreased filtration rate, indicating depletion of blood volume. No such effect was seen in Series III and IV. In the collecting duct furosemide completely abolished the normal reabsorption of sodium and fluid and initiated net secretion of potassium. Partial inhibition of salt and water transport in the collecting duct was observed with acetazolamide and the low dose of mannitol (III). Both treatments resulted in potassium secretion. In Series IV the high rate of mannitol infusion was associated with complete inhibition of salt and water reabsorption from the medullary collecting system similar to that of Series I. The greater excretory response in this group compared to the furosemide series was due to increased delivery of tubular load to the collecting duct. It is concluded that a major site of action of furosemide is in the medullary duct, resulting in quantitative inhibition of salt and water reabsorption from this nephron segment. The partial transport inhibition during acetazolamide or modest mannitol diuresis can be explained by the presence of poorly absorbable solute in duct fluid. The mechanism of inhibition of reabsorption after the high rate of mannitol infusion remains undetermined.     

Massive obesity and the kidney. A morphologic and statistical study.

The renal morphology of 5 grossly obese patients with normal renal function and many of the features of the Pickwickian syndrome was studied at autopsy. The most striking feature was that of increased glomerular size. Measurements of two parameters of glomerular areas indicated statistically significant glomerular enlargement for both as compared to controls. Glomerulomegaly was primarily the result of vascular dilatation and a variable mesangial component. This abnormality was related to several factors, including increased blood volume, hypoxia, and increased right ventricular pressure. Polycythemia, commonly noted in other similar conditions with glomerulomegaly, is believed to be of no importance in the pathogenesis of glomerular enlargement.     

Protection of renal cells against free radical damage in vitro. A morphologic and functional study on human and rabbit kidney cells

The morphologic and functional effects of free radicals on renal cells in vitro were investigated, as well as the possibility of avoiding them by pretreatment with scavenger enzymes or a xanthine oxidase inhibitor. Cultured human kidney cells, incubated together with a free radical-generating system, with and without protective agents, were examined by light and scanning electron microscopy. The vimentin filament structure of the incubated cells was visualized by immunofluorescence. The membrane function was studied in human kidney cells by using a dye exclusion test and in rabbit kidney slices by determination of the sodium-potassium pump activity. Exposure of the cells to free radicals caused rapid development of severe morphologic lesions, including extensive cytoskeletal disorganization. After pretreatment, only a few cells had similar, although less severe, lesions. The results of the dye exclusion test and indirect evaluation of the sodium-potassium pump activity did not indicate any major damage to the cell membranes after exposure to free radicals.     

Effects of mannitol on cardiac ultrastructure and microcirculation following anoxia.

Electron microscopic and microcirculatory effects of hyperosmolal mannitol were evaluated in the isolated perfused isovolumic rat heart. Specimens for ultrastructural examination were obtained in 26 experiemnts after 15 min of sequential aerobic, anoxic, and reoxygenated perfusion using an isosmolal perfusate of Krebs-Ringer-Henseleit bicarbonate buffer (KRB) (osmolality equals 290 mosmol/kg) vs. a hyperosmolal solution of KRB + mannitol (equals 350 mosmol/kg). No significant changes were noted during aerobic perfusion. Anoxic hearts perfused with isosmolal KRB demonstrated the most severe ultrastructural alterations including: mitochondrial swelling with disruption of cristae, myofibrillar fusion and contraction bands, and subsarcolemmal edema and vacuolization. These subcellular changes were not only partially reversed by oxygenated isosmolal perfusion but were significantly reversed during both the anoxic and reoxygenation perfusion periods with mannitol added. Following silicone rubber injection of the microcirculation, only focal capillary endothelial cell swelling was noted, and no difference in arteriolar or capillary filling was observed with either perfusate. Thus, mannitol significantly reversed the postanoxic ultrastructural changes consistently observed in the absence of increased osmolality. No gross effect on vascular patency could be demonstrated.     

Gentamicin and tobramycin nephrotoxicity. A morphologic and functional comparison in the rat.

Fischer 344 rats were treated with tobramycin or gentamicin, 40 mg/kg/day, for up to 10 days or with tobramycin, 120 mg/kg/day, for up to 14 days. Serum creatinine and BUN at the time of sacrifice were determined, and kidney tissues were examined by light and electron microscopy. Rats receiving gentamicin demonstrated progressive renal proximal tubular necrosis which was nearly universal at the end of 10 days. Their BUN and creatinine levels rose progressively over the same period. Even at the higher dosage, tobramycin therapy resulted in only rare foci of proximal tubular necrosis and minimal elevation of BUN and creatinine. Although they occurred later and were substantially less severe, the ultrastructural changes induced by tobramycin were the same as those seen following gentamicin administration. These results indicate that the mechanism of tobramycin-induced renal injury is probably similar to that of gentamicin and that tobramycin is significantly less nephrotoxic in this experimental model.     

Bilirubin, UDP-glucuronyl transferase of liver in postmature rats. A functional and morphologic comparison

Postmaturity was induced in dated pregnancies in Wistar rats by daily injection of 25 units of chorionic gonadotrophin, beginning on day 18 of gestational life. Animals were either delivered operatively on day 23 of postconceptual age or allowed to deliver spontaneously on day 24 by stopping the gonadotrophin. The hepatic bilirubin UDP-glucuronyl transferase activity (E.C.2.4.1.17) was quantitated in these animals and compared with that of control animals of normal gestations operatively and spontaneously delivered of similar postconceptual age. Normal animals at birth have very little hepatic bilirubin UDP-glucuronyl transferase activity, but it rapidly achieves adult activities in the first 4 days of neonatal life. In contrast, the postmature animals of 23 and 24 days of postconceptual age exhibited marked suppression of the hepatic bilirubin UDP-glucuronyl transferase activity, but they exhibited rapid neonatal maturation after delivery. The ultrastructure of the hepatocytes from the postmature rats of 24 days postconceptual age exhibited the same paucity of smooth endoplasmic reticulum of 21-day rats, which is in striking contrast to of postnatal life. The findings are interpreted to suggest that the intrauterine milieu actually suppresses fetal maturation of liver function.     

Effects of dipyridamole on postischemic vasodilation and extracellular adenosine

Postischemic vasodilation (PIVD) was studied in pump-perfused dog gracilis muscles. The hemodynamic responses to 1, 3, and 5 min of ischemia were evaluated in the presence and absence of intraarterial infusions of dipyridamole in concentrations that inhibit cellular transport of adenosine. Dipyridamole infusion produced concentration-dependent reductions in vascular resistance and increased the time for 50% recovery (t0.5) in vascular resistance by 39% following 5 min of ischemia. The t0.5 for PIVD was unaffected by dipyridamole following 1 and 3 min of ischemia. Dipyridamole elevated tissue adenosine content two- to three-fold at 1, 3, and 5 min of ischemia compared with saline controls. Intra-arterial infusions of adenosine deaminase along with dipyridamole completely prevented the dipyridamole-induced increase in tissue adenosine, demonstrating that dipyridamole increases extracellular adenosine during muscle ischemia. The significance of these findings is analyzed using a two-compartment model for the distribution of adenosine. The data indicate that a severalfold increase in interstitial adenosine content does not alter PIVD and that the hemodynamic effects of dipyridamole following 5 min of ischemia may be due to some mechanism other than enhanced accumulation of adenosine.     

Biochemical and morphologic studies on the effect of bile acids on the epithelium of the rat jejunum

The influence of bile salts on the mucosal surface of rat jejunum was tested with an in vivo technique of segmental perfusion. Sodium taurocholate and chenodesoxycholate were applied in a concentration of 3 mmol/l. The release of 5 brush border membrane enzymes, 5 cytosolic, 1 mitochondrial, and 2 lysosomal enzymes during a perfusion time of 150 min as well as morphological alterations after bile salt treatment were investigated. Among the membrane enzymes, due to their superficial localization, the solubilization of enteropeptidase and alpha-1,4-glucosidase was highest both in the control perfusion and in the presence of bile salts. At the same time, cytoplasmic enzyme activities were liberated extensively whereas lysosomal and mitochondrial enzymes were scarcely detectable. This disproves any serious injury of the enterocytes. Electronmicroscopic results supported this suggestion. After administration of taurocholate (in physiological concentration), only an occasional diminution of the glycocalyx was observed and even chenodeoxycholate (in an unphysiological concentration) caused only negligible destructions of intestinal brush borders. Investigations with ruthenium red to contrast the glycocalyx showed a partially unchanged structure. Microvesiculation from the microvilli was observed in many electron microscopic photographs. That is a possibility for the release of membrane-bound and cytosolic enzymes without destruction of enterocytes.     

Effects of hypertonic mannitol on cardiac lymph in nonischemic myocardium.

This investigation was designed to elucidate the effects of hypertonic mannitol on the nonischemic myocardium. In anesthetized open-chest dogs, we collected cardiac lymph for 2 h before and for 4 h during the infusion of hypertonic mannitol or normal saline. We studied the changes in the volume of lymph flow and the release of lysosomal enzyme acid phosphatase and protein into the cardiac lymph. In group 1 (n = 7) and group 3 (n = 8), the effects of 1-h and 4-h infusions of mannitol were studied, respectively. In these dogs, mannitol caused significant rises in lymph flow and release of total acid phosphatase into the cardiac lymph. In group 3, protein efflux increased significantly. In group 2 (n = 5) and group 4 (n = 4), infusion of normal saline for 1 and 4 h did not significantly change the release of total acid phosphatase and proteins into the cardiac lymph. Thus, infusion of hypertonic mannitol for 1--4 h in the nonischemic myocardium may have some deleterious effects because of its apparent ability to impair lysosomal membranes and to increase capillary permeability.     

Tissue content of adenosine,inosine and hypoxanthine in the rat kidney after ischemia and postischemic recirculation

Summary The effect of renal ischemia of 15 s to 60 min duration on the tissue levels of adenosine, inosine and hypoxanthine was investigated in Sprague Dawley rats. A sharp increase in the tissue levels of adenosine from 5.13±0.56 to 31.3±2.96 nmol/g wet weight after 1 min of ischemia was found. The tissue levels of inosine and hypoxanthine in the controls were 3.62±0.51 and 3.19±0.76 nmol/g wet weight, respectively. Maximal levels of adenosine (38.1±6.3 nmol/g wet weight) were reached after 10 min of ischemia. The hypoxanthine levels rose steadily up to 922±183 nmol/g wet weight after 60 min of ischemia. Recirculation of 15 min after 60 min ischemia resulted in a fall of adenosine and inosine levels to values comparable to controls, whereas hypoxanthine was elevated above control values. In a second experimental series with tracing of renal blood flow (RBF) by a means of an electromagnetic flow meter a transient marked reduction of RBF after occlusion of the renal artery for 30 s was observed. The 3-fold increase of adenosine tissue levels within 30 s of renal artery occlusion and the inhibition of the postocclusive RBF reduction by theophylline (3.3 mol/100 g body weight) make it likely that this phenomenon may be caused by intrarenal adenosine.Parts of this investigation were presented at the 46th Meeting of the German Physiological Society in Regensburg, March 15–20, 1976.Supported by the Deutsche Forschungsgemeinschaft Os 42/2     

Induction of glomerulosclerosis by dietary lipids. A functional and morphologic study in the rat

Clinical and experimental data indicate that glomerular function and morphology may be influenced by plasma lipids. In familial lecithin-cholesterol-acyltransferase (LCAT) deficiency and in Fabry's disease, lipids accumulate in glomeruli and are assumed to induce sclerosis. The present study was undertaken to examine if dietary lipids could exert effects on the glomeruli of normal, unilaterally nephrectomized rats, and of rats with two-kidney, one clip (2-K,1C) hypertension. In rats with two kidneys on a diet rich in fat and cholesterol, cholesterol concentrations in very low density lipoproteins increased. In these rats the number of glomeruli with sclerotic foci was significantly higher than in rats on a low fat, cholesterol free diet. After 6 months on the diet the percentage of glomeruli with sclerosis (SC) was 13.2 +/- 4.1 (N = 9) in rats with a cholesterol diet and 1.8 +/- 0.6 (N = 11) in control rats (p less than 0.05). The fat and cholesterol diet exacerbated glomerular lesions in the remnant kidney model of uninephrectomized rats. The sclerosis in rats with only one kidney was 38.2 +/- 9.5 (N = 6) on a cholesterol diet compared with 8.7 +/- 3.0 (N = 6) in control rats after 6 months (p less than 0.05). After 3 to 4 months on a fat rich diet cholesterylester was increased in isolated glomeruli. The composition of the dietary lipids influenced the development of glomerular lesions. A linseed oil diet that is rich in unsaturated fatty acids, especially linolenic acid, did not cause major plasma lipid abnormalities and was accompanied by a low sclerosis (1.2 +/- 0.3; N = 9) for rats with two kidneys. In rats with chronic 2-K, 1C hypertension the percentage of glomeruli with partially sclerosed tufts in the unclipped kidney was significantly higher on a fat and cholesterol diet (F) than on a control diet (N) (SC: diet F 31.0 +/- 4.0, N = 13; diet N 12.2 +/- 2.6, N = 12; P less than 0.05). In the clipped kidney, protected against the arterial hypertension, only an increased number of glomeruli with mesangial expansion was noted in rats with the cholesterol diet. Glomerular hemodynamic factors seem to play an important pathogenetic role in the induction of glomerular sclerosis by a lipid rich diet. The fact that dietary lipids can aggravate glomerular lesions in states of arterial hypertension and nephron loss may have implications for the progression of renal disease in humans.     

Effects of red light on postischemic myocardium during reperfusion

Effects of low-intensity red light on lipid peroxidation in isolated rat heart in the postischemic period were studied. It was established that both laser and wideband luminescent irradiation applied during reperfusion reduced the content of lipid peroxidation products in tissues to a near-control level. This effect is possibly associated with reactivation of antioxidant enzymes.     

Effects of actovegin on the central nervous system during postischemic period

In a rat model of 5-min clinical death caused by massive blood loss actovegin prevented the development of metabolic disorders induced by hypoxia and reoxygenation as well as the damage to the central nervous system in the early postresuscitation period. Intracarotid administration of actovegin increased the activity of reduction-oxidation enzymes, intensified aerobic metabolism of glucose, prevented lactate accumulation in the brain, reduced structural disorders in the central nervous system, and provided faster restoration of the major reflexes after a 5-min total ischemia. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 126, No. 10, pp. 395–398, October, 1998