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Cathepsins B, H and L have been shown to participate in processes of tumor growth, vascularization, invasion and metastasis. Their levels in tumor tissue extracts can provide useful clinical information to predict disease-free and overall survival in breast, lung, colorectal, brain and head and neck cancer patients. Recently we have found that both cysteine cathepsins and their endogenous protein inhibitors stefins and cystatin C can also predict prognosis when measured extracellularly. In melanoma and colorectal cancer patients high serum levels of cathepsins B and H correlated with shorter survival. Similarly, increased extracellular levels of stefins A and B and cystatin C correlated significantly with high risk of adverse outcome in cancer patients. However, the cathepsin B/cystatin C complex was found to be less abundant in sera of patients with malignant tumors than in those with benign diseases or in healthy controls, suggesting an imbalance between the enzyme and its inhibitor in cancer patients.
The aim of the present study was to investigate amoxicillin (AMX) distribution in muscle interstitial fluid by microdialysis in healthy, awake rats. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Probe recoveries in each rat were determined by retrodialysis with cefadroxil. AMX was administered as a bolus dose of 50 mg.kg(-1), and microdialysis samples were collected during 180 min. Concentrations of unbound drug in blood and muscle were analyzed simultaneously by a population approach. Simulations were conducted using a hybrid, physiologically based pharmacokinetic model to investigate the potential impact of tissue blood flow on muscle AMX distribution. A two-compartment pharmacokinetic model described adequately the unbound amoxicillin concentration-time profiles in blood and muscle. Muscle AMX distribution equilibrium was rapidly achieved. Consequently, the best results were obtained by considering concentrations in muscle as part of the central compartment. The ratio of the concentration of unbound drug in muscle to that in blood (Rmodel) was estimated to 0.80 by the model, which is close to the mean value obtained by noncompartmental data analysis (Rarea= 0.86 +/- 0.29). Simulations conducted with a hybrid, physiologically based pharmacokinetic model suggest that a muscle blood flow reduction of 30% to 50%, such as could be encountered in critical care patients, has virtually no effect on muscle AMX concentration profiles. In conclusion, this study has clearly demonstrated that AMX distributes rapidly and extensively within muscle interstitial fluid, consistent with theory, and that altered muscle blood flow seems unlikely to have a major effect on these distribution characteristics.
Each of the five true hyponatremias is discussed as a defect in the free water-excreting mechanisms of the body, in order to formulate a rational approach to diagnosis and treatment. One artificial and three real causes of elevations in plasma sodium are also discussed.
Radiosulfate, (35)SO(4), and radiobromide, (82)Br, were administered simultaneously to rats and dogs. In rats, the apparent volume of distribution of (82)Br averaged 30% of body weight and was constant between 0.5 and 35 hr after injection. The apparent volume of distribution of (35)SO(4), corrected for urinary loss, increased by 6% body weight/hr: the extrapolated volume at zero time was 88% of bromide space. Analysis of individual tissues and carcasses for (82)Br and inorganic (35)SO(4) showed that equilibration of both isotopes in several organs and in the whole carcass was rapidly achieved within 1 to 2 hr: no further increase in measured spaces occurred in 24 hr. The carcass inorganic sulfate space was 92%+/-2% of the bromide space in intact rats, and showed no increase with time. However, a progressively greater fraction of the injected (35)SO(4) was not recovered, owing to metabolic alteration. In eviscerated rats, the inorganic sulfate space was a smaller and much more constant fraction (79.8% +/-0.4%) of the bromide space, showing that at least 20% of body bromide (and hence chloride) is nonextracellular. The viscera chiefly responsible for the higher ratio of spaces in the intact animal were the liver, small bowel, and kidney. In the last two organs, excess inorganic (35)SO(4) (beyond the bromide space) was attributable to trapped transcellular fluid in which sulfate had been concentrated more than chloride (or bromide). Excess sulfate in liver and cartilage could not be explained in this manner: the results suggest passive binding of sulfate, but could reflect active cell uptake in these tissues. No excess sulfate was found in skin or tail. The implications of these observations with respect to the distribution of body chloride and the measurement of extracellular space are discussed. The extracellular volume of the rat is estimated to be 24% of body weight.
Ascorbate is an antioxidant vitamin that the brain accumulates from the blood supply and maintains at a relatively high concentration under widely varying conditions. Although neurons are known to use this vitamin in many different chemical and enzymatic reactions, only recently has sufficient evidence emerged to suggest a role for ascorbate in interneuronal communication. Ascorbate is released from glutamatergic neurons as part of the glutamate reuptake process, in which the high-affinity glutamate transporter exchanges ascorbate for glutamate. This heteroexchange process, which also may occur in glial cells, ensures a relatively high level of extracellular ascorbate in many forebrain regions. Ascorbate release is regulated, at least in part, by dopaminergic mechanisms, which appear to involve both the D1 and D2 family of dopamine receptors. Thus, amphetamine, GBR-12909, apomorphine, and the combined administration of D1 and D2 agonists all facilitate ascorbate release from glutamatergic terminals in the neostriatum, and this effect is blocked by dopamine receptor antagonists. Even though the neostriatum itself contains a high concentration of dopamine receptors, the critical site for dopamine-mediated ascorbate release in the neostriatum is the substantia nigra. Intranigral dopamine regulates the activity of nigrothalamic efferents, which in turn regulate thalamocortical fibers and eventually the glutamatergic corticoneostriatal pathway. In addition, neostriatonigral fibers project to nigrothalamic efferents, completing a complex multisynaptic loop that plays a major role in neostriatal ascorbate release. Although extracellular ascorbate appears to modulate the synaptic action of dopamine, the mechanisms underlying this effect are unclear. Evidence from receptor binding studies suggests that ascorbate alters dopamine receptors either as an allosteric inhibitor or as an inducer of iron-dependent lipid peroxidation. The applicability of these studies to dopamine receptor function, however, remains to be established in view of reports that ascorbate can protect against lipid peroxidation in vivo. Nevertheless, ample behavioral evidence supports an antidopaminergic action of ascorbate. Systemic, intraventricular, or intraneostriatal ascorbate administration, for example, attenuates the behavioral effects of amphetamine and potentiates the behavioral response to haloperidol. Some of these behavioral effects, however, may be dose-dependent in that treatment with relatively low doses of ascorbate has been reported to enhance dopamine-mediated behaviors. Ascorbate also appears to modulate glutamatergic transmission in the neostriatum. In fact, by facilitating glutamate release, ascorbate may indirectly oppose the action of dopamine, though the nature of the neostriatal dopaminergic-glutamatergic interaction is far from settled. Ascorbate also may alter the redox state of the NMDA glutamate receptor thus block NMDA-gated channel function.(ABSTRACT TRUNCATED AT 400 WORDS)
OBJECTIVE: Both atrial natriuretic peptide (ANP) and the dihydropyridine derivative nicardipine lower arterial pressure and induce a shift of plasma fluid from the vascular towards the interstitial compartment. Because some calcium antagonists increase the plasma concentration of ANP, and the effect of ANP on transcapillary fluid shift requires the presence of angiotensin II, we examined the consequences of blocking the ANP and renin-angiotensin systems on the hypotensive and haemoconcentrating effects of nicardipine. METHODS: We evaluated the effects of 45-min 0.1 or 1 micrograms/kg per min nicardipine infusion on arterial pressure and haematocrit in anaesthetized, acutely binephrectomized Sprague-Dawley rats. RESULTS: Infusion of nicardipine resulted in a dose-dependent decrease in arterial pressure. Haematocrit increased by an amount corresponding to the decrease in plasma volume calculated for the relevant dose. In the presence of monoclonal anti-ANP antibodies the nicardipine-induced changes in haematocrit and arterial pressure were not affected. In rats pretreated for 2 weeks with the angiotensin converting enzyme inhibitor enalapril, as well as in rats receiving the angiotensin II receptor antagonist losartan acutely, the nicardipine-induced increase in haematocrit was abolished. In enalapril-treated rats the increase in haematocrit was entirely restored when angiotensin II was infused at a subpressor dose. The nicardipine-induced decrease in arterial pressure was not affected by pharmacological blockade of the renin-angiotensin system. CONCLUSIONS: These results demonstrate that the transcapillary shift of fluid induced by nicardipine is independent of ANP and requires the presence of a functional renin-angiotensin system, whereas its hypotensive action is independent of both ANP and angiotensin II.
A 26-year-old man with hypothalamic hypodipsia-hypernatremia syndrome is reported, who presented with adipsia, hypernatremia, and impaired osmolality-mediated arginine vassopressin (AVP) secretion. A chorionic gonadotropin-secreting tumor was detected in the anterior hypothalamus and treated with external irradiation. After the treatment, hypernatremia persisted and was not corrected by fluid loading, osmolality-mediated AVP secretion remained impaired. Despite the absence of signs of hydropenia, hypovolemia was suggested by low blood pressure and elevated plasma indices of the renin-angiotensin system, and supported by blood volume determination. The plasma aldosterone concentrations were inappropriately low for the renin-angiotensin status. The plasma atrial natriuretic polypeptide (ANP) level was normal in spite of hypovolemia and increased more than double after fluid loading. Hypernatremia, primarily caused by hypodipsia and impaired osmolality-mediated AVP secretion, secondarily sustained ANP secretion and suppressed aldosterone release, which conceivably contributed to the development and perpetuation of hypovolemia in this patient.
The present studies were designed to further investigate the possibility of heterogeneity of nephron function during Ringer loading in the rat, and to determine the specific nephron segment responsible for this finding. As in previous studies from this laboratory with smaller rats (50-125 g), net addition of sodium between late distal tubule and papillary base (6.9 vs. 10.4% of the filtered load, respectively, P <0.005) was found in more mature rats (170-230 g). In contrast, there was net reabsorption of sodium between these two segments in nonvolume-expanded animals, 1.70 vs. 0.45% of the filtered sodium load, P <0.005. Because nephron heterogeneity of sodium transport during extracellular volume expansion is the most likely explanation for these findings, further studies were performed to determine the specific juxtamedullary nephron segment responsible for the net addition pattern between late distal tubule and papillary base in Ringer-loaded animals. First, a comparison was made of sodium delivery to the late proximal tubule of superficial nephrons vs. the delivery rate to the bend of Henle's loop of juxtamedullary nephrons in both hydropenia and Ringer loading. Fractional sodium delivery was quite comparable between the superficial and juxtamedullary nephrons in both hydropenia and Ringer loading although the absolute level was much greater in both groups of nephrons in the Ringer studies. Chlorothiazide (15 mg/kg loading and 15 mg/kg per h) given during Ringer loading markedly increased late distal sodium delivery, 19% of the filtered load, but did not prevent net addition of sodium at the papillary base. In contrast, furosemide (5 mg/kg loading and 5/mg/kg per h) given during Ringer loading completely reversed the segmental pattern, 35.5 and 28.8% at late distal tubule and papillary base, respectively, P <0.005. These studies demonstrate that the net addition of sodium between late distal tubule and papillary base during Ringer loading is not limited to immature rats and that the segmental pattern does not occur in non-volume-expanded animals. Further, the reversal of the net addition pattern with furosemide, but not chlorothiazide, and the comparable proximal nephron delivery rates in Ringer loading suggest that the loop of Henle of juxtamedullary nephrons reabsorbs less sodium than the same portion of superficial nephrons in this setting. A model is proposed to explain this finding.
Traditional microdialysis techniques provide qualitative data, although quantitative data are often required for pharmacodynamic analyses. This study evaluated a potentially useful in vivo delivery technique to calibrate microdialysis probes for ethanol. We measured in vivo delivery extraction fractions within subjects across 2 days and found no change over time. We tested the effect of diffusion direction on extraction fraction and found that it was higher for ethanol diffusion out of the probe than for diffusion into the probe, both in vitro and in vivo. The in vivo extraction fraction ratio of diffusion(IN) versus diffusion(OUT) was 0.65+/-0.03. Finally, we predicted extracellular brain ethanol concentrations after 1 g/kg ethanol administration using in vivo delivery, "no net flux" dialysis, or in vivo delivery corrected for diffusion direction with the in vivo extraction fraction ratio. Both in vivo delivery and "no net flux" dialysis predicted brain concentrations that were approximately one-third lower than blood concentrations, whereas the corrected in vivo delivery predicted extracellular concentrations very similar to blood concentrations. We conclude that microdialysis calibration methods for ethanol require a measure of extraction fraction for diffusion into the probe. Further studies are needed to establish whether this effect is common to other alcohols.
The antioxidants in the aqueous phase of human plasma include ceruloplasmin, albumin (the protein itself and possibly also albumin-bound bilirubin), ascorbic acid, transferrin, haptoglobin, and hemopexin. Assays that attempt to answer the question "what is the most important antioxidant?" are compared, it being concluded that the answer is different depending on the nature of the prooxidant stress imposed in the assay.
Prostaglandin E2 concentration in perfusate from microdialysis tubing implanted in subcutaneous adipose tissue of sheep did not consistently change during feeding. Noradrenaline infused into this tissue produced a prompt increase of glycerol concentration in the perfusate, but this changed to a slight decrease towards the end of the infusion. At approximately the time of this decrease, levels of prostaglandin E2 in the perfusate increased.
A young male sustained very serious head and soft tissue injuries in a motor vehicle accident (MVA). Three interesting problems developed in the sodium (Na) and water area in the second week in hospital. First, on day 11 after the MVA, his urine output increased to 3 liters per day; the urine osmolality was 1000 mOsm/kg H2O and Na and Cl were the principal urine osmoles. There appeared to be a salt wasting syndrome because he had a very large natriuresis (close to 900 mmol/24 hr) at a time when his central venous pressure was low. To help identify the nephron site responsible for a natriuresis with a high urine osmolality, additional studies were carried out in normal volunteers who took a loop or a thiazide diuretic on different occasions while ADH was acting. The pattern of natriuresis in the patient was similar to that after the thiazide but not the loop diuretic. The second problem concerned his hypernatremia (153 mM) because his urine was hypertonic and his intravenous therapy was isotonic saline. To explain hypernatremia while receiving more electrolyte-free water, we speculated that there was a water shift into cells resulting from particles generated and retained in his intracellular fluid. Given the large shift of water required, a lesion in muscle was suspected, a form of rhabdomyolysis. The third problem concerned the rate of catabolism of lean body mass. The metabolic consequences of generating these intracellular particles and the large amount of urea that was excreted could reflect a large degree of protein catabolism.
We studied the long-term hemodynamic effect of prizidilol (a precapillary vasodilator and beta-adrenoceptor blocker) in 14 men aged 25-66 years with mild and moderate essential hypertension (EH). Cardiac output (by Cardiogreen) and intraarterial blood pressure (BP) were measured at rest and during exercise before and after 8 months of therapy. Changes in body fluid volumes were measured by isotope dilution techniques. After 8 months on prizidilol, eight of the 14 patients were normotensive, and the mean casual BP was lowered by 23/17 mm Hg to 140/91 mm Hg. The intraarterial systolic and diastolic pressures fell by 15-20% of the pretreatment levels at rest supine, sitting, and during 50, 100 and 150 W exercise. The fall in BP was due to a marked reduction in total peripheral resistance ranging from 17 to 23% at rest and during exercise. Cardiac output was unchanged at all work loads, whereas heart rate fell. The stroke volume increased in all settings; at maximum work load by 30%. Body weight and body fluid volumes did not change significantly. Except for some coldness in hands and feet in one patient, which disappeared after 2-3 months, no side effects were observed. We conclude that, in mild and moderate EH, prizidilol induces a substantial fall in BP with an excellent hemodynamic profile both at rest and during exercise.
The production and urinary excretion of the natriuretic factor and sodium output decreased in patients with rheumatic heart defects as left-atrial dilatation progressed and signs of circulatory insufficiency grew more apparent. It is suggested that prolonged left-atrial dilatation is associated with a fall of volume receptor sensitivity and insufficient left-atrial production of substances activating the natriuretic factor involved in abnormal water-salt metabolism in these patients.
The effect of glutamine-supplemented total parenteral nutrition was studied in 18 neonatal piglets (1.97 kg, 3 d old) for 8 d. They were grouped as follows: total parenteral nutrition with 0 (controls), 5 or 10 g glutamine/100 g total amino acids. Live weight gain (g/d) tended (P < 0.07) to increase with supplementation (129, 143, and 166 [SD = 20] for control, 5% and 10% glutamine), but there was no effect on total gain (g) in body protein (180, 171, 197; SD = 25), fat (135, 126, 143; SD = 33) or ash (13, 13, 16; SD = 5) for control, 5% and 10% glutamine groups, respectively. Total body water gains were significantly higher in the 10% group than in controls, with the 5% group showing intermediate gains (control = 696 g; 5% glutamine = 822 g, 10% glutamine = 970 g, SD = 119). Increased glutamine supplementation was accompanied by a trend (P < 0.08) toward increasing total body chloride space, an indicator of extracellular volume, explaining, in part, the observed differences in water gains. These results indicate that glutamine may not be a conditionally indispensable amino acid for the neonate on total parenteral nutrition. Furthermore, glutamine supplementation to total parenteral nutrition leads to disturbances in water balance that could cause increased accumulation, particularly in the extracellular space.
Sodium, chloride, thiocyanate, and sucrose spaces were measured in whole body and different tissues of rat. For each analytical method, when all tissue spaces were added the sum was in good agreement with corresponding total body fluid space obtained by dilution methods. There was surprisingly good agreement among the three ionic space measures in the total body, when one considers that there were discrepancies as large as 2- to 8-fold within certain of the different tissues. Some differences could be explained by the facts that sodium is a constituent of bond mineral and that there are marked differences between these four measures when observed in the water of the gastrointestinal contents.