Interactions between hypoxia and hypercapnic acidosis on calcium signaling in carotid body type I cells.
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The effects of hypercapnic acidosis and hypoxia on intracellular Ca(2+) concentration ([Ca(2+)](i)) were determined with Indo 1 in enzymatically isolated single type I cells from neonatal rat carotid bodies. Type I cells responded to graded hypoxic stimuli with graded [Ca(2+)](i) rises. The percentage of cells responding was also dependent on the severity of the hypoxic stimulus. Raising CO(2) from 5 to 10 or 20% elicited a significant increase in [Ca(2+)](i) in the same cells as those that responded to hypoxia. Thus both stimuli can be sensed by each individual cell. When combinations of hypoxic and acidic stimuli were given simultaneously, the responses were invariably greater than the response to either stimulus given alone. Indeed, in most cases, the response to hypercapnia was slightly potentiated by hypoxia. These data provide the first evidence that the classic synergy between hypoxic and hypercapnic stimuli observed in the intact carotid body may, in part, be an inherent property of the type I cell. (+info)
Comparative effects of potassium chloride and bicarbonate on thiazide-induced reduction in urinary calcium excretion.
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BACKGROUND: The chronic low-grade metabolic acidosis that occurs in various renal disorders and in normal people, and that is related both to dietary net acid load and age-related renal functional decline, may contribute to osteoporosis by increasing urine calcium excretion. Administration of potassium (K) alkali salts neutralizes acid and lowers urine calcium excretion. Urine calcium excretion also can be reduced by the administration of thiazide diuretics, which are often given with supplemental K to avoid hypokalemia. We determined whether the K alkali salt potassium bicarbonate (KHCO3) and the thiazide diuretic hydrochlorothiazide (HCTZ) combined is more effective in reducing urinary calcium than KHCO3 alone or HCTZ combined with the conventionally coadministered nonalkalinizing K salt potassium chloride (KCl). METHODS: Thirty-one healthy men and women aged 50 or greater were recruited for a four-week, double-blind, randomized study. After a baseline period of 10 days with three 24-hour urine and arterialized blood collections, subjects were randomized to receive either HCTZ (50 mg) plus potassium (60 mmol daily) as either the chloride or bicarbonate salt. Another 19 women received potassium bicarbonate (60 mmol) alone. After two weeks, triplicate collections of 24-hour urines and arterialized bloods were repeated. RESULTS: Urinary calcium excretion decreased significantly in all groups. KHCO3 alone and HCTZ + KCl induced similar decreases (-0.70 +/- 0.60 vs. -0.80 +/- 1. 0 mmol/day, respectively). Compared with those treatments, the combination of HCTZ + KHCO3 induced more than a twofold greater decrease in urinary calcium excretion (-1.8 +/- 1.2 mmol/day, P < 0. 05). Both HCTZ + KHCO3 and KHCO3 alone reduced net acid excretion significantly (P < 0.05) to values of less than zero. CONCLUSIONS: KHCO3 was superior to KCl as an adjunct to HCTZ, inducing a twofold greater reduction in urine calcium excretion, and completely neutralizing endogenous acid production so as to correct the pre-existing mild metabolic acidosis that an acid-producing diet usually induces in older people. Accordingly, for reducing urine calcium excretion in stone disease and osteoporosis, the combination of HCTZ + KHCO3 may be preferable to that of HCTZ + KCl. (+info)
Bradykinin and nitric oxide generation by dialysis membranes can be blunted by alkaline rinsing solutions.
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BACKGROUND: Bradykinin (BK) generation following the first contact of blood with the dialysis materials is thought to enhance hypersensitivity reactions (HSRs). Some of the effects of BK are mediated by nitric oxide (NO). We have recently reported that the pH of diluted blood modulates the kinin system. The present study was aimed to investigate the role of the pH of culture media and filter-washing solutions and BK and NO generation, either in vitro and ex vivo. METHODS: BK was measured by a specific enzyme-linked immunosorbent assay (ELISA), and NO synthase (NOS) activity by 3H-citrulline production after incubation with 3H-arginine and nitrites by using the Griess reagent. In in vitro experiments, NOS activity was detected in endothelial cells (ECs) cultured with graded BK concentrations at various pH values. Blood from 30 patients in regular dialysis was ex vivo circulated in one single passage through minifilters prerinsed with pH 7 or pH 8 phosphate buffer (PB) solutions. The out-flowing blood was tested for BK and nitrite content and was incubated with cultured ECs to evaluate its capacity to modulate NOS activity. RESULTS: BK induced in vitro a dose-dependent increase in NOS activity of ECs, which was mediated by tyrosine kinase phosphorylation. NO generation was enhanced at pH 7.2, which remained unchanged at pH 7.6. In ex vivo experiments, blood out-flowing after one passage on filters washed with pH 7 PB solutions had increased BK levels (P < 0.0001), increased nitrites (P < 0.05), and enhanced EC NOS activity (P < 0. 05) in comparison to data found when filters were washed with pH 8 PB. Only when the filters were rinsed with a solution at pH 7 did PAN DX and AN69 membranes show a distinct BK generation capability, and cuprophane a peculiar capability to enhance NOS. Such effects were prevented when dialyzers were prerinsed with pH 8 PB. Multiple regression analysis showed that the pH of the uremic blood was the driving factor for BK and NOS activation (r = 0.54, P < 0.02). CONCLUSIONS: BK and NO generation are modulated by environmental pH. Rinsing the blood and dialysate compartments of filters with an alkaline solution prior to use may mitigate the activation of mediators likely to be involved in some HSRs. (+info)
Hypoxaemia induced by CO(2) or helium pneumoperitoneum is a co-factor in adhesion formation in rabbits.
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A prospective randomized trial in a rabbit model was performed to test the hypothesis that the increase in adhesion formation following prolonged pneumoperitoneum is mediated by peritoneal hypoxaemia. Laparoscopic standardized opposing lesions were performed in uterine horns and pelvic sidewalls by bipolar coagulation and CO(2) laser in six groups of eight animals. Pure CO(2) or helium pneumoperitoneum was used for 10 (groups I and IV) or 45 min (groups II and V) to confirm the effect of duration of pneumoperitoneum and 96% of CO(2) or helium with 4% of oxygen (group III and VI) for 45 min to assess the effect of the addition of oxygen. After 7 days, adhesion formation was scored by laparoscopy. By two-way analysis of variance, total, extent, type and tenacity of adhesion scores increased (P = 0.0003, P = 0.0004, P = 0.0004 and P = 0.004) with increasing duration of pneumoperitoneum and decreased (P = 0.02, P = 0.03, P = 0.01 and P = 0.05) with the addition of oxygen. No differences were found between CO(2) and helium. In conclusion these data confirm the effect of pneumoperitoneum upon adhesions and demonstrate its reduction by oxygen, strongly suggesting that the main cause of adhesion formation is the relatively superficial hypoxaemia produced by the pneumoperitoneum. (+info)
Causes and effects of heterogeneous perfusion in tumors.
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A characteristic of solid tumors is their heterogeneous distribution of blood flow, with significant hypoxia and acidity in low-flow regions. We review effects of heterogeneous tumor perfusion are reviewed and propose a conceptual model for its cause. Hypoxic-acidic regions are resistant to chemo- and radiotherapy and may stimulate progression to a more metastatic phenotype. In normal tissues, hypoxia and acidity induce angiogenesis, which is expected to improve perfusion. However, aggressive tumors can have high local microvessel density simultaneously with significant regions of hypoxia and acidosis. A possible explanation for this apparent contradiction is that the mechanisms regulating growth and adaptation of vascular networks are impaired. According to a recent theory for structural adaptation of vascular networks, four interrelated adaptive responses can work as a self-regulating system to produce a mature and efficient blood distribution system in normal tissues. It is proposed that heterogeneous perfusion in tumors may result from perturbation of this system. Angiogenesis may increase perfusion heterogeneity in tumors by increasing the disparity between parallel low- and high-resistance flow pathways. This conceptual model provides a basis for future rational therapies. For example, it indicates that selective destruction of tumor vasculature may increase perfusion efficiency and improve therapeutic efficacy. (+info)
Mitigation of amphotericin B nephrotoxicity by mannitol.
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Renal transplant recipients are susceptible to a number of fungal infections amenable to therapy with amphotericin B, but azotaemia is an almost invariable sequel to the use of this agent. As intravenous mannitol has been shown to minimize nephrotoxicity induced by amphotericin B in dogs we treated four kidney transplant recipients who had systemic fungal infections with mannitol and amphotericin B. None showed significant reduction in renal function though a mild metabolic acidosis did develop. (+info)
Effect of acidosis on the properties of the glutaminase mRNA pH-response element binding protein.
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The pH-responsive stabilization of the rat renal glutaminase (GA) mRNA during metabolic acidosis is mediated by a pH-response element (pH-RE). The primary pH-RE within the GA mRNA consists of a direct repeat of an 8-base adenosine and uridine-rich sequence, which binds a specific cytosolic protein, the pH-response element binding protein (REBP). The functional analysis of this system was performed in LLC-PK(1)-F(+) cells, a pH-responsive line of porcine proximal tubule-like cells. Cytosolic extracts of LLC-PK(1)-F(+) cells also contain a protein that binds with high affinity to the rat GA mRNA pH-RE. The apparent binding of this protein is increased threefold in cytosolic extracts prepared from LLC-PK(1)-F(+) cells that were grown in acidic medium (pH = 6.9, HCO(3)- = 10 mM). Extracts prepared from the renal cortex of rats that were made acutely acidotic also exhibit a similar increase in binding to the RNA probe that contains the direct repeat of the pH-RE. The temporal increase in binding correlates with the temporal increase in GA mRNA. Scatchard analysis indicates that the increased binding is due to an increase in both the affinity and the maximal binding of the pH-REBP. Thus, increased binding of the pH-REBP to the GA mRNA may initiate its stabilization and increased expression during acidosis. (+info)
"Added lactose" and "added sucrose" cow's milk formulae in nutrition of low birthweight babies.
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During the manufacture of dried milks for infant feeding the composition of cow's milk may be modified by the addition of extra carbohydrate powder to lower the relative proportions of protein and minerals, and in practice various carbohydrates are used in a largely empirical manner. In other circumstances it is known that the quality of dietary carbohydrate affects intestinal tolerance, deposition of body fat (in rats), and concentrations of plasma lipids (in man). Therefore, in this study the effects of feeding newborn infants on added lactose formula and added sucrose formula have been investigated. 29 low birthweight babies were observed throughout the first 3 months of life. The added carbohydrate achieved a satisfactory composition in terms of mineral and protein concentration of the reconstituted milk, but the "added lactose" group experienced more diarrhoea and a greater degree of metabolic acidosis during the first week of life. The added lactose group was slightly fatter and the plasma triglyceride concentration slightly higher than in the "added sucrose" group. Despite teleological evidence in favour of lactose, we found no objective contraindication to the addition of sucrose to cow's milk in the manufacture of infant feeding formulae. Both milks contained only small quantities of linoleic acid and the polyunsaturated fatty acid content of the plasma and adipose tissue lipids fell to low levels, but no clinical evidence of "essential fatty acid deficiency" was found. (+info)