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PubMed2005

Microscopic images of intraspheroidal pH by 1H magnetic resonance chemical shift imaging of pH sensitive indicators.

OBJECTIVE: We investigate microscopic pH heterogeneity within tumor spheroids using a novel 1H NMR methodology that provides high resolution measurements of intraspheroidal pH. MATERIAL AND METHODS: High resolution microscopic images of intraspheroidal pH were obtained by 1H NMR using chemical shift selective excitation of the H2 resonance of imidazole added to the incubation medium. Imidazole accumulated in the intraspheroidal space in a pH dependent manner. Maps of intraspheroidal pH could be obtained by transforming pixel by pixel (32 x 32 micro) the regional variation of imidazole H2 intensity into a relative pH scale. RESULTS: Our analysis revealed drastic intraspheroidal pH alterations depending on the size of the spheroid, ca. 0.6 pH units more acidic in the necrotic core than in the periphery, for spheroids of 600 mum diameter. The presence of concentric regions having similar intraspheroidal pH was consistently observed. The thickness of these regions decreased from pH 7.2 to pH 6.8 and increased below the latter pH value. CONCLUSION: Our observations are compatible with the general model of spheroid growth where the more external layers of cells are in active growth and depict more alkaline pH values while the inner layers remain quiescent or evolve to a necrotic core, depicting more acidic pH values.

Animals↗
PubMed1992

pH responses to sucrose and the formation of pH gradients in thick 'artificial mouth' microcosm plaques.

Artificial microcosm plaques were grown in a five-plaque culture system for up to 6 weeks, reaching a maximum depth of several mm. Procedures for long-term pH measurement with glass electrodes were established; they showed that the application of 5 or 10% sucrose for 6 min with a slow continuous flow of a basal medium containing mucin (BMM) generated the pH changes characteristic of in vivo Stephan curves. These pH responses were reproducible between plaques. Plaque mass and thickness were critical variables. Successive, sucrose-induced pH curves in plaques up to 4 mm thickness showed minor reductions only in the amplitude and rates of pH change. In plaques over 4 mm thick there was a pronounced reduction in pH response to successive sucrose applications, indicating increased diffusion limitations--a result of plaque growth to seal in the freshly-inserted pH electrode. In plaques of 6 mm maximum thickness, 10% sucrose induced a decrease to below pH 5.5 lasting 24 h, compared to the pH response in 2 mm thick plaque, which returned to the resting pH in 2 h. Differences in pH of up to 0.9 units were identified in thick plaques between inner and outer layers. The BMM flow rate was a critical determinant of the amplitude of the pH response to sucrose and subsequent return to resting pH. These results confirm, for microcosm plaque, the importance of clearance dynamics and diffusion-limited gradients in regulating plaque pH.

Animals↗
PubMed1990

Measurement of tumor pH during microwave induced experimental and clinical hyperthermia with a fiber optic pH measurement system.

The influence of hyperthermia on tissue pH was investigated using a modified version of the fiber optic monitoring system. This newly developed system was tested for use in tissues and found to be suitable for pH measurement during microwave induced hyperthermia. The fiber optic pH probe (0.7 mm diameter) could be easily used in the electromagnetic fields produced by the microwave applicators, whereas only the display unit required some shielding. Tissue pH of experimental and clinical tumors was measured concurrently with local microwave hyperthermia treatment. The mean initial intratumor pH of a rat rhabdomyosarcoma was 7.03 (SD 0.13, n = 19) and the pH of human subcutis was 7.45 (SD 0.02, n = 8). In rat tumor a primary pH decrease was observed during heating which was fully reversed during cooling. The coefficient of temperature dependence was -0.016 pH unit/degree C (SD 0.004, n = 12). After approximately 1 hr of heating at 43 degrees C a further pH decrease of 0.1-0.3 unit occurred which was not reversed directly after treatment. Measurements during clinical local microwave hyperthermia treatments after radiotherapy revealed similar changes in pH values, primary as well as secondary. The estimated coefficient of temperature dependence for the reversible pH change, which occurred in subcutis as well as in tumor tissue, was -0.016 pH unit/degree C (SD 0.004, n = 12). The fiber optic pH measurement system is expected to be a valuable tool in the thorough investigation of temperature and time related pH changes in tumor during experimental as well as clinical hyperthermia treatment.

Acid-Base Equilibrium↗
PubMed2005

Interaction of pH with mercuric chloride toxicity to penaeid prawns from a tropical estuary, East Coast of India: enhanced toxicity at low pH.

Toxicity tests were conducted to study the interaction of pH and the response of two size groups of penaeid prawns i.e. Penaeus monodon and Penaeus indicus to different sets of five concentrations of HgCl2 (0.01-0.09 mg l(-1)) under a broad range of pH conditions (5-9). Behavioural responses varied according to test solution concentration and nominated values of pH. Abnormality was detected in the higher concentrations with lower pH in smaller size group of P. monodon. High mortality was observed at higher concentration of test solution with low pH. Irrespective of species and size group LC50 demonstrated similar trend of variation with respect to time period. At pH 9 the threshold limit for 65-75 mm size group of P. monodon and P. indicus was 0.043 and 0.049 mg l(-1) respectively while it was 0.041 and 0.035 mg l(-1) respectively at pH 8; and 0.038 and 0.044 mg l(-1) respectively at pH 7. Relative toxicities were significantly varied except for bigger size groups in the studied pH ranges. The result was pronounced at pH 5 with maximum 1.61 times for inter-hour relative toxicity in contrast to all. At pH below 7 of mercury resulted more toxic compared to high pH range (>7) might be due to acid toxicity itself. At each pH smaller size groups were sensitive while bigger shown tolerant. P. monodon were more sensitive than P. indicus. The toxic order of pH effect was 9<8<7<6<5. Toxicity increased significantly (p>0.01) in acidic medium compared to alkaline.

Animals↗
PubMed1981

Control of electron transfer in the cytochrome system of mitochondria by pH, transmembrane pH gradient and electrical potential. The cytochromes b-c segment.

1. A study is presented of the effects of pH, transmembrane pH gradient and electrical potential on oxidoreductions of b and c cytochromes in ox heart mitochondria and 'inside-out' submitochondrial particles. 2. Kinetic analysis shows that, in mitochondria at neutral pH, there is a restraint on the aerobic oxidation of cytochrome b566 with respect to cytochrome b562. Valinomycin plus K+ accelerates cytochrome b566 oxidation and retards net oxidation of cytochrome b562. At alkaline pH the rate of cytochrome b566 oxidation approaches that of cytochrome b562 and the effects of valinomycin on b cytochromes are impaired. 3. At slightly acidic pH, oxygenation of antimycin-supplemented mitochondria causes rapid reduction of cytochrome b566 and small delayed reduction of cytochrome b562. Valinomycin or a pH increase in the medium promote reduction of cytochrome b562 and decrease net reduction of cytochrome b566. 4. Addition of valinomycin to mitochondria and submitochondrial particles in the respiring steady state causes, at pH values around neutrality, preferential oxidation of cytochrome b566 with respect to cytochrome b562. The differential effect of valinomycin on oxidation of cytochromes b566 and b562 is enhanced by substitution of 1H2O of the medium with 2H2O and tends to disappear as the pH of the medium is raised to alkaline values. 5. Nigericin addition in the aerobic steady state causes, both in mitochondria and submitochondrial particles, preferential oxidation of cytochrome b562 with respect to cytochrome b566. This is accompanied by c cytochrome oxidation in mitochondria but c cytochrome reduction in submitochondrial particles. 6. In mitochondria as well as in submitochondrial particles, the aerobic transmembrane potential (delta psi) does not change by raising the pH of the external medium from neutrality to alkalinity. The transmembrane pH gradient (delta pH) on the other hand, decrease slightly. 7. The results presented provide evidence that the delta psi component of the aerobic delta microH+ (the sum of the proton chemical and electrical activities) exerts a pH-dependent constraint on forward electron flow from cytochrome b566 to cytochrome b562. This effect is explained as a consequence of anisotropic location of cytochromes b566 and b562 in the membrane and the pH-dependence of the redox function of these cytochromes. Transmembrane delta pH, on the other hand, exerts control on electron flow from cytochrome b562 to c cytochromes.

Animals↗
PubMed1992

Long-lived complexes between peptide and class II major histocompatibility complex are formed at low pH with no requirement for pH neutralization.

The binding of peptide antigens to class II histocompatibility glycoproteins can be markedly enhanced at pH values approximating those found in acidic endosomal compartments in antigen-presenting cells (APC). It has been proposed by others that low pH may increase the conformational flexibility of class II, facilitating both the association and dissociation of peptides. Neutralization of pH, as class II is expressed on the plasma membrane of APC, could then serve to trap peptide in a stable complex. If this were the only mechanism accounting for enhanced peptide binding at low pH, one would predict that there should be a concordance between the pH conditions required for enhanced binding and those associated with increased peptide dissociation. Furthermore, long-lived complexes of class II and peptide should not be observed at low pH without neutralization. In the present communization, I provide the data that support the generality of my previous conclusion that both affinity and maximal binding are regulated by pH in experiments using purified class II and biotin-labeled peptides. The pH profile for binding and dissociation using three different class II glycoproteins was analyzed, and the results demonstrated that enhanced binding is not coupled to enhanced dissociation. Peptide complexes were observed to be quite stable at pH 4.5 and above. This result was further substantiated in experiments where biotin-peptide/class II complexes were extensively dialyzed at low pH followed by analysis on Western blots probed with avidin. Finally, a low pH assay system was devised to analyze the formation of stable peptide/class II complexes without pH neutralization. Our results indicate that stable complexes can be formed at low pH without the requirement for a shift to neutral pH.

Amino Acid Sequence↗
PubMed1981

Effects of Environmental pH on the Internal pH of Chlorella pyrenoidosa, Scenedesmus quadricauda, and Euglena mutabilis.

The effect of external pH on two laboratory-cultured acid-intolerant species (Chlorella pyrenoidosa Chick and Scenedesmus quadricauda Turp. Bréb.) and one acid-tolerant species from a natural population (Euglena mutabilis Schmitz) was examined by measuring internal pH. These measurements were made with the weak acid (14)C-dimethyloxazolidine-2,4-dione after cells had been incubated for 2 and 6 hours at external pH levels from 3.0 to 8.0. Photosynthetic and respiration rates of the three species were also measured over the range of external pH levels.All three species regulated their internal pH levels over the 6-hour incubation time. C. pyrenoidosa and S. quadricauda had internal pH levels around 7.0, regardless of external pH. E. mutabilis had a wider internal pH range, from 5.0 at low external pH to 8.0 at high external pH. External pH had no effect on either photosynthetic or respiration rates. Statistical comparisons showed that there was a significant difference between the acid-intolerant and acid-tolerant species with regard to the level of internal pH maintained and the response of internal pH to external pH.

Journal Article↗
PubMed2001

Simultaneous monitoring of gastric and oesophageal pH reveals limitations of conventional oesophageal pH monitoring in milk fed infants.

BACKGROUND: Monitoring oesophageal pH conventionally detects "acid reflux" (pH less than 4). The pH of the gastric contents determines whether or not reflux can be detected. AIM: To monitor gastric and oesophageal pH simultaneously in order to determine the effect of milk feeds on gastric pH and how this would influence interpretation of the oesophageal pH record. METHODS: Milk fed infants for whom oesophageal pH monitoring was requested underwent simultaneous gastric and oesophageal pH monitoring using a dual channel pH probe. RESULTS: Twenty of 24 records were technically satisfactory. Mean reflux index was 1.0%, range 0.0-4.0%. Gastric pH was less than 4 for 24.5% (range 0.6-69.1%) of the total time. The average time the gastric pH was greater than 4 after feeds was 130 minutes (range 29-212 minutes). The corrected reflux index (limited to the time the gastric pH was less than 4) was 2.6% (range 0.0-11.0%). CONCLUSION: The pH of the gastric contents may be greater than 4 for prolonged intervals, during which oesophageal pH monitoring using current criteria cannot detect reflux nor correlate it with clinical events. A low reflux index may reflect prolonged buffering of gastric acidity rather than the absence of reflux.

Animals↗
PubMed1988

Regulation of cell pH by ambient bicarbonate, carbon dioxide tension, and pH in the rabbit proximal convoluted tubule.

UNLABELLED: To study the regulation of cell pH by ambient pH, carbon dioxide tension (PCO2), and bicarbonate (HCO3), cell pH was measured in the isolated, in vitro microperfused rabbit proximal convoluted tubule using the fluorescent dye (2',7')-bis-(carboxyethyl)-(5,6)-carboxyfluorescein. For the same changes in external pH, changes in [HCO3] and PCO2 affected cell pH similarly ([HCO3]: pHi/pHe = 0.67, PCO2: pHi/pHe = 0.64, NS). Isohydric changes in extracellular [HCO3] and PCO2 did not change cell pH significantly. Changes in peritubular [HCO3] elicited larger changes in cell pH than changes in luminal [HCO3], which were enhanced by peritubular 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonate (SITS). The cell pH defense against acute increases and decreases in PCO2 was inhibited by sodium, but not by chloride removal. Peritubular SITS inhibited the cell pH defense against increases and decreases of PCO2, whereas luminal amiloride inhibited cell pH defense against increases in PCO2. CONCLUSIONS: (a) Steady-state cell pH changes in response to changes in extracellular [HCO3] and PCO2 are quantitatively similar for a given change in extracellular pH; (b) the rate of the basolateral Na/(HCO3)3 cotransporter is a more important determinant of cell pH than the rate of the apical membrane mechanism(s); (c) cell pH defense against acute changes in PCO2 depends on the basolateral Na/(HCO3)3 cotransporter (acid and alkaline loads) and the luminal Na/H antiporter (acid loads).

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1997

Is pH paper an acceptable, low-cost alternative to the blood gas analyzer for determining pleural fluid pH?

BACKGROUND: Our laboratory uses pH paper rather than a blood gas analyzer to measure pleural fluid pH to decrease cost and avoid analyzer malfunction due to viscous fluids. METHODS: To compare these two methods of determining pleural fluid pH, 42 patients undergoing diagnostic or therapeutic thoracentesis had two 1-mL aliquots of pleural fluid anaerobically collected in a heparinized syringe and placed on ice. pH measurements were made using litmus paper (pHydron Vivid 6-8 brand litmus paper; MicroEssential Labs; Brooklyn, NY) and the model 995-Hb blood gas analyzer (AVL Instruments; Roswell, GA) within 1 h of collection. Agreement analysis was performed in three ways: on the entire group; in subcategories of complicated or uncomplicated parapneumonic effusions (<7.1, 7.1 to 7.3, >7.3); and in subcategories of poor prognosis or better prognosis malignant effusions(<7.3, >7.3). RESULTS: pH measured with pH paper was significantly more variable (SD=0.55, coefficient of variation [CV]=7.5%) than was pH measured with the blood gas analyzer (SD=0.11, CV=1.5%). There was no significant correlation between values obtained with the two techniques (r=-0.26, SD of the differences=0.59). Using the pH subcategories, there was 72% discordance in classification between litmus paper and arterial blood gas (ABG) determinations for patients with parapneumonic effusions. In patients with malignant effusions, there was 30% discordance. The pH values obtained by the ABG analyzer predicted tube thoracostomy 72% of the time, whereas the pH values obtained using pH paper were consistent only 36% of the time. CONCLUSION: Determination of pleural fluid pH using pH paper is unreliable and should not be considered an acceptable alternative to the blood gas analyzer. There is no need to determine pH on purulent samples. Hospital laboratories will be more likely to allow the use of the ABG analyzer on fluids other than blood if clinicians keep this in mind.

Blood Gas Analysis↗
PubMed1982

pH distributions in transplanted neural tumors and normal tissues of BDIX rats as measured with pH microelectrodes.

The distribution of pH values was measured in transplanted neuroectodermal TV1A tumors and in brain and kidney of BDIX rats in vivo. Tissue damage during pH measurements could be minimized by the use of Hinke-type pH glass microelectrodes with maximum diameters of the pH-sensitive tips of less than or equal to 10 micrometers (sensitivity, 58 to 60 mV/pH unit at 37 degrees; response time (95%), less than or equal to 3 sec; drift, less than or equal to 0.01 pH unit/hr). The advantages and limitations of this technique are discussed in relation to other methods for the analysis of extracellular pH. In tumors weighing 1.0 to 2.5 g, pH values ranged from 6.8 to 7.1 (mean, 7.0). The pH distribution in tumors weighing 4 to 6 g was shifted to slightly lower values, with an average pH of 6.9 (range, 6.7 to 7.1). No marked pH differences were found between the tumors and normal tissues. The pH values measured in brain and kidney ranged from 6.6 to 7.3 (mean, 7.0) and 6.7 to 7.3 (mean, 7.1), respectively. Within single tumors, local pH variations in the range of 0.2 to 0.3 pH unit were observed. The local pH values measured in certain tumor areas are, however, sufficiently low to partially inhibit proliferation and colony formation in cultured malignant cells.

Animals↗
PubMed1983

Drug absorption by the rat jejunum perfused in situ. Dissociation from the pH-partition theory and role of microclimate-pH and unstirred layer.

In anaesthetized rats the rate of appearance of benzoic acid and aminopyrine in jejunal venous blood was measured; the pH of the luminal perfusion solution was varied between 4 and 10.5. The pH-absorption curves were less steep than predicted by the unmodified pH-partition theory. A reduction of the mucosal unstirred layer thickness by means of the segmented-flow technique considerably increased the absorption rate without essentially changing the shape of the pH-absorption curves. The pH at the surface of the jejunal mucosa was 6.0, 6.5, 6.6, and 8.0 for luminal solutions of pH 4.0, 6.0, 8.0, and 10.8, respectively. From the absorption data the microclimate-pH was calculated which would explain best the observed pH-absorption curves. These calculated pH-values correspond well to the values measured at the mucosal surface. Therefore, it was concluded that a microclimate-pH caused the deviation of the intestinal pH-absorption curves of benzoic acid and aminopyrine from the prediction of the unmodified pH-partition theory. The mucosal unstirred layer represented only a considerable permeation resistance and was not responsible for the deviating shape of the pH-absorption curves.

Aminopyrine↗
PubMed1998

Comparison of simultaneous pH measurements made with 8-hydroxypyrene-1,3,6-trisulphonic acid (HPTS) and pH-sensitive microelectrodes in snail neurones.

We have evaluated the pyrene-based ratiometric fluorescent dye, 8-hydroxypyrene-1,3,6-trisulphonic acid (HPTS), by using it in conjunction with glass pH-sensitive microelectrodes to measure intracellular pH (pHi) in voltage-clamped snail neurones. Intracellular acidification with propionic acid, and alkalinization following the activation of H+ channels allowed the calibration of the dye to be compared with that of the pH microelectrode over the pH range 6.50-7.50. HPTS calibrated in vitro and glass pH-sensitive microelectrodes produced similar absolute resting pHi values, 7. 16+/-0.05 (n=10) and 7.17+/-0.06 (n=9) respectively in nominally CO2/HCO3--free saline. At both extremes of the pH range there were small discrepancies. At acidic pHi, 6.87+/-0.09 (n=5), the intracellular HPTS measurement differed by -0.08+/-0.03 pH units from the pH-sensitive microelectrode measurement. At alkaline pHi, 7. 32+/-0.10 (n=5), HPTS measurements produced pH values that differed by +0.07+/-0.04 pH units from those of the pH-sensitive microelectrode. Some of the discrepancy could be accounted for by the slow response of the recessed-tip pH-sensitive microelectrode (time constant 77+/-15 s, n=3). Further experiments showed that HPTS, used at an intracellular concentration of 200 microM to 2 mM, did not block activity-dependent pHi changes. The intracellular HPTS concentration was calculated by measurement of intracellular chloride during a series of HPTS-KCl injections. Comparison of HPTS with 2',7'-bis(2-carboxyethyl)-5,6-carboxyfluorescein (BCECF), at the same concentration, showed that HPTS produces a larger change in ratio over the pH range 6.00-8.00.

Animals↗
PubMed1987

Na+/H+ exchange is the major mechanism of pH regulation in cultured sympathetic neurons: measurements in single cell bodies and neurites using a fluorescent pH indicator.

The regulation of intracellular pH in single cell bodies and in neurites of cultured neurons from rat superior cervical ganglion was studied by continuous monitoring of pH transients using the fluorescent indicator bis(carboxyethyl)carboxy-fluorescein. Intracellular pH was 7.03 +/- 0.05 (n = 8) in bicarbonate-free media at pH 7.4 and was not affected by depolarization with high potassium. Brief exposure to NH4Cl caused rapid cytoplasmic acidification followed by an exponential return of intracellular pH to the resting value. The apparent first order rate constant for recovery from an NH4Cl-induced acid load was 0.2 +/- 0.03 min-1 (37 degrees C) and was similar in media at pH 6.5 or 7.8. Recovery from an acid load was blocked by removal of extracellular Na+ or by amiloride but was not dependent on extracellular Cl- or phosphate or blocked by inhibitors of anion transport, in the presence or absence of bicarbonate. Addition of 5-10 mM bicarbonate at pH 7.4 resulted in a slight alkalinization of the cytoplasm and enhanced complete restoration of pHi after an NH4Cl-induced acid load. Nerve growth factor did not affect intracellular pH of either growing cells deprived of nerve growth factor up to 6 days or of newly isolated neurons left at 4 degrees C for a week before exposure to nerve growth factor. Phorbol 12-myristate 13-acetate had no effect on the pH of cell bodies of growing cells and increased pH of cells deprived of nerve growth factor by less than 0.05 pH units. It is concluded that: pH regulation in cultured sympathetic neurons is largely achieved by Na+/H+ exchange; Bicarbonate may also participate in pH regulation, but not by its exchange with Cl-.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed2000

Effects of microenvironmental extracellular pH and extracellular matrix proteins on angiostatin's activity and on intracellular pH.

Antiangiogenic agents target migratory and proliferative endothelial cells (EC) in the process of forming new vessels, resulting in growth inhibition or cell death. Here we have shown that the antiangiogenic activity of angiostatin on EC is enhanced in culture when the microenvironmental extracellular pH (pH(e)) is reduced to levels similar to that of many tumors. In a migration/scratch assay and during tube formation, angiostatin in combination with reduced pH(e) synergistically resulted in an increased EC death--an effect not seen with either stimulus individually. Lowering of pH(e) decreased intracellular pH (pH(i)), and a further lowering of pH(i) occurred when low pH(e) was combined with angiostatin. These data suggest that low pH(e) plays a role in the relative specificity and efficacy of angiostatin for tumor neovasculature and indicate roles for both pH(e) and pH(i) in the mechanism of angiostatin action. A receptor for angiostatin, the alpha-subunit of ATP synthase, was found on the surface of EC. We show that cell surface receptor distribution is increased on Matrigel, a basement-like matrix, as opposed to fibronectin or RGD peptide substrates, and redistributed to a more punctuate appearance at low pH(e). Furthermore, positive cell surface histochemical staining for alpha-ATP synthase was blocked by preincubation with angiostatin. These data indicate that substrate and pH(e) are critical parameters in the evaluation of this antiangiogenic substance, and probably for others as well.

Angiogenesis Inhibitors↗
PubMed2006

pH-Dependent behaviour of soluble protein aggregates formed during heat-treatment of milk at pH 6.5 or 7.2.

The pH-dependent behaviour of soluble protein aggregates produced by the pre-heating of reconstituted skim milk at 90 degrees C for 10 min was studied, in order to understand the role of these aggregates in acid gelation of heated milk. The following milk samples were prepared: (1) control (unheated reconstituted milk, pH 6.5); (2) milk heat-treated at pH 6.5 (mHtd6.5) and (3) milk heat-treated at pH 7.2 (mHtd7.2). They were centrifuged and the supernatants (SPNT 1) pH-adjusted to yield a series of pH values ranging from 6.5 or 7.2 to 4.6 using HCl at 20 degrees C or GDL at 20 and 38 degrees C. pH-Adjusted SPNTs 1 were re-centrifuged. The resulting supernatants (SPNTs 2) were analysed by OD (at 600 and 280 nm) and SDS-PAGE in order to characterise proteins still soluble as a function of pH. Particle size in SPNTs 1 was analysed by Steric Exclusion Chromatography. The OD600 nm revealed that during acidification soluble casein in both control and heat-treated samples exhibits variations in its optical properties or size as previously shown with micellar casein. In heat-treated samples, soluble casein and heat-induced covalent soluble aggregates precipitate at the same pH value. A progressive acidification of the soluble phase did not separate them. Increasing the temperature of acidification from 20 to 38 degrees C resulted in an increase in the precipitation pH of the proteins. However choice of acidifier did not have a significant effect on OD profiles. The soluble covalent aggregates from mHtd7.2 were smaller, more numerous, and had a higher content of kappa-casein than mHtd6.5. Both types of aggregates began to precipitate at the same pH value but precipitation occurred over a narrower pH-range for soluble aggregates prepared from mHtd7.2. This may explain the higher gelation pH of mHtd7.2 compared with mHtd6.5.

Animals↗
PubMed1999

Food but not a chemically defined diet interferes with maintenance of intragastric pH at a predefined level using continuous pH-stat-adjusted intravenous infusion of ranitidine in healthy volunteers.

Eight healthy volunteers were used to determine the influence of a normal diet (food) versus an isocaloric chemically defined diet (CDD) on the dose of ranitidine infused continuously over 12 hr, required to maintain the intragastric pH > or = 5 or above. The dose of ranitidine used was adjusted by the pH-stat instrument, Gastrojet, and a target pH of 5.0 was selected. The average ranitidine dose was 43.5 mg for food, 28.3 mg for CDD, and 25.7 mg for fasting. Despite the higher dose of ranitidine used with food, the control of pH was lower than the desired and preset value of pH > or = 5: the average mean pH was 3.99 for food, 5.11 for CDD, and 5.75 for fasting. The percentage of time of pH > or = 5 was 32.0% for food, 73.7% for CDD, and 80.1% for fasting. Thus, when persons are fed a normal diet there is a need for higher doses of ranitidine to maintain the gastric pH > or = 5.0. Even with frequent monitoring of intragastric pH with the Gastrojet, there is much greater variability in pH control with food than with CDD or fasting, and the preset and desired pH level was not achieved. This difficulty in achieving desired end points of pH control when switching from a fasting to a fed state needs to be considered when intravenous ranitidine is used to obtain strict control of intragastric pH.

Adult↗
PubMed2004

Acute extracellular acidification reduces intracellular pH, 42 degrees C-induction of heat shock proteins and clonal survival of human melanoma cells grown at pH 6.7.

Two human melanoma cell lines, SK-Mel-28 and DB-1, were used for in vitro studies of the mechanisms underlying heat resistance of human tumour cells adapted to growth in acidic environments. Adaptation to growth at low pH was characterized by resistance to 42 degrees C cytotoxicity and accompanied by an increase in endogenous levels of Hsp70 and/or Hsp27. Acute extracellular acidification to levels below pH 6.5 was required to sensitize the melanoma cells to 42 degrees C. Furthermore, cells grown at low pH were more resistant to sensitization by acute acidification than cells grown at pH 7.3. The intracellular pH (pHi) of cells grown at pH 6.7 was less than the pHi of cells grown at pH 7.3 both before and after acute acidification. A pHi threshold existed for melanoma cells growing at pH 7.3 below which they became sensitized to 42 degrees C. This pHi threshold differed between the SK-Mel-28 and DB-1 cells. In contrast, a pHi threshold for heat sensitization did not exist for cells growing at pH 6.7: any reduction in pHi before heating resulted in increased cell killing. Since cells grown at low pH lack a pHi threshold for heat sensitization, they are sensitized more to 42 degrees C per unit decrease in pHi than cells grown at pH 7.3. Acute acidification abrogated the 42 degrees C-induction of Hsp70 and Hsp27 in the melanoma cells. The pHi thresholds for abrogation of these HSPs are slightly higher than or comparable with the thresholds for cytoxicity for each cell line grown at pH 7.3, but abrogation occurred over a narrower range of pHi compared with cytotoxicity. Abrogation of heat-induced expression of these HSPs correlates with cytotoxicity in both cell lines with the exception of Hsp27 expression in SK-Mel-28 cells. In conclusion, strategies that reduce pHi in melanoma cells growing at low pH, such as in acidotic regions of tumours, could selectively sensitize them to hyperthermia because they lack a pHi threshold for heat sensitization.

Blotting, Western↗