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PubMed1997

Cholera and pertussis toxins increase acidification of endocytic vesicles without altering ion conductances.

Acidification of endocytic vesicles, driven by the vacuolar H+ pump, is affected by parallel ion transporters. Because adenosine 3',5'-cyclic monophosphate (cAMP) and heterotrimeric G proteins may alter ion transporters, I tested whether cholera and pertussis toxins affected acidification of rat liver endosomes. Fluorescein-labeled dextran-loaded "10-min" endosomes from cholera toxin-treated rats exhibited ATP-dependent rates of acidification in the presence and absence of Cl- or K+ that were approximately 60-120% (P < 0.05) faster than rates from control endosomes. This increase was greater for "older" "20-min" endosomes and less for 'early" "2-min" endosomes. Ion transport functions of 10-min and 20-min toxin-exposed endosomes were similar to those of 2-min control endosomes. Cholera toxin also increased ATP-dependent steady-state intravesicular H+ concentration by 38-218% (P < 0.05). Pertussis toxin increased endosome acidification rates by 20-54% (P < 0.05). Both toxins increased liver cAMP content, and endosomes prepared from perfused livers exposed to 0.75 mM dibutyryl cAMP exhibited similar increases in acidification rates. These studies indicate that both cholera and pertussis toxins markedly alter the function of rat liver endosomes. The mechanism is unlikely to reflect major changes in vesicle ion transporters but rather may indicate either an increase in the number of H+ pumps per endosome and/or changes in fusion, remodeling, and maturation of early endocytic vesicles in response to cAMP.

Acids↗

PubMed1975

Peritubular pH and PCO'2 in renal tubular acidification.

The influence of peritubular capillary pH and PCO'2 on renal tubular acidification was studied in rats by luminal and peritubular perfusion techniques. Luminal stopped-flow microperfusions were carried out with bicarbonate or alkaline phosphate solutions and luminal pH continuously measured by antimony micorelectrodes. Peritubular calpillary microperfusions were carried out with mammalian Ringer solution kept at different pH and PCO'2. The acidification process was assessed in terms of 1)maximal pH differences, 2)rates of pH change, and 3)rates of bicarbinate reabsorption or H'+ ion secretion. During peritubular perfusions at physiological pH and PCO'2 tubular acidifying capacity was maintained at near-normal levels. Perfusingcapillaries at high pH and low PCO'2, especially with bicarbonate Ringer, acidification was markedly depressed; it was moderately reduced at a peritubular pH of 5.6. At a capillary pH of 7.4, acidification was similiar at low and physiological PCO'2and enhanced at elevated PCO'2. Systemic respiratory acidosis enhanced acidification in the proximal tubule, but reduced it in distal segments.

Acid-Base Equilibrium↗

PubMed1981

Electrical effects of acidification in the rabbit proximal convoluted tubule.

The electrical characteristics of acidification were examined in isolated rabbit proximal convoluted tubules (PCT). In PCT perfused and bathed with an ultrafiltrate-like solution, the transepithelial potential difference due to active transport (transport PD) averaged -2.4 mV. The transport PD shifted in a negative direction by 1 mV (to -3.4 mV) when carbonic anhydrase inhibitors were added to the bath solution, and in a positive direction by 1.4 mV (to -1.0 mV) when bath sodium bicarbonate concentration was lowered. The positive shift was prevented by addition of either carbonic anhydrase inhibitors or the anion transport inhibitor SITS to the bath. These findings suggested electrogenic acidification. However, when electrogenic sodium transport was inhibited by removal of glucose and alanine from the luminal fluid, a positive PD suggesting electrogenic acidification was not observed. In tubules lacking glucose and alanine in the luminal fluid the rate of total CO2 absorption was 97.2 before and 35.4 pmol.mm-1.min-1 after inhibition of carbonic anhydrase. These findings do not support an independent electronic acidification mechanism. Nonelectrogenic acidification may secondarily after transepithelial PD by changes in transcellular current flow or by changes in paracellular resistance.

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

PubMed1983

Suppression of distal urinary acidification after recovery from chronic hypocapnia.

This study examined urinary acidification shortly after recovery from chronic hypocapnia induced by hypoxemia. Distal acidification was evaluated by measuring the urinary PCO2 and urine-blood PCO2 difference (U-B PCO2) when blood PCO2 had returned to normal. In posthypocapnic rats, maximal alkalinization of the urine by acute sodium bicarbonate loading failed to increase urine PCO2 and U-B PCO2 to the level of posthypoxemic control rats and normal control rats with comparable blood pH and urine bicarbonate concentration. To test the hypothesis that decreased distal hydrogen ion secretion in posthypocapnic rats resulted from intracellular alkalosis secondary to protracted hypocarbia, posthypocapnic rats were exposed to hypercapnia of brief duration (30 min) and prolonged duration (120 min) in an attempt to restore distal acidification to normal. In posthypocapnic rats, hypercapnia of brief duration was associated with a significant increase in urine PCO2 and a fall in urine pH. Prolonged hypercapnia resulted in a marked increase in urine PCO2 and a further fall in urine pH. At any urinary bicarbonate concentration, however, the urine PCO2 and U-B PCO2 posthypocapnic rats exposed to hypercapnia were still significantly lower than in normal control rats identically subjected to prolonged hypercapnia and with comparable blood PCO2 and blood pH. Our findings indicate that distal acidification after abrupt recovery from chronic hypocapnia is decreased as if the kidneys were still under the influence of sustained hypocapnia. These findings could not be ascribed to extracellular alkalemia but could be explained by postulating that decreased urinary acidification resulted from persistence of cell alkalinity secondary to the accumulation of non-CO2 buffers generated during protracted hypocarbia. Alternatively, factors other than cell pH could mediate the adaptive decrease in distal hydrogen ion secretion of posthypocapnic rats.

Alkalosis, Respiratory↗

PubMed1986

Chronic metabolic acidosis augments acidification along the inner medullary collecting duct.

The inner medullary collecting duct (IMCD) of the rat is a major site of acidification. However, previous micropuncture studies have failed to demonstrate acidification along the terminal IMCD during chronic acid feeding. To more completely evaluate this question we used the microcatheterization method in rats fed ammonium chloride for 3-7 days. Arterial pH was 7.30 +/- 0.015, and PCO2 was set at 40 +/- 0.6 mmHg. The IMCD data were analyzed as a function of IMCD length between 40% and the tip. Equilibrium pH decreased from 6.21 +/- 0.11 to 5.47 +/- 0.03, whereas PCO2 was unchanged (28 +/- 1 mmHg between the deep samples and tip). Bicarbonate delivery decreased from 92 +/- 14 to 10 +/- 1 nmol/min, titratable acid increased from 462 +/- 33 to 762 +/- 40 nmol/min, and ammonium delivery increased from 2,235 +/- 121 to 3,528 +/- 140 nmol/min. Thus estimated net acid increased from 2,638 +/- 134 to 4,303 +/- 161 nmol/min. To determine whether increasing delivery of buffer to the IMCD would stimulate acid secretion in acute acidosis, rats were studied during the infusion of HCl and creatinine. Arterial pH was 7.18 +/- 0.02. IMCD acidification was not increased compared with our previously published studies during HCl infusion [Am. J. Physiol. 241 (Renal Fluid Electrolyte Physiol. 10): F669-F676, 1981]. We conclude that chronic ammonium chloride ingestion stimulates IMCD acidification and that this increase may be an intrinsic modification of the acidification mechanism of the IMCD.

Acidosis↗

PubMed1988

Suppression of acidification along inner medullary collecting duct.

The purpose of these experiments was to evaluate the effect of acute respiratory alkalosis (ARA) and chronic bicarbonate drinking (CBD) on inner medullary collecting duct (IMCD) acidification. Microcatheterization was used to measure pH and PCO2, and samples were simultaneously obtained for measurement of bicarbonate, titratable acid (TA), and ammonium. In ten ARA rats (arterial pH was 7.54 +/- 0.02; PCO2 was 20 +/- 1 mmHg), IMCD equilibrium pH was not different (deep pH was 5.65 +/- 0.06 and PCO2 was 20 +/- 1 mmHg; tip pH was 5.54 +/- 0.07 and PCO2 was 22 +/- 1 mmHg). Delivery of bicarbonate, TA, and ammonium also did not differ between collection sites. Thus net acidification along the IMCD was negligible. Nine rats drank NaHCO3 for 5-8 days (pH = 7.48 +/- 0.02) but did not receive NaHCO3 during the experiment so that arterial pH fell to 7.40 +/- 0.01. IMCD equilibrium pH was different at deep (pH was 5.68 +/- 0.06; PCO2 was 32 +/- 1 mmHg) and tip (pH was 5.57 +/- 0.04; PCO2 was 27 +/- 1 mmHg; P less than or equal to 0.05) collection sites. However, only minimal changes in the delivery of bicarbonate, TA, and ammonium were noted, and net acidification along the IMCD was negligible. In ten control rats, net acidification was 219 nmol/min between collection sites (P less than 0.001). We conclude that ARA and CBD abolish acidification along the IMCD. In addition, CBD produces an intrinsic modification along the IMCD, which suppresses acid secretion and persists after acute recovery from alkalemia.

Alkalosis, Respiratory↗

PubMed1989

Peptide hormone effects on urinary acidification and acid-base balance: PTH, ADH, and glucagon.

That the adaptation of the kidney to the acid-base status may be controlled by peptide hormones is considered. In the proximal tubule parathyroid hormone (PTH) inhibits reabsorption of both bicarbonate and phosphate. The former effect is compensated for by an increase in bicarbonate absorption in Henle's loop, and the latter effect serves to augment phosphate concentration in the distal tubular fluid, which stimulates proton secretion in collecting ducts, the net effect of PTH administration being an enhancement of urinary acidification. In the thick ascending limb, both antidiuretic hormone (ADH) and glucagon inhibit bicarbonate absorption. In distal and cortical collecting tubules ADH stimulates net bicarbonate absorption and glucagon net bicarbonate secretion, which results in stimulation and inhibition of final urine acidification, respectively. Acute acid loading stimulates endogenous PTH secretion, which, by enhancing urinary acidification, constitutes a homeostatic response of the parathyroid glands. The major effects of ADH on urinary acidification serve at least to counterbalance disturbing consequences on urinary ammonia excretion of physiological variations in the urinary flow rate. The physiological significance of the effects of glucagon is unclear at present. Thus other peptide hormones may add to PTH and corticosteroid hormones to modulate urinary acidification, which leads to the concept of a pluri-hormonal control of acid-base balance.

Acid-Base Equilibrium↗

PubMed1990

Apical acidification by rabbit papillary surface epithelium.

The rabbit papillary surface epithelium (PSE) is a simple cuboidal epithelium that covers the outer surface of the renal papilla and has an apical surface that faces the urinary space. We studied acid-base transport in this epithelium by dissecting it from the papilla, mounting it in a modified Ussing chamber, and following pH changes in the apical bathing solution. The experiments demonstrated that the PSE is capable of acidifying the apical solution at a substantial rate. The acidification rate was similar with 100% nitrogen and 100% oxygen (with and without 10 microM antimycin A), ruling out a dependence on oxidative metabolism. Addition of 1 mM iodoacetate decreased apical acidification by 55%, suggesting a dependence on glycolysis. The net rate of lactate secretion was only 17% of the total acid secretion rate, indicating that apical acidification was not directly caused by secretion of lactic acid alone. Removal of sodium or potassium from the apical solutions or the addition of 1 mM N-ethylmaleimide failed to eliminate the apical acidification. Although the rate of PSE apical acidification is comparable to that of the rabbit outer medullary collecting duct (on a unit surface area basis), its contribution to urinary net acid excretion is likely to be small, owing to the small relative surface area of the PSE. However, by altering the pH of urine locally within the pelvic recesses, the PSE has the potential of modifying the formation of renal stones within the pelvic recesses.

Acids↗

PubMed1990

Acidification mechanisms on the basolateral membrane of renal vesicles from the developing nephron.

The present study examined acidification mechanisms on the basolateral membrane of the early renal vesicle, an undifferentiated ball of cells that will develop into parts of the glomerulus, proximal tubule, loop of Henle, and a portion of the distal convoluted tubule. Renal vesicles were dissected from newborn rabbit kidneys and bathed in vitro. To examine the basolateral membrane acidification mechanisms, intracellular pH (pHi) was measured by use of the pH-sensitive dye (2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. Evidence for Cl(-)-base exchange included the fact that removal of bath Cl-resulted in cell alkalinization (7.35 +/- 0.03 to 7.48 +/- 0.05; P less than 0.01). Cell alkalinization induced by Cl- removal was also observed in presence of a voltage clamp without bath Na+ (7.18 +/- 0.02 to 7.39 +/- 0.04; P less than 0.01) and was inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). pHi recovery after acute alkalinization resulting from CO2 removal was 0.20 +/- 0.03 pH units/min in the presence of Cl-, 0.07 +/- 0.01 in experiments with 0.2 mM DIDS, and 0.07 +/- 0.01 in absence of bath Cl-. The early renal vesicle also has a basolateral Na(+)-H+ antiporter. Removal of bath Na+ resulted in cell acidification (7.36 +/- 0.09 to 7.18 +/- 0.06; P less than 0.01), which was inhibited by 2 mM amiloride. Cell pH recovery after acute acidification (NH4Cl prepulse technique) was entirely dependent on bath Na+ and inhibited by amiloride. Thus the renal vesicle has basolateral membrane Na(+)-H+ and Cl(-)-base exchangers that can defend against cell acidification and alkalinization, respectively.

Acids↗

PubMed1991

Cytosolic acidification stimulates a calcium influx that activates Na(+)-H+ exchange in LLC-PK1.

We have previously shown that cytosolic acidification-stimulated Na(+)-H+ exchange in LLC-PK1 cells is inhibited by calmodulin antagonists. To investigate further the role of Ca(2+)-calmodulin-dependent processes in intracellular pH (pHi) regulation in these cells, we studied the effects of pHi changes on cytosolic Ca2+ concentration ([Ca2+]i). In fura-2/acetoxymethylester (fura-2/AM)-loaded cells maintained in isotonic Na(+)-free buffer containing 1.8 mM CaCl2, [Ca2+]i was 168 +/- 59 nM (n = 5). After NH4Cl-induced alkalinization, [Ca2+]i decreased to 83 +/- 28 nM and partially recovered to 126 +/- 42 nM. Cytosolic acidification, after NH4Cl washout, caused an increase in [Ca2+]i to 481 +/- 166 nM (P less than 0.05; n = 5) that was dependent on extracellular Ca2+. An increase in [Ca2+]i was also observed in cells acidified with KCl-nigericin, with a return of [Ca2+]i to baseline with cell alkalinization. No increase in 45Ca2+ efflux occurred in association with initial NH4Cl-induced [Ca2+]i decrease, suggesting Ca2+ flux into an intracellular store during alkalinization. Membrane depolarization did not alter [Ca2+]i. The acidification-induced [Ca2+]i increase was inhibited by preincubation with verapamil or the calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7). Na(+)-dependent pHi recovery in 2,'7'-bis(carboxyethyl)-5(6)-carboxyfluorescein acetoxymethylester (BCECF/AM)-loaded LLC-PK1 cells and cytosolic acidification-stimulated basolateral Na(+)-H+ exchange activity in LLC-PK1/CL4 cells were both attenuated in the absence of extracellular Ca2+. The results indicate that cytosolic acidification activates an influx of extracellular Ca2+ in LLC-PK1 cells. Furthermore, in the absence of Ca2+ influx, Na(+)-H+ exchange is inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonium Chloride↗

PubMed1994

Acidification of vasopressin-induced endosomes in toad urinary bladder.

It is well established that water channels (WC) are removed from the apical membrane of vasopressin-sensitive epithelia by endocytosis. The processing and the ultimate fate of endocytosed WC is, however, incompletely understood. In many cells, endosome acidification plays an important role in the processing and sorting of endocytosed proteins. Endosome acidification in the toad urinary bladder was therefore examined in vivo by fluorescence ratio video microscopy after induction of endocytosis by vasopressin removal and transepithelial water flow in the presence of the pH-sensitive fluid phase marker 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein-dextran. Fifteen minutes after induction of endocytosis, the majority of endosomes had a neutral or slightly acidic pH. The number of acidic endosomes increased progressively with time. Two hours after endocytosis began, 98% of the endosomes had a pH < 6.0. Bafilomycin completely blocked endosome acidification, indicating that H+ transport is mediated by a vacuolar H(+)-adenosinetriphosphatase. Bafilomycin had no effect on transepithelial water flow in bladders repetitively stimulated by vasopressin. These findings, as well as the work of other investigators, suggest that if WC recycling occurs, it is not dependent on acidification of the endosomal compartment. Acidification of vasopressin-induced endosomes most likely represents a terminal event in the endocytic pathway.

Acids↗

PubMed1994

Glutamate-induced intracellular acidification of cultured hippocampal neurons demonstrates altered energy metabolism resulting from Ca2+ loads.

1. Glutamate-evoked increases in intracellular free H+ concentration ([H+]i) were recorded from single rat hippocampal neurons grown in primary culture with carboxy SNARF-based dual emission microfluorimetry. The possibility that this acidification resulted from altered energy metabolism was investigated. 2. The response to 10 microM glutamate (delta pH = 0.41 +/- 0.14, mean +/- SD) was blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist CGS19755 (10 microM) and required extracellular Ca2+. 3. Substituting the metabolic inhibitor 2-deoxyglucose for glucose in the extracellular buffer prevented glutamate-induced acidification. 4. Ba2+, which carries charge through Ca2+ channels, including the Ca2+ uniporter on the inner mitochondrial membrane, substituted for Ca2+ in mediating glutamate-induced cytoplasmic acidification. 5. Microinjection of ruthenium red, a compound that blocks mitochondrial Ca2+ sequestration, significantly inhibited glutamate-induced acidification. 6. The mitochondrial uncoupler, carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazone (FCCP, 0.1 microM), mimicked and partially occluded the glutamate-induced [H+]i increase. 7. These findings indicate that glutamate-induced Ca2+ loads are sequestered by mitochondria, uncouple respiration, and produce metabolic acidosis. The glutamate-induced acidification is symptomatic of metabolic stress and may indicate that mitochondria play an important role in glutamate-induced neuronal death.

Animals↗

PubMed2004

Hydrogen peroxide-mediated cytosolic acidification is a signal for mitochondrial translocation of Bax during drug-induced apoptosis of tumor cells.

Absence of the proapoptotic protein Bax renders tumor cells resistant to drug-induced apoptosis. We have shown that hydrogen peroxide (H(2)O(2))-mediated cytosolic acidification is an effector mechanism during drug-induced apoptosis of tumor cells. Here, we report that Bax is critical in determining the sensitivity of tumor cells to H(2)O(2)-induced apoptosis. More importantly, exposure of colorectal carcinoma (HCT116) and leukemia cells (HL60 and CEM) to H(2)O(2) or its intracellular production during drug-induced apoptosis is a signal for mitochondrial translocation of Bax. Furthermore, we provide evidence that drug-induced H(2)O(2)-mediated Bax translocation in tumor cells is caspase independent but involves cytosolic acidification. Inhibiting cytosolic acidification prevents Bax translocation, and contrarily enforced acidification of the intracellular milieu results in mitochondrial recruitment of Bax, even in the absence of a trigger. These findings provide a novel mechanism for mitochondrial translocation of Bax and directly implicate H(2)O(2)-mediated cytosolic acidification in the recruitment of the mitochondrial pathway during drug-induced apoptosis of tumor cells.

Apoptosis↗

PubMed1994

Urinary acidification and urinary excretion of calcium and citrate in women with bilateral medullary sponge kidney.

Urinary acidification ability, acid-base status and urinary excretion of calcium and citrate were evaluated in 10 women with bilateral medullary sponge kidney (MSK) and in 10 healthy women. Patients with MSK had higher fasting urine pH compared to normal controls (p < 0.01). Four patients had incomplete renal tubular acidiosis (iRTA), 3 had hypercalciuria, and 5 patients had hypocitraturia. The 24-hour urinary excretion of calcium was increased in the females with MSK (5.23 +/- 0.78 mmol) compared to the healthy females (3.49 +/- 0.29 mmol) (p < 0.02), and increased in MSK patients with iRTA (7.32 +/- 1.45 mmol) compared to patients with normal urinary acidification (3.83 +/- 0.12 mmol) (p < 0.01). The patients with iRTA had reduced levels of plasma standard bicarbonate (20.5 +/- 1.0) after fasting compared to patients with normal urinary acidification (23.8 +/- 0.8) and healthy women (22.7 +/- 0.6) (p < 0.01), and reduced levels of 24-hour urinary excretion of citrate (0.93 +/- 0.25 mmol) compared to patients with normal urinary acidification (3.58 +/- 0.51) and healthy women (2.78 +/- 0.49) (p < 0.005). A positive correlation was found between the degree of acidosis during ammonium chloride loading and urinary excretion of calcium (r = 0.71, p = 0.02), and a negative correlation between the degree of acidosis during ammonium chloride loading and urinary citrate excretion (r = 0.87, p = 0.001). The results suggest that defective urinary acidification might play an important role in the mechanism of hypercalciuria and hypocitraturia in patients with medullary sponge kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis, Renal Tubular↗

PubMed1983

Characterization of acidification in the cortical and medullary collecting tubule of the rabbit.

Ouabain and lithium decrease acidification in open-circuited bladders by eliminating the electrical gradient favoring acidification. The effect of ouabain and lithium on acidification in cortical and medullary collecting tubules derived from starved New Zealand white rabbits was studied by using the techniques of isolated nephron microperfusion and microcalorimetric determination of total CO2 flux. Bath and perfusion solutions were symmetric throughout all studies, and solutions contained 25 meq of bicarbonate and were bubbled with 93.3% O2/6.7% CO2 gas mixtures. In cortical collecting tubules, ouabain (10(-8) M) addition to bath resulted in a decrease in both potential difference (PD), from -16.4 to -2.2 mV (P less than 0.001), and total CO2 flux (JTCO2), from +6.0 to 1.5 pmol/mm per min (P less than 0.005). In medullary collecting tubules neither PD nor JTCO2 changed with the addition of ouabain in either 10(-8) or 10(-4) M concentration. Replacement of 40 mM NaCl with 40 mM LiCl in both perfusate and bath in cortical collecting tubules resulted in decreases in both PD, from -11.6 to 0.4 mV (P less than 0.005), and JTCO2, from +10.8 to +4.2 pmol/mm per min (P less than 0.025). This substitution had no effect on medullary collecting tubules. When control flux rates were plotted against animal bladder urine pH, both medullary and cortical tubules showed good inverse correlation between these variables, with higher values of flux rate for the medullary tubules. The data support a role for transepithelial PD in acidification in the cortical collecting tubule and also suggest that both cortical and medullary segments of the collecting tubule participate when urinary acidification is increased during starvation in the rabbit.

Acid-Base Equilibrium↗

PubMed2006

Projected climate change impact on oceanic acidification.

BACKGROUND: Anthropogenic CO2 uptake by the ocean decreases the pH of seawater, leading to an 'acidification' which may have potential detrimental consequences on marine organisms. Ocean warming or circulation alterations induced by climate change has the potential to slowdown the rate of acidification of ocean waters by decreasing the amount of CO2 uptake by the ocean. However, a recent study showed that climate change affected the decrease in pH insignificantly. Here, we examine the sensitivity of future oceanic acidification to climate change feedbacks within a coupled atmosphere-ocean model and find that ocean warming dominates the climate change feedbacks. RESULTS: Our results show that the direct decrease in pH due to ocean warming is approximately equal to but opposite in magnitude to the indirect increase in pH associated with ocean warming (ie reduced DIC concentration of the upper ocean caused by lower solubility of CO2). CONCLUSION: As climate change feedbacks on pH approximately cancel, future oceanic acidification will closely follow future atmospheric CO2 concentrations. This suggests the only way to slowdown or mitigate the potential biological consequences of future ocean acidification is to significantly reduce fossil-fuel emissions of CO2 to the atmosphere.

Journal Article↗

PubMed1993

Calcium-mediated intracellular acidification and activation of Na(+)-H+ exchange in adrenal glomerulosa cells stimulated with potassium.

Intracellular pH (pHi) regulation by Na(+)-H+ exchange is important in cellular responses to hormones and growth factors, particularly those which raise cytosolic Ca2+ (Cai). Since elevation of Cai occurs when adrenal glomerulosa cells are stimulated by angiotensin II (Ang II) and high external K+ (Ko), we evaluated the relationship of Na(+)-H+ exchange to calcium movement particularly during high Ko stimulation of bovine glomerulosa cells. Inhibition of Na(+)-H+ exchange by dimethylamiloride markedly reduced aldosterone secretion in response to 8 mM Ko. This high Ko stimulation was accompanied by a rise in dimethylamiloride-sensitive Na+ influx and pHi acidification which was extracellular Ca2+ (Cao) dependent. High Ko also produced a rise in Ca2+ influx, Cai levels and Ca2+ efflux at 37 C. However, at 4 C, Ca2+ influx remained intact, but Ca2+ efflux and cellular acidification were inhibited. In contrast, Ang II produced protein kinase C (PKC) activation accompanied by a Na(+)-H+ exchange-dependent rise in pHi which was independent of Cao. After PKC depletion by phorbol ester pretreatment, Ang II also produced a Cao-dependent cell acidification as with high Ko. Thus, Na(+)-H+ exchange is activated by both Ang II and high Ko but by different mechanisms. High Ko stimulation induces an enhanced cellular acidification, whereas Ang II induces alkalinization driven by PKC activation of the antiporter. These findings suggest that a physiological role of Na(+)-H+ exchange may be, in part, to counteract the acidification produced by enhanced active Ca2+ efflux (via Ca2+ pumping) during both high Ko and Ang II stimulation of aldosterone secretion.

Aldosterone↗

PubMed2000

Direct measurement of hormone-induced acidification in intact bone.

Previous findings have shown that osteoblasts respond to parathyroid hormone (PTH) with an increase in extracellular acidification rate (ECAR) in addition to the known effect of PTH to increase local acidification by osteoclasts. We, therefore, investigated use of the Cytosensor to measure the ECAR response of whole intact bone to PTH employing microphysiometry. The Cytosensor measures a generic metabolic increase of cells to various agents. Using neonatal mouse calvaria, we found that the area surrounding the sagittal suture was particularly responsive to PTH. In this bone, the increase in ECAR was slower to develop (6 minutes) and more persistent than in cultured human osteoblast-like SaOS-2 cells and was preceded by a brief decrease in ECAR. Salmon calcitonin also produced an increase in ECAR in this tissue but with a different pattern than that elicited by PTH. Because PTH stimulates osteoclastic bone resorption in mouse calvaria via a cyclic adenosine monophosphate (cAMP)-mediated mechanism, we showed that the adenylyl cyclase activator forskolin also stimulated ECAR in this tissue. When the protein kinase A (PKA) pathway was activated by maintaining a high intracellular concentration of cAMP using N6-2'-0-dibutyryladenosine-cAMP (db-cAMP), there was a reduction of PTH-induced acidification, while isobutylmethylxanthine pretreatment potentiated the PTH-induced acidification, consistent with a PKA-mediated pathway. Thapsigargin and the protein kinase C (PKC) activator phorbol myristate acetate had no effect on the PTH-induced increase in ECAR in calvaria, indicating that PKC does not play a major role in the ECAR response in intact bone. These results indicate the utility of using microphysiometry to study ECAR responses in intact tissue and should enable elucidation of the relative importance of extracellular acidification by osteoblasts and osteoclasts to the anabolic and catabolic activities of PTH, respectively.

1-Methyl-3-isobutylxanthine↗