Measurement of intracellular pH with microelectrodes in rat kidney in vivo

Henderson, Ronald W.; Bell, Pamela; Cohen, Robert; Browning, Colm; Iles, Richard A.

doi:10.1152/ajprenal.1986.250.2.f203

Cited by 13 publications

(10 citation statements)

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“…Relatively few studies have focused on the effects of inhibition of CA on intracellular pH. In agreement with our findings, CA inhibitors were reported to increase intracellular pH in kidney cells (Henderson et al, 1986), choroids plexus epithelial cells (Johanson and Murphy, 1990), and submandibular gland cells (Pirani et al, 1987). Further, CAII was shown to play a major role in osteoclast differentiation and bone resorption by its effect on the steady state of intracellular pH (Lehenkari et al, 1998).…”

Section: Discussionsupporting

confidence: 90%

Carbonic anhydrase II regulates differentiation of ameloblasts via intracellular pH‐dependent JNK signaling pathway

Wang

Suzawa

Ohtsuka

et al. 2010

Journal Cellular Physiology

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Differentiation of ameloblasts from undifferentiated epithelial cells is controlled by diverse growth factors, as well as interactions between epithelium and mesenchyme. However, there is a considerable lack of knowledge regarding the precise mechanisms that control ameloblast differentiation and enamel biomineralization. We found that the expression level of carbonic anhydrase II (CAII) is strongly up-regulated in parallel with differentiation of enamel epithelium tissues, while the enzyme activity of CA was also increased along with differentiation in ameloblast primary cultures. The expression level of amelogenin, a marker of secretory-stage ameloblasts, was enhanced by ethoxzolamide (EZA), a CA inhibitor, as well as CAII antisense (CAIIAS), whereas the expression of enamel matrix serine proteinase-1 (EMSP-1), a marker for maturation-stage ameloblasts, was suppressed by both. These agents also promoted ameloblast proliferation. In addition, inhibition of ameloblast differentiation by EZA and CAIIAS was confirmed using tooth germ organ cultures. Furthermore, EZA and CAIIAS elevated intracellular pH in ameloblasts, while experimental decreases in intracellular pH abolished the effect of CAIIAS on ameloblasts and triggered the activation of c-Jun N-terminal kinase (JNK). SP600125, a JNK inhibitor, abrogated the response of ameloblasts to an experimental decrease in intracellular pH, while the inhibition of JNK also impaired ameloblast differentiation. These results suggest a novel role for CAII during amelogenesis, that is, controlling the differentiation of ameloblasts. Regulation of intracellular pH, followed by activation of the JNK signaling pathway, may be responsible for the effects of CAII on ameloblasts.

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Section: Discussionsupporting

confidence: 90%

Carbonic anhydrase II regulates differentiation of ameloblasts via intracellular pH‐dependent JNK signaling pathway

Wang

Suzawa

Ohtsuka

et al. 2010

Journal Cellular Physiology

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“…We found that AZ had no effect on resting E m in our cells, results consistent with findings in rat kidney (14). The lack of a measurable effect of AZ on E m was not due to an inability to detect hyperpolarization in our system, as a decrease in cell fluorescence was readily observed in response to pinacidil, a K ϩ channel activator.…”

Section: Discussionsupporting

confidence: 89%

Inhibition of hypoxia-induced calcium responses in pulmonary arterial smooth muscle by acetazolamide is independent of carbonic anhydrase inhibition

Shimoda¹,

Luke

Sylvester³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Hypoxic pulmonary vasoconstriction (HPV) occurs with ascent to high altitude and can contribute to development of high altitude pulmonary edema (HAPE). Vascular smooth muscle contains carbonic anhydrase (CA), and acetazolamide (AZ), a CA inhibitor, blunts HPV and might be useful in the prevention of HAPE. The mechanism by which AZ impairs HPV is uncertain. Originally developed as a diuretic, AZ also has direct effects on systemic vascular smooth muscle, including modulation of pH and membrane potential; however, the effect of AZ on pulmonary arterial smooth muscle cells (PASMCs) is unknown. Since HPV requires Ca2+ influx into PASMCs and can be modulated by pH, we hypothesized that AZ alters hypoxia-induced changes in PASMC intracellular pH (pH(i)) or Ca2+ concentration ([Ca2+](i)). Using fluorescent microscopy, we tested the effect of AZ as well as two other potent CA inhibitors, benzolamide and ethoxzolamide, which exhibit low and high membrane permeability, respectively, on hypoxia-induced responses in PASMCs. Hypoxia caused a significant increase in [Ca2+](i) but no change in pH(i). All three CA inhibitors slightly decreased basal pH(i), but only AZ caused a concentration-dependent decrease in the [Ca2+](i) response to hypoxia. AZ had no effect on the KCl-induced increase in [Ca2+](i) or membrane potential. N-methyl-AZ, a synthesized compound lacking the unsubstituted sulfonamide group required for CA inhibition, had no effect on pH(i) but inhibited hypoxia-induced Ca2+ responses. These results suggest that AZ attenuates HPV by selectively inhibiting hypoxia-induced Ca2+ responses via a mechanism independent of CA inhibition, changes in pH(i), or membrane potential.

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“…In agreement with our findings, acetazolamide has also been reported to increase pH i in turtle bladder cells, 18 kidney cells, 19 choroid plexus epithelial cells, 20 and the mandibular gland. 21 Under different conditions and in different cells, acetazolamide has also been reported to decrease 22 or have no effect 23 on pH i .…”

Section: Carbonic Anhydrase Inhibition and Ph Isupporting

confidence: 93%

“…26 Others found the same acetazolamide-induced inhibition of renal Cl/HCO 3 exchange in vivo and suggested that in the presence of acetazolamide, H ϩ extrusion continues, but the rate of reaction of OH Ϫ with CO 2 is diminished as a result of carbonic anhydrase inhibition. 19,27 In our experiments the hydrophilic benzolamide was approximately as effective as acetazolamide and ethoxzolamide, indicating that inhibition of the extracellular membrane-bound form of carbonic anhydrase is responsible for the intracellular alkalinization, K Ca channel activation, and vasorelaxation. It is unclear how inhibition of this enzyme can mediate changes in pH i , but it seems possible that this extracellular enzyme might modulate Cl/HCO 3 exchange, resulting in an attenuated HCO 3 extrusion and increase in pH i .…”

Section: Carbonic Anhydrase Inhibition and Ph Imentioning

confidence: 53%

Inhibition of Carbonic Anhydrase Accounts for the Direct Vascular Effects of Hydrochlorothiazide

et al. 1999

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Abstract-Hydrochlorothiazide has been shown to exert direct vasodilator effects by activation of calcium-activated potassium (K Ca ) channels in human and guinea pig isolated resistance arteries. Since hydrochlorothiazide binds to and inhibits the enzyme carbonic anhydrase and because K Ca channel activation is pH sensitive, we investigated the role of intracellular and extracellular carbonic anhydrase in the vascular effects of thiazide diuretics. Small arteries were isolated from guinea pig mesentery and studied by use of a microvascular myograph technique. In some experiments, tone and intracellular pH (pH i ) were measured simultaneously with 2Ј,7Ј-bis(2-carboxyethyl)-5(6)Ј-carboxyfluorescein (BCECF-AM). Bendroflumethiazide, a thiazide diuretic with minimal inhibitory effects on carbonic anhydrase, had little effect on noradrenaline-induced tone (16Ϯ8% relaxation) compared with hydrochlorothiazide (74Ϯ12% relaxation). In contrast to hydrochlorothiazide, the action of bendroflumethiazide was unaffected by 100 nmol/L charybdotoxin, a selective blocker of K Ca channels. All inhibitors of carbonic anhydrase relaxed noradrenaline-induced tone in a concentration-dependent manner, and this effect was blocked by charybdotoxin. Key Words: hydrochlorothiazide Ⅲ carbonic anhydrase inhibition Ⅲ muscle, smooth, vascular Ⅲ pH i Ⅲ potassium channels T hiazide diuretics were developed in the 1950s by chemical modification of carbonic anhydrase inhibitors. Although their blood pressure-lowering effects have been well documented, their mechanism of action is still not fully resolved. The principal site of action of thiazides is the early segment of the distal nephron, where they inhibit a luminal transmembrane-coupled NaCl transport system. In the long term, thiazides act by reducing peripheral resistance rather than by their diuretic effects, 1 and therefore a direct vascular effect has been proposed.Previous studies in isolated human and guinea pig resistance arteries have established a direct vasodilator activity of hydrochlorothiazide. This vasorelaxant response to hydrochlorothiazide was abolished by charybdotoxin and iberiotoxin, both selective blockers of large-conductance Ca 2ϩ -activated potassium (K Ca ) channels, but not by inhibitors of other vascular K ϩ channels. 2 On the basis of the fact that thiazide-like drugs such as cicletanine and diazoxide lead to hyperpolarization in vascular smooth muscle cells 3 and the fact that hydrochlorothiazide increases 86 Rb efflux as a marker of K ϩ efflux, 2,4 it was proposed that hydrochlorothiazide opens K Ca channels, thereby leading to K ϩ efflux and membrane hyperpolarization. The resultant closure of voltage-dependent Ca 2ϩ channels leads to a fall in [Ca 2ϩ ] i and vasorelaxation. 5 In addition to [Ca 2ϩ ] i , the open state probability of the K Ca channel is also modulated by intracellular pH (pH i ). Channel opening is inhibited by intracellular acidosis in carotid body cells, 6 while in isolated blood vessels intracellular alkalinization leads to relaxation asso...

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Measurement of intracellular pH with microelectrodes in rat kidney in vivo

Cited by 13 publications

References 0 publications

Carbonic anhydrase II regulates differentiation of ameloblasts via intracellular pH‐dependent JNK signaling pathway

Carbonic anhydrase II regulates differentiation of ameloblasts via intracellular pH‐dependent JNK signaling pathway

Inhibition of hypoxia-induced calcium responses in pulmonary arterial smooth muscle by acetazolamide is independent of carbonic anhydrase inhibition

Inhibition of Carbonic Anhydrase Accounts for the Direct Vascular Effects of Hydrochlorothiazide

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