Carbonic Anhydrase Inhibitor Sulthiame Reduces Intracellular pH and Epileptiform Activity of Hippocampal CA3 Neurons

Leniger, Tobias; Wiemann, Martin; Bingmann, D.; Widman, Guido; Hufnagel, A.; Bonnet, Udo

doi:10.1046/j.1528-1157.2002.32601.x

Cited by 74 publications

(42 citation statements)

References 33 publications

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“…In our cells, all three CA inhibitors (AZ, BZ, and EZ) resulted in a small but significant acid shift in basal pH i . This is consistent with CA inhibition-induced acidosis described in corneal endothelium (4), nonpigmented ciliary epithelium (52), lactotrophs (11), neuronal cells (19,20), and rat heart, brain, liver, and spleen tissue (36), and rules out the possibility that, at least in the case of highly diffusible EZ, there was a lack of intracellular penetration of the drug. Our findings suggest that CA actively participates in regulation of basal pH i in PASMCs under normal conditions.…”

Section: Discussionsupporting

confidence: 85%

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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Section: Discussionsupporting

confidence: 85%

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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“…In brain tissues, CA inhibition by acetazolamide reduces extracellular pH, probably due to CO 2 retention, and increases intracellular pH in thalamic neurons 9 or decreases it in hippocampal neurons. 7 The change of intracellular pH directly influences neuronal activity and may play a role in seizure termination. Recently, Tricarico et al 12 hypothesized that the therapeutic effects of acetazolamide in hypokalemic periodic paralysis linked to mutations of the ␣1 subunit of the L-type Ca 2ϩ channel are mediated by direct activation of the KCa 2ϩ channel in the sarcolemma of muscles, which is probably independent of the acid-base balance in the environment.…”

Section: Discussionmentioning

confidence: 99%

Acetazolamide acts directly on the human skeletal muscle chloride channel

et al. 2006

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Acetazolamide, a carbonic anhydrase inhibitor, is used empirically in neuromuscular diseases with episodic ataxia, weakness, and myotonia, although not all of the mechanisms responsible for its therapeutic effects are understood. To elucidate whether acetazolamide acts directly on the human skeletal muscle voltage-gated chloride channel (ClC-1), which is associated with myotonia, we evaluated the effects of acetazolamide on ClC-1 expressed in cultured mammalian cells, using whole-cell recording. Acetazolamide significantly shifted the voltage dependency of the open probability (P(o)) toward negative potentials in a dose-dependent manner, resulting in an increase of chloride conductance at voltages near the resting membrane potential. This effect was attenuated when using a pipette solution containing 30 mmol/L Hepes. These results suggest that acetazolamide can influence the voltage-dependent opening gate of ClC-1 through a mechanism related to intracellular acidification by inhibiting carbonic anhydrase, and that the therapeutic effects of acetazolamide in neuromuscular diseases may be mediated by activation of ClC-1.

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“…It is of note that intracellular acidification has also been seen with other anti-epileptics, including acetazolamide and sulthiamine, indicating that exceptions exist to the general schema presented in Fig. 1 (Leniger et al, 2002). …”

Section: Pharmacological Inhibitorsmentioning

confidence: 95%

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Zhao

Carney

Falgoust

et al. 2016

Progress in Neurobiology

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Epilepsy is a common central nervous system (CNS) disease characterized by recurrent transient neurological events occurring due to abnormally excessive or synchronous neuronal activity in the brain. The CNS is affected by systemic acid–base disorders, and epileptic seizures are sensitive indicators of underlying imbalances in cellular pH regulation. Na+/H+ exchangers (NHEs) are a family of membrane transporter proteins actively involved in regulating intracellular and organellar pH by extruding H+ in exchange for Na+ influx. Altering NHE function significantly influences neuronal excitability and plays a role in epilepsy. This review gives an overview of pH regulatory mechanisms in the brain with a special focus on the NHE family and the relationship between epilepsy and dysfunction of NHE isoforms. We first discuss how cells translocate acids and bases across the membrane and establish pH homeostasis as a result of the concerted effort of enzymes and ion transporters. We focus on the specific roles of the NHE family by detailing how the loss of NHE1 in two NHE mutant mice results in enhanced neuronal excitability in these animals. Furthermore, we highlight new findings on the link between mutations of NHE6 and NHE9 and developmental brain disorders including epilepsy, autism, and attention deficit hyperactivity disorder (ADHD). These studies demonstrate the importance of NHE proteins in maintaining H+ homeostasis and their intricate roles in the regulation of neuronal function. A better understanding of the mechanisms underlying NHE1, 6, and 9 dysfunctions in epilepsy formation may advance the development of new epilepsy treatment strategies.

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Carbonic Anhydrase Inhibitor Sulthiame Reduces Intracellular pH and Epileptiform Activity of Hippocampal CA3 Neurons

Cited by 74 publications

References 33 publications

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

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

Acetazolamide acts directly on the human skeletal muscle chloride channel

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

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