Carbonic anhydrase inhibition and brain electrolyte composition

Koch, Alan; Woodbury, Dixon M.

doi:10.1152/ajplegacy.1960.198.2.434

Cited by 58 publications

(24 citation statements)

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“…The chloride space as a measure of brain ECF is still accepted by some workers and was used recently by Woodbury, Koch, and Brodie (4,13) in studies of brain intracellular pH in rats. Davson and Spaziani (6) found a chloride space of 32%o 5 for rat brain slices, but after washing out the specimens with a nitrate solution, 10%o of the chloride remained in the tissue.…”

Section: Discussionmentioning

confidence: 99%

“…These findings were interpreted as indicating that the upper limit of the true ECF is only 22%o, some 10%o of the chloride being intracellular. Allen (14) (4). Recently, Brodie and Woodbury (13), using the latter system, found the initra-cellular pH of rat brain cortex to be 7.04 U, representing a cell to plasma gradient of 0.37 pH U.…”

Section: Discussionmentioning

confidence: 99%

“…Employing the H2CO3-HCO3-systems, Koch and Woodbury (4) found that brain pH dropped 0.06 U when plasma pH was reduced 0.22 U by maintaining rats in an atmosphere containing 12.57% CO2 for 10 minutes. Results comparable to the present ones were obtained by Brodie and Woodbury (13) with the use of 30%o CO2 and an exposure time of 15 minutes.…”

Section: Discussionmentioning

confidence: 99%

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Intracellular Acid-Base Relations of Dog Brain with Reference to the Brain Extracellular Volume *

Kibler¹,

O’Neill²,

Robin³

1964

J. Clin. Invest.

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There is now abundant evidence that a substantial hydrogen ion gradient exists between extracellular and intracellular water. The mechanism maintaining this gradient is not known, but for most cells it does not appear to be a function of simple Gibbs-Donnan equilibrium. Moreover, under a variety of circumstances, changes in the pH of one fluid compartment may occur without producing comparable changes in the other (1). Apparently, therefore, studies of acid-base metabolism cannot be restricted just to a consideration of extracellular hydrogen ion concentration but should include independent estimates of the pH changes within cells.In vivo studies of intracellular pH in the mammalian species have dealt largely with muscle and erythrocytes. Recently, estimates of whole body intracellular pH have been made in dogs and in humans by the 5,5-dimethyl-2,4-oxazolidinedione (DMO) technique (2, 3), and the pH of brain cells has been measured in rats by the H2CO3-HC03-system (4). However, no systematic study has appeared concerning acid-base regulation in brain cells. In our study the effects of various experimental modifications of extracellular pH on the intracellular pH of brain have been determined in dogs by the DMO technique.The DMO method, first introduced by Waddell and Butler for the indirect measurement of the internal pH of muscle cells (5) ECF nor any agreement concerning the substance to be used in determining brain ECF, we used both endogenous chloride and radiolabeled sulfate spaces as estimates of the extracellular fluid space of the brain. The data obtained in these studies have proven to be relevant not only to acid-base metabolism in the brain but also to the problem of the magniitude of brain extracellular volume. Materials and MethodsDog experiments. Forty-three adult, mongrel dogs weighing between 10 and 14 kg were studied. Each dog was anesthetized with sodium phenobarbital in a dose of 125 mg per kg. After insertion of an endotracheal tube, spontaneous ventilation was abolished with iv succinyl choline and artificial ventilation maintained with either an Etsten or Harvard pump set to deliver approximately 4 L of room air per minute. The kidneys were mobilized through an extraperitoneal approach, and the renal pedicles, including blood vessels and ureters, were ligated. Indwelling polyethylene catheters were placed in a femoral artery and an external jugular vein. The animal's scalp and underlying musculature were "peeled" off the skull, and the left posterior aspect of the bony calvaria was rongeured away. After the exposed dura was excised, from the occipital pole of the left cerebral hemisphere approximately three g of tissue was dissected with a sharp knife. Gel foam was placed in the wound and the cranial defect covered with dry gauze. Bleeding eventually stopped spontaneously after an estimated blood loss of approximately 15 ml. Simultaneous with biopsy of the brain, 30 ml of heparinized arterial blood was collected for chemical analysis. Over a 10-minute period 1.5 g DMO in 30 ml of 5%o glucos...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Intracellular Acid-Base Relations of Dog Brain with Reference to the Brain Extracellular Volume *

Kibler¹,

O’Neill²,

Robin³

1964

J. Clin. Invest.

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“…AZM inhibits >99% of brain carbonic anhydrase (75). Inhibition of brain carbonic anhydrase leads to an increase in total CO, concentration in neurons and a increase in the pH and a decrease in the HCO,-concentration within neuroglia.…”

Section: Acetazolamidementioning

confidence: 99%

The Pharmacologic Basis of Antiepileptic Drug Action

1999

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Summary:The development of medications used in the treatment of epilepsy has accelerated over the past decade, and has benefited from a parallel growth in our knowledge of the basic mechanisms underlying neuronal excitability and synchronization. This understanding of the pharmacologic basis of antiepileptic drug (AED) action has, in large part, arisen from recent advances in cellular and molecular biology, coupled with avenues of drug discovery that have departed somewhat from the largely empiric approaches of the past. Physicians now have available to them an ever-growing armentarium of AEDs, neTherapy with antiepileptic drugs (AEDs) remains the mainstay of treatment of patients with epilepsy. Before the Victorian era, therapeutic approaches to epilepsy were largely based on superstition and charlatanism. The first demonstrably effective chemotherapy relied on the use of nonspecific depressants of the central nervous system. Sir Charles Locock introduced bromides in the mid-nineteenth century for the treatment of catamenial epilepsies, and phenobarbital (PB) was adopted in 1912 after the observations of Hauptmann (l), who used that compound to sedate a ward of noisy psychiatric patients and those with epilepsy during the night. Introduction of more specific AEDs for clinical application followed the availability of the first animal-seizure model: the maximal electroshock (MES) model (2). The history of AED design has recently been reviewed in some detail (3).The relation of the human epilepsies to the animal models commonly used for AED development, and to the cellular membrane physiology underlying neuronal excitability, continues to be an imperfect one (Fig. 1) cessitating a firmer appreciation of their mechanisms of action if more rational approaches toward both clinical application and research are to be adopted. An important example in this regard is the concept of rational polypharmacy for patients with epilepsy who are refractory to monotherapy. This review summarizes our current understanding of the molecular targets of clinically significant AEDs, comparing and contrasting their differing mechanisms of action. Key Words: Antiepileptic drug-AED-Anticonvulsant-Mechanism-%-zure-Epilepsy-Ion channel.threshold pentylenetetrazol (PTZ) test in mice (see Table 1) have been carefully standardized (4). The MES model has served to identify AEDs that are functionally similar to phenytoin (PHT), and most of these compounds display in common the ability to inactivate voltage-dependent Na+ channels in a use-dependent fashion. Such compounds suppress sustained repetitive firing in cultured neurons. Activity in this model seems highly predictive of the ability of those AEDs to protect against partial and secondarily generalized tonic-clonic seizures (Fig. 2). Carbamazepine (CBZ), as well as several newer agents such as felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), and topiramate (TPM), fit this model of AED activity. Some of these (i.e., PHT, CBZ, LTG) may also attenuate the release of excitatory neurotransmi...

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“…2 and 3 are the respective semilogarithmic plots for "Na brain and nerve exchange. The ordinate is the function 1-24Na Space/TES, where TES is the 'theoretical equilibrium space' for sodium in brain or nerve which should be equal to the ratio of the chemically determined value of the tissue sodium concentration to the plasma water sodium concentration (Ames, Sakanove & Endo, 1964;Ferguson'& Woodbury, 1969;Hanig & Aprison, 1967;Koch & Woodbury, 1960;Lowry et al' 1946;Luciano, 1968;Reed et at. 1964).…”

Section: Victor Levin and Clifford S Patlakmentioning

confidence: 99%

A compartmental analysis of ²⁴Na kinetics in rat cerebrum, sciatic nerve and cerebrospinal fluid

Levin¹,

Patlak²

1972

The Journal of Physiology

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SUMMARY1. The kinetics of 24Na exchange in rat cerebrospinal fluid, brain and sciatic nerve were studied during steady-state plasma isotope conditions. The entrance of 24Na into brain and sciatic nerve was found to fit a three compartmental model. Using newly derived equations for compartmental analysis, the first compartment 24Na space of brain was found to be about 22 % and the second compartment space about 6 %; the corresponding sciatic nerve spaces were 26 and 11 %, respectively. In the discussion, arguments are presented that suggest that the first compartment is the extracellular space (ECS) and the second compartment is the intracellular space. The tj for compartmental equilibration between plasma and brain ECS was 2 hr and from ECS to intracellular space 14 hr; in nerve the respective ti's were i hr and 10 hr.2. A third compartment of 18 % was found in sciatic nerve which was interpreted to be anatomically confined to the epi-and perineurium; in brain the corresponding space was 2 % and was felt to be anatomically and kinetically an inactive closed compartment in parallel with the blood.3. There were two tj's for plasma-c.s.f. 24Na equilibration of less than 10 min and 2 hr.4. Profiles of brain, from cortex to ventricle, at 6 min, demonstrated a gradient of decreasing 24Na radioactivity from ventricle to cortex.

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Carbonic anhydrase inhibition and brain electrolyte composition

Cited by 58 publications

References 0 publications

Intracellular Acid-Base Relations of Dog Brain with Reference to the Brain Extracellular Volume *

Intracellular Acid-Base Relations of Dog Brain with Reference to the Brain Extracellular Volume *

The Pharmacologic Basis of Antiepileptic Drug Action

A compartmental analysis of ²⁴Na kinetics in rat cerebrum, sciatic nerve and cerebrospinal fluid

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Carbonic anhydrase inhibition and brain electrolyte composition

Cited by 58 publications

References 0 publications

Intracellular Acid-Base Relations of Dog Brain with Reference to the Brain Extracellular Volume *

Intracellular Acid-Base Relations of Dog Brain with Reference to the Brain Extracellular Volume *

The Pharmacologic Basis of Antiepileptic Drug Action

A compartmental analysis of 24Na kinetics in rat cerebrum, sciatic nerve and cerebrospinal fluid

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Product

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A compartmental analysis of ²⁴Na kinetics in rat cerebrum, sciatic nerve and cerebrospinal fluid