Identification of inosine and hypoxanthine as endogenous inhibitors of [3H] diazepam binding in the central nervous system

Skolnick, Phil; Marangos, Paul J.; Goodwin, Frederick K.; Edwards, Mary E.; Paul, Soumen

doi:10.1016/0024-3205(78)90128-5

Cited by 195 publications

(53 citation statements)

References 10 publications

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“…Since endogenous adenosine can be released in the CNS (Mcllwain, 1972) diazepam may also act by potentiating an inhibitory neuromodulating action of adenosine (Phillis, 1979). A role for purines in diazepam action is also implied by the observation that the adenosine metabolites, inosine and hypoxanthine, can compete for the benzodiazepine binding sites (Skolnick et al, 1978). The present study extends these observations and has demonstrated that a diazepam-adenosine interaction exists in peripheral neuroeffector systems.…”

Section: Discussionsupporting

confidence: 72%

“…Firstly, it has been demonstrated that diazepam inhibits adenosine accumulation in brain slices (Mah & Daly, 1976). Secondly, the search for an endogenous ligand for the benzodiazepine binding sites revealed that the adenosine metabolites, inosine and hypoxanthine, could compete with diazepam for the binding sites (Skolnick, Marangos, Goodwin, Edwards & Paul, 1978). In addition, Phillis (1979) has shown that diazepam potentiates the adenosine-induced depression of electrical activity in cortical neurones in ' Present address: Department of Pharmacology, Organon Laboratories Limited, Newhouse, Lanarkshire, MLI 5SH.…”

Section: Introductionmentioning

confidence: 99%

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Potentiation of the Effects of Adenosine on Isolated Cardiac and Smooth Muscle by Diazepam

Clanachan

Marshall

1980

British J Pharmacology

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Adenosine (10−7 to 3 times 10−4 m) or 2‐chloroadenosine (10−8 to 10−5 m) produced concentration‐dependent inhibition of the responses of the rat isolated vas deferens to electrical field stimulation. In electrically driven (2 Hz) guinea‐pig isolated left atria, adenosine (10−6 to 10−3 m) or 2‐chloroadenosine (10−8 to 10−7 m) produced concentration‐dependent decreases in isometric tension. Diazepam (10−6 and 10−5 m) had no direct effect per se, but significantly potentiated the inhibitory action of adenosine on both tissues without altering the inhibitory effect of 2‐chloroadenosine. The adenosine uptake inhibitors, hydroxynitrobenzylthioguanosine (HNBTG, 10−5 m) and dipyridamole (10−5 m) also potentiated the inhibitory actions of adenosine in rat vas deferens, but not those of 2‐chloroadenosine. Following adenosine uptake inhibition in rat vas deferens by HNBTG (10−5 m), diazepam (10−5 m) failed to produce any significant further potentiation of the inhibitory action of adenosine. It is concluded that the potentiation of adenosine by diazepam is possibly due to an inhibition of adenosine uptake.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Potentiation of the Effects of Adenosine on Isolated Cardiac and Smooth Muscle by Diazepam

Clanachan

Marshall

1980

British J Pharmacology

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“…Hypoxanthine has aroused particular interest because of its putative role as an endogenous ligand of benzodiazepine receptors in the brain and its possible role in termination of epileptic activity (8,97,98). It is also an inhibitor of cyclic nucleotide phosphodiesterase in bovine brain tissue (9).…”

Section: Neurochemical Aspects O F Hypoxanthinementioning

confidence: 99%

“…Hypoxanthine seems to play a role in posthypoxic reoxygenation cell injury through oxygen radical production (7) and is therefore involved in the pathogenesis of a number of diseases. Hypoxanthine also modulates a number of other processes because it reacts with benzodiazepine receptors (8) and inhibits phosphodiesterase in the brain (9). Hypoxanthine inhibits the effect of several cytotoxic drugs and may therefore influence treatment with such drugs (10).…”

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confidence: 99%

Hypoxanthine as an Indicator of Hypoxia: Its Role in Health and Disease through Free Radical Production

Saugstad¹

1988

Pediatr Res

379

206

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Hypoxia is a common insult during the perinatal and neonatal period. New and better ways to evaluate hypoxia are needed. In 1975 we demonstrated high concentrations of the purine metabolite hypoxanthine in umbilical cord plasma after intrauterine hypoxia and proposed that hypoxanthine could be used as an indicator of hypoxia (1). Since then a large number of studies have been published dealing with different aspects of hypoxanthine in hypoxia. However, investigators in this field have encountered several methodologic problems: 1) Hypoxanthine leaks rapidly from erythrocytes (2, 3); if plasma is not separated promptly from red cells, falsely elevated plasma hypoxanthine concentrations will be found. 2) There are large variations in purine metabolism among species. 3) No clear definition of clinical hypoxia is available. Many authors do not distinguish between the terms hypoxemia and hypoxia, which adds to the confusion. We define tissue hypoxia as: "oxygen deficiency resulting in altered or interrupted energy metabolism" (4). It is important to be aware that hypoxia has two stages. In the first stage it is compensated because the cells are able to meet energy demands through anaerobic metabolism and other mechanisms. (We are not dealing with physiologic adaptation to hypoxia.) In the second stage of hypoxia or uncompensated hypoxia, energy demands are not met and cell injury ensues. At present there are no techniques for distinguishing between these two stages in clinical medicine, and such a distinction would be useful. Theoretically hypoxanthine should only be elevated in uncompensated hypoxia, while pH and lactate changes occur in compensated hypoxia. It seems, however, that hypoxanthine is also elevated to some extent in uncompensated hypoxia.Renewed interest in hypoxanthine developed when it was realized that hypoxanthine is a potential free radical generator (5, 6). Hypoxanthine seems to play a role in posthypoxic reoxygenation cell injury through oxygen radical production (7) and is therefore involved in the pathogenesis of a number of diseases. Hypoxanthine also modulates a number of other processes because it reacts with benzodiazepine receptors (8) and inhibits phosphodiesterase in the brain (9). Hypoxanthine inhibits the effect of several cytotoxic drugs and may therefore influence treatment with such drugs (10).Herein we summarize the extensive literature on hypoxanthine published during the last decade and try to answer the question: How useful in clinical medicine are hypoxanthine measurements in plasma and other body fluids? Is hypoxanthine a better marker of hypoxia than lactate or pH? Further, we discuss the significance of hypoxanthine as a potential oxygen radical generator and put forward a hypothesis for the pathogenesis of an "oxygen radical disease in neonatology". In hypoxia there is an accelerated breakdown of AMP to hypoxanthine. Figure 1 illustrates several important aspects of hypoxanthine metabolism in hypoxia. Normally about 90% of the hypoxanthine formed is reutilized through the sa...

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“…A variety of endogenous ligands for the benzodiazepine binding sites have been proposed (Skolnick et al, 1978;Marangos et al, 1979;Braestrup et al, 1980;Massotti & Guidotti, 1980;Davies & Cohen 1980;Woolf & Nixon 1981) ranging in nature from purines to high molecular weight proteins. An involvement of purines in the actions of benzodiazepines has been suggested and Phillis and his coworkers (Bender et al, 1980b;Phillis et al, 1980;Wu et al, 1981); have proposed that inhibition of adenosine uptake could be involved in some of the pharmacological effects of benzodiazepines.…”

Section: Introductionmentioning

confidence: 99%

Benzodiazepines modulate the A₂ adenosine binding sites on 108CC15 neuroblastoma × glioma hybrid cells

Snell

1984

British J Pharmacology

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Identification of inosine and hypoxanthine as endogenous inhibitors of [3H] diazepam binding in the central nervous system

Cited by 195 publications

References 10 publications

Potentiation of the Effects of Adenosine on Isolated Cardiac and Smooth Muscle by Diazepam

Potentiation of the Effects of Adenosine on Isolated Cardiac and Smooth Muscle by Diazepam

Hypoxanthine as an Indicator of Hypoxia: Its Role in Health and Disease through Free Radical Production

Benzodiazepines modulate the A₂ adenosine binding sites on 108CC15 neuroblastoma × glioma hybrid cells

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Identification of inosine and hypoxanthine as endogenous inhibitors of [3H] diazepam binding in the central nervous system

Cited by 195 publications

References 10 publications

Potentiation of the Effects of Adenosine on Isolated Cardiac and Smooth Muscle by Diazepam

Potentiation of the Effects of Adenosine on Isolated Cardiac and Smooth Muscle by Diazepam

Hypoxanthine as an Indicator of Hypoxia: Its Role in Health and Disease through Free Radical Production

Benzodiazepines modulate the A2 adenosine binding sites on 108CC15 neuroblastoma × glioma hybrid cells

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Benzodiazepines modulate the A₂ adenosine binding sites on 108CC15 neuroblastoma × glioma hybrid cells