Uptake of quaternary ammonium compounds into rat liver plasma membrane vesicles

Ruifrok, Peter G.

doi:10.1016/0006-2952(82)90039-9

Cited by 11 publications

(3 citation statements)

References 14 publications

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“…We have previously suggested that Nmethylatropine might be a substrate for a quaternary ammonium uptake system . However, as in our previous study, using the lumen-perfused mouse stomach assay, the biochemically-defined uptake inhibitor (Ruifrok, 1982), taurocholate, and the potential alternative substrates, hexamethonium and choline, were ineffective. However, the ability to estimate log[A50] values in the presence of high concentrations of N-methylatropine, seemingly when the uptake process was saturated, did allow a pKB value (9.58 + 0.07) to be estimated which agreed with values previously found .…”

Section: Discussionsupporting

confidence: 60%

“…Taurocholate (100pM), a recognized inhibitor of quaternary ammonium ion uptake in biochemical systems (Ruifrok, 1982) and hexamethonium (100pM), a potential alternative substrate, had no effect on the Schild plot (Figure 3b). Similarly, choline (100#M), a quaternary base with its own specific uptake process, did not affect the profile of antagonism (Figure 3b).…”

Section: M3-receptorsmentioning

confidence: 99%

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Pharmacological analysis of agonist‐antagonist interactions at acetylcholine muscarinic receptors in a new urinary bladder assay

Durant

Shankley²,

Welsh

et al. 1991

British J Pharmacology

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1 Agonist-antagonist interactions at acetylcholine (ACh) muscarinic receptors have been analysed by use of an improved urinary bladder assay, isolated and intact, from the mouse. With 5-methylfurmethide as agonist, validated cumulative concentration-effect curves were obtained in less than 7 min by re-dosing before the response plateaux began to fade.2 The pKB value estimated for pirenzepine was 6.76. The pKB values estimated for atropine and Nmethylatropine from data obtained at concentrations which produced dose-ratios greater than 20 and 60 were 8.90 and 9.58, respectively. 3 The deviation from simple competitive behaviour at low dose-ratios with atropine and Nmethylatropine was consistent with the operation of saturable antagonist removal processes. The deviation observed with atropine was corrected by pre-incubation with methylbutyrate, an alternative substrate for 'atropine esterase'. 4 The simple competitive behaviour of N-methylatropine was restored following pre-incubation with the neuronal choline uptake blocker hemicholinium-3 (HC-3). However, the pK, estimated for Nmethylatropine under these conditions was low. This latter result could be accounted for by the observed behaviour of HC-3 as a competitive antagonist of ACh muscarinic receptors (pK4 = 4.01). 5 We conclude that the modified mouse urinary bladder assay is suitable for the quantitative analysis of muscarinic receptor interactions. In addition, we postulate the existence of a previously undescribed uptake mechanism for quaternary muscarinic receptor antagonists.

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Section: Discussionsupporting

confidence: 60%

Section: M3-receptorsmentioning

confidence: 99%

Pharmacological analysis of agonist‐antagonist interactions at acetylcholine muscarinic receptors in a new urinary bladder assay

Durant

Shankley²,

Welsh

et al. 1991

British J Pharmacology

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“…Preliminary attempts have been made to explore this hypothesis with the ultimate aim of blocking the removal process so that competitive behaviour is achieved over the full concentration range of N-methylatropine. Taurocholic acid 5 mM has been found (Ruifrok, 1982) to decrease the uptake of quaternary ammonium compounds, including Nmethylatropine, into rat liver plasma membranes, but its use to block a similar process in the mouse stomach assay was precluded because this agent also inhibited 5mef control responses.…”

Section: When Investigating Agonist-antagonist Interactions Itmentioning

confidence: 99%

Pharmacological analysis of muscarinic receptors coupled to oxyntic cell secretion in the mouse stomach

Black¹,

Shankley²

1985

British J Pharmacology

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1 In the light of recent attempts to subclassify muscarinic receptors, agonist-antagonist interactions at muscarinic receptors have been re-examined using improved techniques, on the mouse, isolated, lumen-perfused stomach gastric acid assay.2 Using 5-methylfurmethide as the muscarinic agonist, the pKB estimated for atropine was significantly lower on the stomach assay (7.78) than on the guinea-pig trachea (8.93). However pKB values for N-methylatropine, the quaternary ammonium derivative of atropine, at concentrations producing dose-ratios above 20 on the stomach assay (pKB = 9.67), and over the full concentration range studied on the trachea (pKB = 9.69) were not significantly different.3 The deviation from simple competitive behaviour at low dose-ratios with N-methylatropine in the stomach assay is consistent with the effects of a saturable uptake mechanism for quaternary ammonium compounds. 4 The pKB values for pirenzepine on the stomach (6.67) and the trachea (6.87) were not significantly different suggesting that pirenzepine behaves more like N-methylatropine in terms of expressed affinity. 5 We conclude that the oxyntic cell muscarinic receptors are homogeneous with those in the guineapig trachea. An initial exploration suggests that there is a relationship between the lipophilicity (log P) of the antagonists and the degree of apparent underestimation of antagonist affinity in the stomach assay. This supports the hypothesis that the underestimation of antagonist affinity is due to the loss of antagonist into the gastric secretion from the receptor compartment. Apparently, relatively selective inhibition of acid secretion, compared to atropine, could be explained without the need to postulate heterogeneity of muscarinic receptor populations.

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Transport and Metabolism in the Hepatobiliary System

Meijer

1989

Comprehensive Physiology

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Uptake of quaternary ammonium compounds into rat liver plasma membrane vesicles

Cited by 11 publications

References 14 publications

Pharmacological analysis of agonist‐antagonist interactions at acetylcholine muscarinic receptors in a new urinary bladder assay

Pharmacological analysis of agonist‐antagonist interactions at acetylcholine muscarinic receptors in a new urinary bladder assay

Pharmacological analysis of muscarinic receptors coupled to oxyntic cell secretion in the mouse stomach

Transport and Metabolism in the Hepatobiliary System

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