Selective depletion of noradrenaline: a proposed mechanism of the adrenergic neurone‐blocking action of bretylium

Abbs, E.T.; Robertson, Michelle

doi:10.1111/j.1476-5381.1970.tb09887.x

Cited by 24 publications

(27 citation statements)

References 13 publications

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“…Previous experiments with bretylium and debrisoquine (Abbs & Robertson, 1970; Robertson & Abbs, 1971;Abbs & Pycock, 1973) support the hypothesis (Abbs, 1966;Carlsson, 1966) that adrenergic neurone-blocking agents may act by a selective displacement of a small 'store' of noradrenaline which is essential for the proper functioning of adrenergic nerves.…”

Section: Introductionsupporting

confidence: 49%

“…Collection and treatment of blood samples for determination of noradrenaline levels in plasma Splenic venous blood was collected before, during, and for 30 s after stimulation of splenic nerves as described by Abbs & Robertson (1970). This technique allowed the determination of 'resting' plasma levels of noradrenaline, plasma levels after drug treatment and the determination of the noradrenaline overflowing into plasma of splenic venous blood in response to nerve stimulation.…”

Section: Preparation Of Animalsmentioning

confidence: 99%

“…Anaesthesia was induced with ether and maintained with chloralose (80 mg/kg, i.v.). The animals were then prepared either for removal of spleens or for collection of splenic venous blood as described by Abbs & Robertson (1970). Blood pressure was recorded routinely from the left femoral artery.…”

Section: Preparation Of Animalsmentioning

confidence: 99%

“…Spleens were removed and fractionated as described by Abbs & Robertson (1970) to produce the P1 (cell debris and mitochondria), P2 (microsomes), S (supernatant layer) and T (unfractionated homogenate) fractions. The fractions were then deproteinized with perchloric acid and stored overnight at -200 C until required for purification and assay.…”

Section: Subcellular Fractionation Of the Spleenmentioning

confidence: 99%

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The Relation Between the Adrenergic Neurone‐blocking and Noradrenaline‐depleting Actions of Some Guanidine Derivatives

Abbs

Dodd

1974

British J Pharmacology

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1 The effects of some guanidine derivatives, (-)-N 1-phenylethyl) guanidine (PEG), guanethidine and debrisoquine have been investigated on the content and subcellular distribution of noradrenaline in cat spleen and on the overflow of noradrenaline from this organ during stimulation of the splenic nerve. 2 PEG and guanethidine, at a dose of 5 mg/kg, produced adrenergic neurone blockade within 15 min and the same dose of debrisoquine produced blockade within 30 minutes. 3 All three compounds produced a decrease of similar magnitude in the noradrenaline content of the high-speed particulate (P2 ) and supernatant (S) fractions of splenic homogenates; these actions were temporally correlated with the adrenergic neurone-blocking action of the compounds. 4 PEG did not produce any further decrease in the noradrenaline content of the subcellular fractions at times up to 18 h after its administration; adrenergic neurone blockade was maintained throughout this period but had disappeared after 7 days when the noradrenaline content of the subcellular fractions was restored to control levels. 5 Guanethidine, in contrast, caused a marked progressive loss of the transmitter from all subcellular fractions-an effect which was maximal 18 h after its administration but continued, as did the adrenergic neurone-blocking action, for at least 72 hours. This additional loss of noradrenaline, over and above that seen after 15 min, is unlikely to be connected with the adrenergic neurone-blocking action of the drug. 6 Dexamphetamine both prevented and antagonized the neurone blockade and the subcellular noradrenaline-depleting action of PEG and guanethidine. The restoration of nerve function after administration of dexamphetamine to animals pretreated with 5 mg/kg of either of these compounds was temporally correlated with a selective repletion of the noradrenaline content of the supernatant fraction of the spleen. 7 Larger doses (15 mg/kg) of PEG or guanethidine produced a selective depletion of noradrenaline in only the supernatant fraction of the spleen. This depletion was temporally correlated with the adrenergic neurone-blocking action of these compounds. The lack of effect of the compounds at this dose level on the noradrenaline contained in the P2 fraction may be due to 'stabilization' of the store of noradrenaline in vivo which gives rise to this fraction on homogenization. 8 It is suggested that the guanidine-type adrenergic neurone-blocking agents displace the noradrenaline which is readily available for release by nerve impulses, and that it is this action that may account for their sympathomimetic properties. 9 The ability of these guanidines to impair the release of noradrenaline by nerve impulses could occur because whilst they are present within the neurone the 'nerve-releasable store', which may in these experiments appear in the supernatant fraction after homogenization, may be unable to refill with transmitter.

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Section: Introductionsupporting

confidence: 49%

Section: Preparation Of Animalsmentioning

confidence: 99%

Section: Preparation Of Animalsmentioning

confidence: 99%

Section: Subcellular Fractionation Of the Spleenmentioning

confidence: 99%

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