A model of two functionally antagonistic receptor populations activated by the same agonist

Szabadi, E.

doi:10.1016/0022-5193(77)90390-3

Cited by 103 publications

(63 citation statements)

References 30 publications

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“…In an attempt to explain the differing slopes, we considered the possibilities that: firstly, the atropine slope is artificially steepened by a vagotonic influence at low dosage, which is overcome by the peripheral anticholinergic action at higher doses; secondly, the hyoscine butylbromide slope is flattened by its faster offset of action. Attempts to model the dose-response curves on this basis, in a manner similar to that proposed by Szabadi (1977), fail. The slope for the anticholinergic action is flattened slightly but insufficiently to parallel that of the adjusted hyoscine butylbromide slope, the combined adjustments accounting for less than half the slope difference.…”

Section: Discussionmentioning

confidence: 99%

Dose‐response relationships of intravenous hyoscine butylbromide and atropine sulphate on heart rate in healthy volunteers.

Grainger¹,

Smith²

1983

Brit J Clinical Pharma

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1 Heart-rate responses to intravenous hyoscine butylbromide, atropine and physiological saline in cumulative dosage regimens have been recorded in six healthy subjects. 2 Atropine sulphate induced bradycardia at low, and tachycardia at higher, dose levels whereas hyoscine butylbromide caused only tachycardia but with a flatter dose-response relationship. 3 Exact potency ratios could not be calculated because of the differing dose-response curves. However, an approximate estimate from a comparison of equiactive doses at the upper part of the curve yielded a value less than one half that obtained from the drugs' affinity constants in guinea-pig ileum. 4 The findings suggest that, in addition to its action as a muscarinic antagonist, hyoscine butylbromide is a ganglion blocker in man as it is in animals.

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Section: Discussionmentioning

confidence: 99%

Dose‐response relationships of intravenous hyoscine butylbromide and atropine sulphate on heart rate in healthy volunteers.

Grainger¹,

Smith²

1983

Brit J Clinical Pharma

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“…According to these authors, many nonmonotonic dose-effect curves can potentially be explained in this way, so there is no basis for assuming that hormesis is underpinned by a single universal mechanism. One of their proposals, following the model proposed by Szabadi [22] , involved two receptors with different affinities for the same ligand and opposing effects on cell physiology (Fig. 1); this could indeed explain certain apparent instances of hormesis, and the authors cited illustrative examples from the literature.…”

Section: The General and The Specific: Hormesis At The Cellular Levelmentioning

confidence: 97%

“…All these changes occur simultaneously at a given stimulus intensity, suggesting a single underlying mechanism, a final common pathway for the various intracellular processes initiated by the diverse stimuli. Mechanisms such as those proposed by Szabadi [22] and by Connolly and Lutz [15] may conceivably lead to, or participate in, such a final common pathway. It has been suggested that hormesis at the cell level is a manifestation of, or is identical to, the UCR [31,32] .…”

Section: The General and The Specific: Hormesis At The Cellular Levelmentioning

confidence: 99%

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Elucidating the Mechanism(s) of Hormesis at the Cellular Level: The Universal Cell Response

Agutter¹

2008

American J. of Pharmacology and Toxicology

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Many environmental stressors elicit biphasic effects from single cells. Such cellular hormesis may be interpreted in terms of (a) the superimposition of simple biochemical processes or (b) the non-specific behaviour of the cell. The latter approach is emphasized in this article and identified with the universal cell response (UCR); however, the importance of identifying molecular-level concomitants of the UCR is also acknowledged. One difficulty is that when the dose of ligand is very low, mass-action assumptions become invalid and reliable analysis of receptor-ligand interactions requires knowledge of the binding mechanism; this difficulty is discussed. The UCR (cellular hormesis) and its possible underlying mechanisms are considered in the framework of a general scheme of cell life, which logically implies cellular homeostasis or homeorhesis. This framework may be particularly helpful for elucidating and perhaps quantifying conditioning hormesis (adaptation to stressors). The findings of studies on the UCR cannot be extrapolated unequivocally to hormesis in whole organisms or populations and cellular-level hormesis cannot be inferred from whole-organism hormesis. Nevertheless, it has been argued that a better understanding of the underlying cellular mechanisms, i.e., of the UCR, may facilitate the analysis of whole-organism and population data.

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“…Introduction is expected to result in the potentiation of the constrictor response [15]. Indeed, some early work indicates that nonThe human dorsal hand vein contains both a-and b-adrenoceptors [1-3].…”

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confidence: 99%

Comparison of the effects of nadolol and bisoprolol on noradrenaline‐evoked venoconstriction in man in vivo

Abdelmawla

Langley

Szabadi

et al. 1998

Brit J Clinical Pharma

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AimsIn an attempt to explore the possible involvement of venodilator b-adrenoceptors in the constrictor response of the human dorsal hand vein to noradrenaline, we examined the ability of nadolol, a non-selective b 1 /b 2 -adrenoceptor antagonist, and bisoprolol a selective b 1 -adrenoceptor antagonist, to potentiate the response. Methods Twelve healthy male volunteers participated in three weekly sessions. In each session nadolol (40 mg), bisoprolol (5 mg ) or placebo was ingested, and (-) noradrenaline acid tartrate (0.33-33.33 ng min −1 ) was infused locally into the dorsal hand vein 2 h after the ingestion of the drugs. Changes in vein diameter were monitored with the dorsal hand vein compliance technique. Subjects were allocated to treatments and sessions according to a double-blind balanced cross-over design. Systolic and diastolic blood pressure, and heart rate were also measured. Results Noradrenaline produced dose-dependent venoconstriction which was antagonized by bisoprolol but remained unaffected by nadolol (ANOVA with repeated measures: F (2, In the present study we compared the effects of is generally acknowledged that venodilator b-adrenoceptors are of the b 2 subtype, the possible involvement of b 1 -pharmacodynamically active small single oral doses [18] of the non-selective b 1 /b 2 -adrenoceptor antagonist, nadolol adrenoceptors has not been excluded [9][10][11][12].The physiological sympathomimetic amine noradrenaline and the selective b 1 -adrenoceptor antagonist, bisoprolol on noradrenaline-evoked venoconstriction in man, using the has affinity for both a-and b-adrenoceptors [9]. Although noradrenaline is a powerful constrictor of the human dorsal dorsal hand vein compliance technique. Our prediction was that if the venoconstrictor response to noradrenaline is hand vein [13][14], it is possible that the constrictor response is attenuated by the activation of masked venodilator attenuated by masked b 2 -adrenoceptors, but not by b 1 -adrenoceptors, nadolol would potentiate the response but b-adrenoceptors. The possible involvement of these masked receptors could be revealed by the use of b-adrenoceptor bisoprolol would be without any effect. On the other hand, if both b 2 -and b 1 -adrenoceptors are involved both antagonists would cause potentiation of the response.

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A model of two functionally antagonistic receptor populations activated by the same agonist

Cited by 103 publications

References 30 publications

Dose‐response relationships of intravenous hyoscine butylbromide and atropine sulphate on heart rate in healthy volunteers.

Dose‐response relationships of intravenous hyoscine butylbromide and atropine sulphate on heart rate in healthy volunteers.

Elucidating the Mechanism(s) of Hormesis at the Cellular Level: The Universal Cell Response

Comparison of the effects of nadolol and bisoprolol on noradrenaline‐evoked venoconstriction in man in vivo

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