I. Development and first check of a new model of functional synergism and antagonism

Brink, F.G. Van Den

doi:10.1016/0014-2999(73)90026-5

Cited by 78 publications

(30 citation statements)

References 3 publications

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“…The adrenoceptor reserve is insufficient to cope with the cholinoceptor stimulus. Once this reserve is exhausted a reduction of the maximum attainable response ensues (Van den Brink, 1973). The dose-response curve is therefore displaced in a fashion resembling irreversible antagonism.…”

Section: Calculation Of Dissociation Constants (Ka)mentioning

confidence: 99%

“…However, this measure is not sufficient for characterization of the receptors by the use of agonists, the individual contributions of both the affinity (measured as the dissociation constant) and the relative efficacy must be determined (Jenkinson, 1973: Triggle & Triggle, 1976 Brink, 1973;Buckner & Saini, 1975). In the present paper we have applied the latter method to several full and partial agonists at f-adrenoceptors of isolated left and right guinea-pig atria and have extended it to determine additionally their relative efficacies.…”

Section: Introductionmentioning

confidence: 99%

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Functional Antagonism as a Means of Determining Dissociation Constants and Relative Efficacies of Sympathomimetic Amines in Guinea‐pig Isolated Atria

Broadley

Nicholson

1979

British J Pharmacology

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I The positive inotropic and chronotropic responses to sympathomimetic amines were examined in guinea-pig isolated atria.2 The order of potency measured from EC3o values was isoprenaline > orciprenaline > salbutamol > fenoterol > terbutaline. Terbutaline and salbutamol were partial agonists on rate and together with orciprenaline and fenoterol also on tension responses. 3 Functional antagonism by carbachol caused a rightwards shift of the dose-response curve and depression of the maximum response. The rate maxima for orciprenaline, fenoterol and terbutaline were above that of isoprenaline. All the tension maxima were below isoprenaline. 4 Dissociation constants (KA) and relative efficacies (er) were determined by analogy with irreversible antagonism. 5 The relative orders of affinity (KA) were isoprenaline > orciprenaline > fenoterol > salbutamol > terbutaline. Affinities were identical on rate and tension. 6 The relative efficacies were all greater than isoprenaline for rate responses. On tension they were the same or less than isoprenaline. 7 The implications of these results are discussed, in particular the fact that a partial agonist has a greater efficacy than a full agonist.

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Section: Calculation Of Dissociation Constants (Ka)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional Antagonism as a Means of Determining Dissociation Constants and Relative Efficacies of Sympathomimetic Amines in Guinea‐pig Isolated Atria

Broadley

Nicholson

1979

British J Pharmacology

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“…This differential ability of L-arginine to reverse histamineinduced contractile responses compared with its effect on the histamine concentrationeffect curve is analogous to the inability of the beta 2 -adrenoceptor agonist, salbutamol, to shift the concentration-effect curves to acetylcholine in human bronchus at concentrations which reversed acetylcholine-induced contractile responses (10) and of the phosphodiesterase type IV inhibitor, Ro 20-1724, to shift the concentration-effect curve to capsaicin in guinea-pig isolated trachea at concentrations which reversed capsaicin-induced contractile responses (11). These findings can be explained in terms of functional antagonism (12,13). Thus, if the receptorsubeffect response relationship to L-arginine has a much lower reserve than for histamine then one may expect only minimal antagonism of the concentration-effect curve for histamine.…”

Section: Discussionmentioning

confidence: 86%

The effect of L-arginine on guinea-pig and rabbit airway smooth muscle function in vitro

Perez

Paul

Harrison

et al. 1998

Braz J Med Biol Res

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We have investigated the effects of L-arginine, D-arginine and Llysine on airway smooth muscle responsiveness to spasmogens in vitro. Both L-arginine and D-arginine (100 mM) significantly reduced the contractile potency and maximal contractile response to histamine but not to methacholine or potassium chloride in guinea-pig epithelium-denuded isolated trachea. Similarly, the contractile response to histamine was significantly reduced by L-arginine (100 mM) in rabbit epithelium-denuded isolated bronchus. The amino acid L-lysine (100 mM) failed to significantly alter the contractile potency of histamine in guinea-pig isolated trachea (P>0.05). In guinea-pig isolated trachea precontracted with histamine, both L-arginine and D-arginine produced a concentration-dependent relaxation which was not significantly altered by epithelium removal or by the presence of the nitric oxide synthase inhibitor, N G -nitro L-arginine methyl ester (L-NAME; 50 µM). Thus, at very high concentrations, arginine exhibit a noncompetitive antagonism of histamine-induced contraction of isolated airway preparations that was independent of the generation of nitric oxide and was not dependent on charge. These observations confirm previous studies of cutaneous permeability responses and of contractile responses of guinea-pig isolated ileal smooth muscle. Taken together, the data suggest that high concentrations of arginine can exert an anti-histamine effect.

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“…However, Van den Brink pointed out that the over-all picture of experimental functional antagonism (isoproterenol-methacoline on calf trachea) was quite different from that calculated with Eq. 1, and postulated a new model of functional interaction allowing the concept of receptor reserve (2). In this paper, another possible explanation is presented, and equations that can explain the experimental dose-response curve of functional antagonism between an adrenergic stimulant and a spasmogen, are introduced.…”

Section: Studies On the Mode Of Antagonism Between Adrenergic β-Mimetmentioning

confidence: 99%

STUDIES ON THE MODE OF ANTAGONISM BETWEEN ADRENERGIC Β-Mimetics AND Β-Blocking AGENTS (III) FUNCTIONAL ANTAGONISM BETWEEN Β-Mimetics AND SPASMOGENS

Ohashi

1976

Japanese Journal of Pharmacology

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Abstract-New equations which can explain the following characteristic phenomena in the functional antagonism between isoproterenol (ISO) and spasmogens in guinea -pig trachea are proposed: (1) The amplitude of relaxation of the muscle induced by ISO varied depending on the concentration of a spasmogen used (histamine or car bachol). (2) The dose-response curves for the relaxation by ISO shifted to the right in a parallel manner as the concentration of the spasmogen increased, and became station ary at higher concentrations of the spasmogen. (3) The slope of the dose-response curve became steeper with increasing concentrations of the spasmogen.When the saturable uptake process of ISO was taken into consideration, a satisfactory parallel was seen between the theoretical dose-response curves and the present experimental results. where El,,, and EIIB are the individual effects of A and B induced on the receptor system RI and RII, respectively, and En, is the maximum effect possible with the effector system con cerned. In the presence of a certain concentration of the functional antagonist [B] the effect induced by the agonist A is reduced by a constant, the term EIIB/E,,, of Eq. 1. However, Van den Brink pointed out that the over-all picture of experimental functional antagonism (isoproterenol-methacoline on calf trachea) was quite different from that calculated with Eq. 1, and postulated a new model of functional interaction allowing the concept of receptor

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I. Development and first check of a new model of functional synergism and antagonism

Cited by 78 publications

References 3 publications

Functional Antagonism as a Means of Determining Dissociation Constants and Relative Efficacies of Sympathomimetic Amines in Guinea‐pig Isolated Atria

Functional Antagonism as a Means of Determining Dissociation Constants and Relative Efficacies of Sympathomimetic Amines in Guinea‐pig Isolated Atria

The effect of L-arginine on guinea-pig and rabbit airway smooth muscle function in vitro

STUDIES ON THE MODE OF ANTAGONISM BETWEEN ADRENERGIC Β-Mimetics AND Β-Blocking AGENTS (III) FUNCTIONAL ANTAGONISM BETWEEN Β-Mimetics AND SPASMOGENS

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