Summary
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1.
A model of a competitive antagonism in which the agonist is subject to saturable uptake was developed in two variants: homogeneous and inhomogeneous distribution of the agonist in the extracellular space of an isolated tissue.
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2.
The predicted changes in the relation of the slope to the position of the concentration-effect curves were compared with the changes found during the positive inotropic action of (±)-isoprenaline and (−)-noradrenaline on guinea-pig papillary muscles. With (±)-isoprenaline a slight increase in slope was detected together with the shift caused by (±)-propranolol. With (−)-noradrenaline the slope increased and then decreased as the (±)-propranolol concentration rose.
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3.
The influence of the negative inotropic effect of high concentrations of (±)-propranolol (≥3×10−6 mol/l) was estimated with (+)-propranolol.
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4.
On preparations from reserpine-pretreated animals a biphasic change in the relation of slope to EC50 of the concentration-effect curves of (−)-noradrenaline was found with cocaine. This finding was not consistent with a simple competitive inhibition of an uptake mechanism which reduces the concentration of (−)-noradrenaline near freely accessible β-adrenoceptors.
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5.
On papillary muscle from reserpine-pretreated animals exposed to 2×10−5 mol/l cocaine (±)-propranolol reduced the slope of the (−)-noradrenaline concentration-effect curve with the shift to the right.
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6.
The “homogeneity” model was used in the statistical evaluation of the parameters of saturable uptake and competitive antagonism from the experimental data. The assumption of saturable uptake of (±)-isoprenaline significantly improved the goodness of fit in comparison to a pure competitive antagonism without uptake, but, with (−)-noradrenaline as agonist, a higher (±)-propranolol-receptor dissociation constant K B was obtained than with (±)-isoprenaline. The expansion of the model to include an uptakeinhibiting effect of (±)-propranolol significantly improved the goodness of fit.
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7.
The K B of (+)-propranolol was about 1/100 the K B of the racemate.
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8.
The model of saturable uptake with competitive antagonism at freely accessible β-adrenoceptors is compatible with the effects of (±)-isoprenaline, but not those of (−)-noradrenaline.
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Ebner, F. The inhibition by (±)-propranolol of the positive inotropic effects of (±)-isoprenaline and (−)-noradrenaline. Naunyn-Schmiedeberg's Arch. Pharmacol. 316, 96–107 (1981). https://doi.org/10.1007/BF00505301
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DOI: https://doi.org/10.1007/BF00505301