ISSN:
1432-1912
Keywords:
Competitive antagonism
;
Saturable uptake
;
Propranolol
;
Noradrenaline
;
Isoprenaline
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary 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. 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. 3. The influence of the negative inotropic effect of high concentrations of (±)-propranolol (≥3×10−6 mol/l) was estimated with (+)-propranolol. 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. 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. 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. 7. The K B of (+)-propranolol was about 1/100 the K B of the racemate. 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00505301
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