Summary
Three β-adrenoceptor-related parameters were measured for 23 agonists on kitten ventricular myocardium: inotropic potencies (EC50's) on papillary muscles, intrinsic activities for stimulation of the adenylyl cyclase in membrane particles, and affinities for β-adrenoceptors labelled with 3H-(−)-propranolol in membrane particles.
For catecholamines a dissociation between inotropic potencies and β-adrenoceptor affinities was observed. Inotropic potencies are 1.3–1.8 orders of magnitude higher than affinities. This dissociation between inotropic activation and binding is similar for (+)- and (−)-enantiomers of catecholamines, despite the higher affinities of the latter. The dissociation is considerably smaller for dopamine and dobutamine, which suggests a role of the β-OH group in the phenomenon. The effect is also smaller with resorcinols than with catechols; it decreases further, or is not observed at all, when one of the ring hydroxyl groups is replaced or absent. With most agonists the degree of dissociation appears to be directly proportional to the degree of adenylyl cyclase stimulation. About 1/4 of maximum adenylyl cyclase stimulation suffices to activate the inotropic processes fully. It is suggested that both the magnitude of the dissociation and the degree of adenylyl cyclase activation are indicators of the degree of change induced by agonist in the conformation of the β-adrenoceptor.
The production of marked inotropic effects by noradrenaline and adrenaline with low β-adrenoceptor occupancy and little adenylyl cyclase stimulation may permit the regulation of heart function. Conditions of desensitization that reduce maximum activation of the adenylyl cyclase may not necessarily reduce maximum inotropic effects of these catecholamines.
The agonist (±)-hydroxybenzylpindolol caused positive inotropic effects only at high β-adrenoceptor occupancy. This is consistent with the idea that sufficient conformational change occurs only near receptor saturation.
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Kaumann, A.J. In kitten ventricular myocardium, the inotropic potency of an agonist is determined by both its intrinsic activity for the adenylyl cyclase and its affinity for the β-adrenoceptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 317, 13–18 (1981). https://doi.org/10.1007/BF00506250
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DOI: https://doi.org/10.1007/BF00506250