title: Kinetics of competitive drug action at 5-hydroxytryptamine2 receptors in isolated rabbit aorta.
abstract: The kinetics of agonist and antagonist interactions with the 5-hydroxytryptamine2 receptor were studied in the isolated rabbit aorta by following the antagonist-induced decrease in the steady-state response to an agonist. A model describing the competitive drug-receptor interactions was fitted to the data and yielded estimates of the association and dissociation rate constants of the agonist and the antagonist. A high concentration of the agonist ([agonist] much greater than KA) was used to reduce the influence of antagonist diffusion to the receptor upon the onset of antagonism. The effect of a diffusion barrier was evaluated by comparing the kinetics of drug competition in the absence and in the presence of the adventitia. The rate constants of the high-affinity antagonists spiperone, methysergide or ketanserin were similar in the absence and in the presence of the adventitia. In contrast, the rate constants of the low affinity antagonist 5-methoxygramine were reduced almost 5-fold in the presence of the adventitia. This observation may be explained by the large partition coefficients of the high-affinity antagonists as compared to the relatively low partition coefficient of 5-methoxygramine. The ratios of the estimated rate constants (k-x/kx) are in good agreement with the dissociation constants of the drugs determined with steady-state methods. In addition the results suggest that the association rate constant is a primary determinant of drug affinity for the receptor. The kinetic rate constants of the high-affinity antagonists measured in this preparation are similar to those previously reported in high-affinity binding studies. We conclude that the kinetic parameters obtained in our experiments reflect primarily the molecular interactions of these drugs with the receptor.
mesh_terms: D000818:Animals; D001011:Aorta; D001667:Binding, Competitive; D004058:Diffusion; D007211:Indoles / Q000378:metabolism; D007650:Ketanserin / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008784:Methysergide / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011817:Rabbits; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D014363:Tryptamines / Q000378:metabolism
chemical_list: D007211:Indoles; D011985:Receptors, Serotonin; D014363:Tryptamines; C008398:methoxygramine; D012701:Serotonin; C030820:tryptamine; D013134:Spiperone; D007650:Ketanserin; D008784:Methysergide