The determination of receptor constants for histamine H₂‐agonists in the guinea‐pig isolated right atrium using an irreversible H₂‐antagonist

Abstract

1 From measurements of chronotropy in the guinea-pig isolated right atrium, a compound (El 309) was found which behaved as an irreversible antagonist at the histamine H2 receptor. 2 E1309 was used to block irreversibly a proportion of the H2 receptors and the dissociation constants, relative efficacies and receptor reserves of four H2-agonists were determined.3 The calculated dissociation constants were similar to the Ki values reported from H2-radioligand binding studies but different from the observed ECm values.4 The order of potency for the four H2-agonists was impromidine > > histamine > dimaprit > 4-methylhistamine. 5 The order of relative efficacy was 4-methylhistamine > dimaprit > histamine > impromidine, the natural agonist not being the most efficacious. This atypical finding is discussed in relation to other receptor classes.

Relation between pharmacological response and receptor binding with histamine blocking drugs. Irreversible antagonism of three analogues of mifentidine on right atrium and cerebral cortex of the guinea-pig

“…With this in mind, the data obtained on the atrial preparations can also easily be explained by site-site interactions between the binding loci for derivatives of mifentidine and for histamine, leading to negative cooperativity. This may also explain the discordance in receptor reserve estimated from our data and by Rising and Steward [19]. The method appfied for the calculation is not valid in our case.…”

“…Using the irreversible antagonism of DAC 5062, a receptor reserve of 97% at maximal response of histamine can be calculated. In contrast, Rising and Steward [19] estimated a receptor reserve of 16% at maximal stimulation of the guinea-pig right atrium by histamine by using an irreversible H2-antagonist. The relative inability to remove DAC4626, DAC5062 and DAC 4680 from the tissue compared to cimetidine, ranitidine and mifentidine might be attributed to the increased lipophilicity of the DAC compounds in combination with the structural organization of the cardiac tissue.…”