Antagonism with dibenamine, D-600, and Ro 3-7894 to estimate dissociation constants and receptor reserves for cardiac adrenoceptors in isolated rabbit papillary muscles

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Abstract
In papillary muscles isolated from reserpinized rabbits, positive inotropic responses to the alpha (α)-adrenergic agonist, (−)-phenylephrine in the presence of 10−7 M timolol and the beta (β)-adrenergic agonist, (−)-isoproterenol were antagonized with the irreversible α-adrenergic antagonist, dibenamine, the irreversible β-adrenergie antagonist, Ro 3-7894, and the calcium blocker, D-600. D-600 was employed as a functional antagonist of both α- and β-adrenoceptor responses. Dissociation constants (KA values) for drug–receptor interactions were calculated by the method of Furchgott and used to estimate fractional receptor occupancy and agonist efficacies. Comparison of responses showed that the receptor reserve for cardiac β-adrenoceptors was greater than for α-adrenoceptors. D-600 was an effective inhibitor of both cardiac α- and β-adrenoceptor responses; however, estimates of KA and receptor reserves were similar to estimates using an irreversible antagonist for α- but not β-adrenoceptors.