In vivo apparent peptide-receptor dissociation rate constants for arginine vasopressin analogs estimated from inhibition of rat pressor responses.

Apparent pressor receptor dissociation rate constants for arginine vasopressin, arginine vasotocin, oxytocin, oxypressin, and [1-deamino, 9-D-alanineamide]arginine vasopressin were estimated by the following method. Two minutes after injection of a moderate dose of agonist into urethane-anesthetized rats prepared for recording mean blood pressure, a large dose of inhibitor was injected. Under these conditions, in the first few moments after inhibitor injection, there should be no rebinding of the agonist after it dissociates, because vacant receptors should be immediately occupied by inhibitor. The rate of the blood pressure drop at the initiation of inhibition was calculated and used as an estimate of the dissociation rate of the agonist. Apparent dissociation rate constants thus estimated were 1.1, 1.1, 6.9, 5.8, and 13.9 min-1 for arginine vasopressin, arginine vasotocin, oxytocin, oxypressin, and [1-deamino, 9-D-alanineamide]arginine vasopressin, respectively. These rate constants were inversely related to the pressor potencies (435, 250, 5, 3, and 0.7 U/mg, respectively) of these five compounds. Such a relationship is to be expected if decreased potency is in part due to a faster "off" rate from pressor receptors.