A NEW APPROACH TO DETERMINE RATES OF RECEPTOR APPEARANCE AND DISAPPEARANCE INVIVO - APPLICATION TO AGONIST-MEDIATED DOWN-REGULATION OF RAT RENAL CORTICAL BETA-1- AND BETA2- ADRENERGIC-RECEPTORS

  • 1 January 1985
    • journal article
    • research article
    • Vol. 27  (1) , 19-26
Abstract
A method was developed for the assessment of agonist-induced down-regulation of receptors in vivo in terms of rates of receptor appearance and disappearance. This method involves computer-assisted analysis of the kinetics of receptor loss during agonist infusion and of the recovery of receptor number upon the removal of the agonist. These kinetics are analyzed in terms of a steady-state model that allows estimation of the rate constants for receptor appearance, Kap, and receptor disappearance, Kdp. Several tests establish that the model can fit experimentally derived data very well. In testing this model, the in vivo down-regulation and recovery of rat renal cortical membrane .beta.1- and .beta.2-adrenergic receptors in response to infusion of the agonist isoproterenol from s.b. implanted osmotic minipumps was studied. During recovery from down-regulation, the .beta.1-receptors have a T1/2 [half life] of 45 h and a kap of 1.6%/h, and the .beta.2-adrenergic receptors at t1/2 of 18 h and a Kap of 3.9%/h. During down-regulation, the t1/2 for both receptors is 12 h, while kap for .beta.1-receptors and .beta.2-receptors are 3 and 2.3%/h, respectively. To the extent that the kinetics of recovery from down-regulation reflect basal receptor metabolism, the data indicate that enhanced receptor clearance of both receptor subtypes from the plasma membrane contibute to down-regulation, but changes in rates of receptor appearance may occur as well. The use of this computer modeling technique for defining kinetics of changes in receptor number from 1 steady state level to another should provide a generally useful means to assess hormone and neurotransmitter receptor metabolism in vivo.