Desensitization of the β-adrenergic receptor-adenylate cyclase complex in rabbit iris-ciliary body induced by topical epinephrine

Topical treatment of the rabbit eye with three successive doses of 2% epinephrine bitartrate alters the in vitro drug response of the β-adrenergic receptor-adenylate cyclase enzyme complex in membrane fragments prepared from the iris and ciliary body. Treated tissues showed a significant decrease in activation of adenylate cyclase by guanosine triphosphate (100 μm), guanosine 5′-diphospho-imido phosphate (0·2 μm), and by isoproterenol (10 μm) in presence of either of the above guanyl nucleotides but showed no significant change in basal adenylate cyclase activity or in activity stimulated by fluoride (10 mm). The epinephrine-induced desensitization of β-adrenergic receptor-coupled adenylate cyclase is associated with a functional impairment of the guanyl nucleotide regulatory protein and possibly with a small decrease in the number of affinity of β-adrenergic receptor ligand binding sites. Agonist-induced changes in receptors and in their molecular effector systems represent basic mechanisms for alteration of tissue responses to drugs and may thus be involved in the therapy of glaucoma with chronic topical epinephrine.