Desensitization ofβ-Adrenergic Receptors by Pheochromocytoma*

Prolonged stimulation of cells by beta-adrenergic receptor agonists may lead to diminished responsiveness of the cells to subsequent activation by catecholamines. This phenomenon has been termed desensitization; the mechanism(s) for desensitization may involve an apparent loss in the number of beta-adrenergic receptors or an alteration in receptor-effector coupling. We have examined the consequences of prolonged stimulation of beta-adrenergic receptors in an interesting rat model harboring pheochromocytoma. New England Deaconess Hospital rats with transplanted pheochromocytomas developed systolic hypertension and plasma norepinephrine concentrations approximately 40-fold greater than controls. beta-Adrenergic receptors were quantitated in several tissues from controls and rats with transplanted pheochromocytoma using the beta-adrenergic receptor antagonist [125I]iodocyanopindolol. Down-regulation of beta 1-receptors was found in heart tissue (22.8 vs. 13.6 fmol/mg protein; P less than 0.001) and adipocytes (29,400 vs. 2,800 sites/cell; P less than 0.001). Also, maximal isoproterenol-stimulated cAMP accumulation in isolated adipocytes was diminished in pheochromocytomic animals (13.1 vs. 4.9 pmol cAMP/10(5) cells/min; P less than 0.05). Interestingly, there was no change in beta-receptors in lung and mesenteric artery, which predominantly contain beta 2-receptors. Furthermore, the competition curves of isoproterenol in the heart membranes from control and pheochromocytomic rats in the absence and presence of guanylylimidodiphosphate indicated uncoupling of the beta-adrenergic receptors in pheochromocytomic animals. Rats with pheochromocytoma secreting large amounts of norepinephrine provide a valuable model system for studying the in vivo development of desensitization.