Desensitization ofβ-Adrenergic Receptors by Pheochromocytoma*

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Abstract
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 alternation in receptor-effector coupling. The consequences of prolonged stimulation of .beta.-adrenergic receptors were examined in an interesting rat model harboring pheochromocytoma. New England Deaconess Hospital rats with transplanted pheochromocytomas developed systolic hypertension and plasma norepinephrine concentrations .apprx. 40-fold greater than controls. .beta.-Adrenergic receptors were quantitated 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 < 0.001) and adipocytes (29,400 vs. 2800 sites/cell; P < 0.001). Also, maximal isoproterenol-stimulated cAMP accumulation in isolated adipocytes was diminished in pheochromocytomic animals (13.1 vs. 4.9 pmol cAMP/105 cells/min; P < 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 desenstiziation.