Regeneration of beta-adrenergic receptors in senescent rats: a study using an irreversible binding antagonist.

Abstract

The drug used in this study, bromoacetylalprenololmenthane, has the ability to bind and block irreversibly a-adrenergic receptors. The drug was bound to membranes prepared from hearts, lungs, and brains of both senescent and young rats with a similar affinity. When this drug was injected into rats in nontoxic doses (up to 70 mg/kg), up to 90% of P-adrenergic receptors were irreversibly blocked 4 hr after injection, whereas the injection of similar amounts of (±)-alprenolol was without effect on receptor number. In senescent animals this blockade lasted considerably longer than in young animals; receptor numbers in hearts and lungs of senescent rats returned to control levels only 1 month after injection. The number of (3-adrenergic receptors in brains of senescent rats was unaffected by this drug. Thus, based upon the long-lasting blockade of -adrenergic receptors in therapeutically important organs, it appears that irreversible binding blockers may have potential in the treatments ofsenescent organisms.3-Adrenergic antagonists continue to be one of the main medications used to treat hypertension (1)-a symptom afflicting about one-third of a population sample of the elderly in the United States (2). The effects and also fate of these antagonists show changes with age (3) that are difficult to explain on the basis ofwhat is known about the age-related features ofthe adrenergic system (1,(4)(5)(6). In this work we studied the regeneration ofreceptors for these antagonists in senescent rats. Such a study can provide information concerning possible development of longer acting antagonists (7) and may eventually help in the clarification ofage effects on the adrenergic system. Bromoacetylalprenololmenthane, whose structure is given in Fig. 1, was used in this study. It was shown previously that this drug binds, at first reversibly, to a binding site of the p-adrenergic receptor and this reversible complex is transformed rapidly through a chemical reaction into a covalent receptor-drug complex that does not further bind molecules of agonists or antagonists (8). Furthermore, this drug has the advantage of high affinity for 3adrenergic receptors (8), as compared to similar compounds (9). Utilization of this drug in senescent rats revealed that the receptor number in some therapeutically important organs-such as heart and lung-remains below control levels for as long as 1 month after treatment. Thus, in senescence the rate ofregeneration, and probably the rate ofde novo synthesis of receptors, is low. The results point to the possibility of using irreversible blockade to perform "molecular surgery"-i.e., to excise part of the receptors in a senescent organism in a reasonably selective way and in a practically permanent manner. MATERIALS AND METHODSThe senescent animals, unless otherwise stated, were 27-month-old Sprague-Dawley rats that have a 2-yr median lifespan and were obtained from Harlan Industries (Indianapolis, IN). The animals used in the regeneration experiment were divided into groups of (i) drug tre...

α- and β-adrenergic receptor activity in circulating blood cells of patients with phaeochromocytoma: effects of adrenalectomy

“…When agonist induced desensitization is permitted to continue, the internalized receptors are partly destroyed (Harden 1983), and receptor synthesis is required for restoration of the full number of surface receptors. This required 1-2 months in rat lung when ß-adrenoreceptors were irreversibly blocked by covalent bindings (Pitha et al 1982); -a comparable time span was found for ß-adrenoceptor regeneration in MNL of patients IV and V after tumour excision. Receptors in the high affinity state seem to be synthesized preferen¬ tially, as isoproterenol-induced cAMP accumula¬ tion is restored faster than the entire ß-receptor population.…”

Rapid recovery of cardiac beta-adrenergic receptors after isoproterenol-induced "down"-regulation.

“…Since the turnover rate of cardiac /3-receptors is normally slow (Pitha et al, 1982), de novo synthesis may not be utilized under physiological conditions. Pathological states, however, may interfere with the adequacy of receptor recycling through several mechanisms involving the energetics of the cell, microtubular assembly, lysosomal integrity, ionic gradients, etc.…”

Dopamine receptor turnover rates in rat striatum are age-dependent.

“…A recent report described aging-related decreases in the regeneration of visceral beta-adrenergic receptors after their irreversible blockade (13), thus suggesting one possible mechanism for the observed age-related deficits in receptor up regulation. A vehicle and decapitated at various times.…”