MOLECULAR PHARMACOLOGY OF ADRENERGIC RECEPTORS IN AGING

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The goals of the proposal are to investigate the regulation of expression of alpha and beta adrenergic receptor subtypes with aging in organs such as the cardiovascular system that have particular relevance to the pathophysiology and pharmacologic treatment of geriatric patients. An extensive body of work has demonstrated that there are important alterations in the physiological effects of catecholamines with increasing age. Exciting recent advances have demonstrated that the effects of catecholamines are mediated via a range of adrenergic receptor subtypes far more diverse than had previously been appreciated. The interplay between the organ-specific expression of these newly described receptor subtypes and possible changes with aging is an important basis for the development of novel drug therapies for the elderly using highly subtype specific adrenergic agonists or antagonists. The first goal of the proposed work is to investigate the distribution of alpha and beta adrenergic receptor subtypes in a number of important organs using molecular biological techniques aimed at quantifying receptor mRNA's and comparing the abundance of these mRNA's across the age range in Fischer 344 rats. Expression of the following genes will be measured: beta1 and beta2; alpha1A, alpha1B and alpha1C; and alpha2A, alpha2B, and alpha2C in a number of important target tissues for catecholamines. The tissues will include: heart, several blood vessels; liver; prostate and bladder; kidney; lung; and brain (cortex and cerebellum). These studies will use Northern blotting or a quantitative application of the polymerase chain reaction to measure particularly rare mRNA's. Results of these studies will be compared with determinations of the amount of receptor protein, assayed either with radioligand binding techniques or with polyclonal rabbit antibodies that will be prepared against peptides specific for the different adrenergic receptor subtypes. The second major goal of the proposal is to investigate the possibility that regulation of these receptor genes is differentially modified by several important pathophysiological states in young versus old rats. In general, with aging there is a decline in the capacity of an organism to respond to pathophysiological perturbations induced by disease or drugs. The effects of excess thyroid hormone on the expression of these genes in the heart and brain of young and old animals will be examined. Also, the effects of a tricyclic antidepressant on the regulation of gene expression in the brains of young and old rats will be compared.