Hepatic beta-adrenoceptor adaptation during propranolol administration is impaired in aging rats.
Aging has been associated with changes in beta-adrenoceptor responses and adaptation to prolonged removal of catecholamine stimulation. We have examined the effect of chronic propranolol administration on rat hepatic membrane beta-adrenoceptor density, agonist affinity and response in young (6-7 months) and old (26-7 months) male Wistar rats. Propranolol administration via miniosmotic pumps for 7 days resulted in similar and sustained plasma propranolol levels (approximately 100 ng/ml) in old and young rats. Pretreatment beta-adrenoceptor responses to isoprenaline were significantly higher in old rats. Propranolol administration was associated with significant increases in beta-adrenoceptor response and density (Bmax) in young rats only. Cyclic adenosine 3',5'-monophosphate (cyclic AMP) responses to prostaglandin E1 (PGE1), guanosine triphosphate (GTP), 5'-guanyl-imidodiphosphate (Gpp(NH)p), forskolin and Mn2+ were not significantly different between young and old rats and were not affected by propranolol administration. Neither aging or propranolol administration was associated with a change in beta-adrenoceptor agonist affinity. These findings demonstrate elevated hepatic beta-adrenoceptor response and impaired hepatic beta-adrenoceptor adaptation to beta-adrenoceptor blockade in aging rats.
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin.
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D
Conlon
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Johnston
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Turner
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O'Malley
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Kilfeather
D000222:Adaptation, Physiological / Q000502:physiology*; D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D008297:Male; D011433:Propranolol / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D000262:Adenylyl Cyclases