The age-related decrease in catecholamine sensitivity is mediated by beta(1)-adrenergic receptors linked to a decrease in adenylate cyclase activity in ventricular myocytes from male Fischer 344 rats.
This study determined whether reduced sensitivity to catecholamines in aged myocytes resulted from deficits in the beta-adrenergic receptor (beta-AR) signaling pathway. Contractions and intracellular Ca(2+) were measured simultaneously in field-stimulated (2Hz, 37 degrees C, fura-2) ventricular myocytes isolated from young adult ( approximately 3 months) and aged ( approximately 24 months) male Fischer 344 rats. Higher concentrations of a beta(1)-AR agonist were required to increase contraction amplitudes in aged compared to younger cells; however, Ca(2+) transients were similar in both groups. There was no age-related difference in contraction or Ca(2+) transient amplitudes in response to a beta(2)-AR agonist. The direct adenylate cyclase agonist forskolin caused smaller increases in contraction and Ca(2+) transient amplitudes in aged compared to younger cells. Phosphodiesterase inhibitors did not reverse the age-related deficit in positive inotropy caused by beta-AR stimulation. Direct measurement of cAMP showed significantly less cAMP formation in response to either beta-AR or adenylate cyclase stimulation in aged compared to younger cells. However, responses to dibutyryl cAMP were similar in young adult and aged myocytes, suggesting that events downstream of cAMP formation are not affected by age. The age-related decrease in catecholamine sensitivity is mediated by beta(1)-ARs, resulting in a defect in cAMP production.
Farrell
Spring R
SR
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5.
Howlett
Susan E
SE
D000262:Adenylyl Cyclases / Q000378:metabolism*; D058665:Adrenergic beta-1 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000375:Aging / Q000378:metabolism*; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D020013:Calcium Signaling; D002395:Catecholamines / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004280:Dobutamine / Q000494:pharmacology; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*
D058665:Adrenergic beta-1 Receptor Agonists; D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D018342:Receptors, Adrenergic, beta-1; D005576:Colforsin; D004280:Dobutamine; D003994:Bucladesine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000420:Albuterol