Reduced catecholamine sensitivity is related to a decrease in adenylate cyclase activity mediated by ß1‐adrenergic receptor signaling in aged ventricular myocytes

Abstract

The aim of this study was to determine whether reduced sensitivity to catecholamines in aged myocytes results from deficits in ß‐adrenergic receptor (AR) signaling. Contraction amplitudes and intracellular Ca2+ were measured in field‐stimulated (2 Hz, 37°C, fura‐2) ventricular myocytes isolated from young adult (3 mos) and aged (24 mos) male Fischer 344 rats. The effect of a ß1‐AR agonist (but not a ß2‐AR agonist) on contraction amplitude was greater in young adult compared to aged myocytes; however, Ca2+ transient amplitudes were similar in both groups. To examine downstream effectors of ß‐AR signaling we assessed the activity of adenylate cyclase and the formation of cAMP. Aged myocytes had smaller increases in contraction and Ca2+ transient amplitudes in response to forskolin compared to young adult cells. In addition, direct measurement of cAMP showed an age‐related decrease in cAMP formation in response to forskolin. This reduction in adenylate cyclase activity is likely responsible for the age‐related decrease in catecholamine sensitivity as administration of dibutyryl cAMP showed no age bias on contraction or Ca2+ transient amplitude. Funding: CIHR & HSFNS.