TY - JOUR
T1 - Age-associated reductions in cardiac β1- and β2-adrenergic responses without changes in inhibitory G proteins or receptor kinases
AU - Xiao, Rui Ping
AU - Tomhave, Eric D.
AU - Wang, Ding Ji
AU - Ji, Xiangwu
AU - Boluyt, Marvin O.
AU - Cheng, Heping
AU - Lakatta, Edward G.
AU - Koch, Walter J.
PY - 1998/3/15
Y1 - 1998/3/15
N2 - While an age-associated diminution in myocardial contractile response to β-adrenergic receptor (β-AR) stimulation has been widely demonstrated to occur in the context of increased levels of plasma catecholamines, some critical mechanisms that govern β-AR signaling must still be examined in aged hearts. Specifically, the contribution of β-AR subtypes (β1 versus β2) to the overall reduction in contractile response with aging is unknown. Additionally, whether G protein-coupled receptor kinases (GRKs), which mediate receptor desensitization, or adenylyl cyclase inhibitory G proteins (G(i)) are increased with aging has not been examined. Both these inhibitory mechanisms are upregulated in chronic heart failure, a condition also associated with diminished β-AR responsiveness and increased circulatory catecholamines. In this study, the contractile responses to both β1-AR and β2-AR stimulation were examined in rat ventricular myocytes of a broad age range (2, 8, and 24 mo). A marked age-associated depression in contractile response to both β-AR subtype stimulation was observed. This was associated with a nonselective reduction in the density of both β-AR subtypes and a reduction in membrane adenylyl cyclase response to both β-AR subtype agonists, NaF or forskolin. However, the age-associated diminutions in contractile responses to either β1-AR or β2-AR stimulation were not rescued by inhibiting G(i) with pertussis toxin treatment. Further, the abundance or activity of β-adrenergic receptor kinase, GRK5, or G(i) did not significantly change with aging. Thus, we conclude that the positive inotropic effects of both β1- and β2-AR stimulation are markedly decreased with aging in rat ventricular myocytes and this is accompanied by decreases in both β-AR subtype densities and a reduction in membrane adenylate cyclase activity. Neither GRKs nor G, proteins appear to contribute to the age-associated reduction in cardiac β-AR responsiveness.
AB - While an age-associated diminution in myocardial contractile response to β-adrenergic receptor (β-AR) stimulation has been widely demonstrated to occur in the context of increased levels of plasma catecholamines, some critical mechanisms that govern β-AR signaling must still be examined in aged hearts. Specifically, the contribution of β-AR subtypes (β1 versus β2) to the overall reduction in contractile response with aging is unknown. Additionally, whether G protein-coupled receptor kinases (GRKs), which mediate receptor desensitization, or adenylyl cyclase inhibitory G proteins (G(i)) are increased with aging has not been examined. Both these inhibitory mechanisms are upregulated in chronic heart failure, a condition also associated with diminished β-AR responsiveness and increased circulatory catecholamines. In this study, the contractile responses to both β1-AR and β2-AR stimulation were examined in rat ventricular myocytes of a broad age range (2, 8, and 24 mo). A marked age-associated depression in contractile response to both β-AR subtype stimulation was observed. This was associated with a nonselective reduction in the density of both β-AR subtypes and a reduction in membrane adenylyl cyclase response to both β-AR subtype agonists, NaF or forskolin. However, the age-associated diminutions in contractile responses to either β1-AR or β2-AR stimulation were not rescued by inhibiting G(i) with pertussis toxin treatment. Further, the abundance or activity of β-adrenergic receptor kinase, GRK5, or G(i) did not significantly change with aging. Thus, we conclude that the positive inotropic effects of both β1- and β2-AR stimulation are markedly decreased with aging in rat ventricular myocytes and this is accompanied by decreases in both β-AR subtype densities and a reduction in membrane adenylate cyclase activity. Neither GRKs nor G, proteins appear to contribute to the age-associated reduction in cardiac β-AR responsiveness.
KW - Aging
KW - Cardiac myocytes
KW - Inhibitory G proteins
KW - β-Adrenergic receptor kinase
KW - β-Adrenergic receptor subtype
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U2 - 10.1172/JCI1335
DO - 10.1172/JCI1335
M3 - Article
C2 - 9502768
AN - SCOPUS:0032521152
SN - 0021-9738
VL - 101
SP - 1273
EP - 1282
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -