Date of Award


Degree Type


Degree Name

Doctor of Philosophy


The purpose of this project was to study the effect of aging on the regulation of Ca{dollar}\sp{lcub}2+{rcub}{dollar} by cardiac sarcoplasmic reticulum (SR) and its potential contribution to the age-related alterations in myocardial contractile performance in Fischer 344 rats.;In cardiac membranes enriched in SR (MSR) and its light (LSR) and heavy (HSR) subfractions fractionated by a sucrose density gradient, the rate of ATP-supported and oxalate-facilitated Ca{dollar}\sp{lcub}2+{rcub}{dollar} uptake was significantly reduced (24-50%) in the aged (26-30 months old) compared with that of the adult rats (6-8 months old). With aging, the Ca{dollar}\sp{lcub}2+{rcub}{dollar}-stimulated phosphoenzyme of the Ca{dollar}\sp{lcub}2+{rcub}{dollar} pumps was reduced in MSR, LSR (25% and 33% respectively) but not in HSR; the Ca{dollar}\sp{lcub}2+{rcub}{dollar}-ATPase activity was significantly reduced in LSR only (35%). The pump turnover rates were not significantly altered with aging in MSR, LSR and HSR. The coupling ratio was reduced by 26-46% in MSR but was not markedly altered in LSR and HSR. The density of the Ca{dollar}\sp{lcub}2+{rcub}{dollar} release channels and the rate of Ca{dollar}\sp{lcub}2+{rcub}{dollar}-induced Ca{dollar}\sp{lcub}2+{rcub}{dollar} release from HSR were not altered with aging. Thus the age-related decline in the active Ca{dollar}\sp{lcub}2+{rcub}{dollar} uptake by SR membranes is likely due to a reduction in the density of active Ca{dollar}\sp{lcub}2+{rcub}{dollar} pumps and/or in the efficiency of Ca{dollar}\sp{lcub}2+{rcub}{dollar} uptake by Ca{dollar}\sp{lcub}2+{rcub}{dollar} pumps. The Ca{dollar}\sp{lcub}2+{rcub}{dollar} release function of SR is not altered with aging. The reduced rate of SR Ca{dollar}\sp{lcub}2+{rcub}{dollar} uptake may contribute to the prolonged myocardial relaxation in aging.;In the intact perfused heart, {dollar}\beta{dollar}-adrenergic agonist isoproterenol-stimulated peak inotropic and lusitropic responses were significantly reduced with aging. Under similar conditions, isoproterenol (0.1 {dollar}\mu{dollar}M)-stimulated phosphorylation of phospholamban in situ was significantly compromised with aging (38%), which was associated with an age-related reduction in the isoproterenol-stimulated accumulation of tissue cyclic AMP (18%). However, the cyclic AMP-dependent phosphorylation of phospholamban and its stimulation of Ca{dollar}\sp{lcub}2+{rcub}{dollar} uptake in vitro were not reduced with aging. It is concluded that the age-related reduction in the phosphorylation of phospholamban, which is in part due to an age-related decline in cyclic AMP accumulation, contributes to the diminished myocardial contractile responses to {dollar}\beta{dollar}-adrenergic stimulation in aging.



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