"The Function Of Sarcoplasmic Reticulum In The Aged Rat Heart" by Ming Tao Jiang

Date of Award

1995

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Abstract

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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