Impaired lusitropy-frequency in the aging mouse: role of Ca2+-handling proteins and effects of isoproterenol

We examined the relationship between age-associated lusitropic impairment, heart rate, and Ca2+-handling proteins and assessed the efficacy of increas ing left, ventricular (LV) relaxation via beta-adrenergic stimulation in ad ult and aging mouse hearts. LV function was measured in isolated, isovolumi c blood-perfused hearts from adult (5 mo), old (24 mo), and senescent (34 m o) mice. Hearts were paced from 5 to 10 Hz, returned to 7 Hz, exposed to 10 (-6) M isoproterenol, and paced again from 7 to 10 Hz. Age-related alterati ons in Na+/Ca2+ exchanger (NCX), sarcoplasmic reticulum (SR) Ca2+-ATPBse (S ERCA2a), and phospholamban (PLB) levels were assessed by immunoblot. Despit e preserved contractile performance, aging caused impaired lusitropy. Incre ased pacing caused an elevation in end-diastolic pressure that progressivel y worsened with age. The time constant of isovolumic pressure decay (tau) w as significantly prolonged in old and senescent hearts compared with adults . Relative to adult hearts, the SERCA2a-to-PLB ratios were reduced 68 and 6 9%, and NCX were reduced 37 and 58% in old and senescent hearts, respective ly. Isoproterenol completely reversed the age-associated lusitropic impairm ents. These data suggest that impaired lusitropy in aging mouse hearts is r elated to a decreased rate of cytosolic Ca2+ removal and that accelerating SR Ca2+ resequestration via beta-adrenergic stimulation can reverse this im pairment.