Impaired lusitropy-frequency in the aging mouse: role of Ca(2+)-handling proteins and effects of isoproterenol.
We examined the relationship between age-associated lusitropic impairment, heart rate, and Ca(2+)-handling proteins and assessed the efficacy of increasing left ventricular (LV) relaxation via beta-adrenergic stimulation in adult and aging mouse hearts. LV function was measured in isolated, isovolumic blood-perfused hearts from adult (5 mo), old (24 mo), and senescent (34 mo) 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 alterations in Na(+)/Ca(2+) exchanger (NCX), sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a), and phospholamban (PLB) levels were assessed by immunoblot. Despite preserved contractile performance, aging caused impaired lusitropy. Increased pacing caused an elevation in end-diastolic pressure that progressively worsened with age. The time constant of isovolumic pressure decay (tau) was significantly prolonged in old and senescent hearts compared with adults. Relative to adult hearts, the SERCA2a-to-PLB ratios were reduced 68 and 69%, and NCX were reduced 37 and 58% in old and senescent hearts, respectively. Isoproterenol completely reversed the age-associated lusitropic impairments. These data suggest that impaired lusitropy in aging mouse hearts is related to a decreased rate of cytosolic Ca(2+) removal and that accelerating SR Ca(2+) resequestration via beta-adrenergic stimulation can reverse this impairment.
Lim
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Cardiac Muscle Research Laboratory, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Liao
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Varma
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Apstein
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D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D003326:Coronary Circulation / Q000502:physiology; D003971:Diastole; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D000099211:Phospholamban
D000318:Adrenergic beta-Agonists; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban