AUGMENTED SPONTANEOUS CA2+ RELEASE IN SENESCENT HEART

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Characteristic changes in excitation-contraction mechanisms accompany cardiac cellular hypertrophy in response to chronic arterial pressure loading in rodents. These changes: prolongation of the transmembrane action potential and cytosolic calcium transient following excitation; reduction of the velocity of Ca2+ uptake into sarcoplasmic reticulum may be considered adaptive. They permit an extended duration of load bearing capacity following excitation. However, under conditions of a Ca2+ stress, e.g. following rapid pacing or elevated bathing [Ca2+](Cao), there is an increased likelihood for cellular Ca2+ overload to occur. Myocardial cellular hypertrophy and a pattern of excitation-contraction adaptations identical to pressure overload in younger rodents occur with advanced age in normotensive rodents. The present study examines whether, as in the pressure hypertrophied myocardium, an occult form of Ca2+ intolerance exists in aged myocardium. Following the imposition of Ca2+ stress, the manifestations of Ca2+ overload are more likely to occur in older vs younger heart. To determine whether myocardial Ca2+ intolerance, manifest as Ca2+ dependence after contractions (AC) or ventricular fibrillation (VF) differ in advanced age, isolated, isovolumic AV-blocked hearts from 24-26 mo (0) and 5-7 mo male rats (Y) (n=8 each) were perfused at constant flow (HEPES, 37xC) with [Ca2+] varied from 1.5 to 10 mM. The [Ca2+] required for both AC, measured from pressure recording following cessation of pacing at 2.0 Hz, and for VF, recorded via surface electrogram and occurring spontaneously during pacing, is reduced in 0. VF occurred in no Y but in 6 of 8 0 hearts. The results indicate an enhanced likelihood for occurrence of Ca2+ dependent abnormalities of cardiac cell function occurs with adult aging. The senescent (24-26 mo) rat heart exhibits exaggerated myocardial and cellular Ca2+ intolerance compared to its younger adult counterpart. Ca2+ intolerance is manifest as a lesser increase in systolic pressure coupled with an exaggerated increase in resting pressure and a greater likelihood for aftercontractions and VF to occur as perfusate [Ca] is increased. Spontaneous Ca2+ oscillations observed directly in cells, or manifest indirectly as SLIF in the perfused heart are the cellular basis for the Ca2+ dependent increase in resting pressure, aftercontractions and possibly for VF.