Early Changes in the Functions of Cardiac Sarcoplasmic Reticulum in Volume-overloaded Cardiac Hypertrophy in Rats

By sequestering activator calcium, the sarcoplasmic reticulum (SR) plays the central role in the excitation–contraction (E–C) cycle of cardiac muscle. Hence, functional changes in the SR in diseased myocardium might critically determine its mechanical characteristics. Previously, we demonstrated that both Ca2+release and uptake were increased in SR isolated from hearts showing compensatory left ventricular (LV) hypertrophy taken from pressure-overloaded rats. However, it has not been elucidated whether such alterations also occur in the volume-overloaded myocardium. Rats in which volume-overloaded hypertrophy had been induced by aortocaval shunt 12 weeks prior to the investigation were compared to sham-operated controls in terms of SR Ca2+uptake and release, and density of Ca2+releasing channels (ryanodine receptors, RyR). Isometric tension and intracellular Ca2+transients were also measured using the bioluminescent Ca2+indicator, aequorin, in isolated LV papillary muscles. The extent of hypertrophy was verified by measuring the ratio of biventricular weight to body weight.In vivo, the aortocaval shunt rats showed normal LV contractility and slightly depressed LV relaxation, indicating a compensatory (adaptive) stage of LV function. In contrast, Ca2+release, uptake, and maximal number of [3H]-ryanodine binding sites were all significantly lower in aortocaval shunt rats than in controls. Both the Ca2+transients and isometric relaxation of the isolated myocardium were significantly prolonged in aortocaval shunt rats, though their amplitudes were similar in the two groups. Thus, the volume-overloaded cardiac hypertropy, even at its hemodynamically compensatory (adaptive) stage, (i) was accompanied by abnormal Ca2+handling, as indicated by prolonged intracellular Ca2+transients and isometric tension traces, (ii) seems to involve subcellular mechanisms related to decreases in SR Ca2+release and uptake functions, as well as to a decrease in the number of RyR. Therefore, changes in the intracellular processes underlying cardiac E–C coupling, including SR function, precede the development of this type of heart disease.