Dynamic changes in sarcoplasmic reticulum function in cardiac hypertrophy and failure

Previous studies have demonstrated that cardiac function changes with devel opment of pressure overload-induced hypertrophy. The present study was unde rtaken to discover the basis for the changes in sarcoplasmic reticulum (SR functions: uptake, las related to the SR Ca2+ pump properties) and release in isolated, perfused hypertrophied rat hearts. Our results demonstrated si gnificant prolongation of the time-to-90%-relaxation, both during the perio d of compensation (8 weeks after banding the ascending aorta, group HR1), w hen systolic function was preserved, and later with progressive hypertrophy (20 weeks after banding, group HR2) and contractile failure (20-22 weeks a fter banding, group F). The initial rates of the oxalate-supported SR Ca2uptake and the maximum transport rate (V-max) Of the SR Ca2+ pump, measured in the left ventricular homogenates. during blockade of the SR Ca2+ releas e channels with ruthenium red, were preserved in group HR1. To correlate ea rly relaxation abnormalities with SR function, the [Ca2+] required for half -maximal pump activation (EC50) was examined and increased significantly in HR1 vs. Sham1 (0.95+/-0.06 vs. 0.81+/-0.04 mu M, P<0.05) indicating that t he affinity of the SR Ca2+ pump for Ca2+ was reduced. The same tendency was demonstrated in groups HR2 (0.94+/-0.06 vs. 0.79+/-0.05) and F (0.89+/-0.0 5 vs. 0.78+/-0.05). In addition, with progression of hypertrophy we observe d a significant decline in the amount of SR Ca2+ pump, as assessed by the V -max, from 31.22+/-1.20 (Sham2) to 26.37+/-1.58 HR2) nmol/mg protein per mi n (P<0.05), and from 33.81+/-1.23 (Sham3) to 25.15+/-1.57 (F) nmol/mg prote in per min, (P<0.01). This decrease was accompanied by a parallel reduction in the number of SR Ca2+ release channels by 14% (HR2) and 23% (F), as det ermined by maximum [H-3] ryanodine binding (B-max). These results suggest t hat pressure overload-induced changes in SR Ca2+ uptake (as reflected by V- max and EC50) and SR Ca2+ release las reflected by B-max), both leading to diminished Ca2+ sequestration, may contribute to impaired cardiac relaxatio n with compensatory hypertrophy and failure.