Abnormal Ca2+ release from cardiac sarcoplasmic reticulum in tachycardia-induced heart failure

Objective: In heart failure, little information is available as to the Ca2+ release function of sarcoplasmic reticulum (SR), which plays a major role in cardiac contractile function. Here, we assessed the rapid kinetics of drug-induced Ca2+ release from cardiac SR in combination with a measurement of ryanodine binding in heart failure. Methods: The SR vesicles were isolated from dog left ventricular (LV) muscles (normal (N), n=10; pacing induced heart failure (HF), n=10). The time course of SR Ca2+ release was continuously monitored by a stopped-flow apparatus using arsenazo(III) as a Ca2+ indicator, and Ca2+ uptake and [H-3]ryanodine binding assays were done using a filtration method. Results: The amount of Ca2+ uptake was reduced in HF to 55% of N (P<0.05). Even the more marked and earlier appeared decrease was seen in the rate constant and the initial rate of polylysine (PL; a specific release trigger)-induced Ca2+ release (P<0.05). However, the PL concentration dependency of the initial rate shifted towards lower concentrations of PL in HF than in N ([PL] at half maximum stimulation=0.13 vs. 0.35 mu M). The [H-3]ryanodine binding assay revealed a lower B-max (pmol/mg) in HF than in N (0.91+/-0.19 vs. 2.64+/-0.59, P<0.05), but no difference in K-d (nM) (0.95+/-0.29 vs. 0.90+/-0.11, P=n.s.). The [PL] dependency on the enhancement of [H-3]ryanodine binding again showed a shift towards lower [PL] in HF than in N. Conclusions: In pacing-induced heart failure, the Ca2+ releasing function of SR is disturbed, which may result in an intra-cellular Ca2+ transient that was slowed down. (C) 1999 Elsevier Science B.V. All rights reserved.