Differential Effects of the Ca 2+ Sensitizers Caffeine and CGP 48506 on the Relaxation Rate of Rat Skinned Cardiac Trabeculae

Abstract

Abstract During heart failure, force production by the heart decreases. This may be overcome by Ca 2+ -sensitizing drugs, which increase myofibril Ca 2+ sensitivity without necessarily altering intracellular Ca 2+ concentration. However, Ca 2+ sensitizers slow the relaxation of intact cardiac muscle. We used diazo-2, a caged chelator of Ca 2+ , to study the effects of the Ca 2+ sensitizers caffeine and CGP 48506 on the intrinsic relaxation rate of cardiac myofibrils. Trabeculae from rat right ventricles were skinned by 1% Triton X-100 and were activated in a 10-μL bath. In steady state experiments, CGP 48506 (10 μmol/L) shifted the force-pCa curve leftward by 0.41±0.03 pCa units (mean±SEM, n=6). An identical shift was induced by caffeine (20 mmol/L). Photolysis of diazo-2 by a flash of light (160 mJ, 310 to 400 nm) caused an immediate decrease in Ca 2+ -activated force produced by the trabeculae. Relaxation was fitted by a double-exponential decay, and the rate constants were found to be independent of force and preflash Ca 2+ concentration. The initial fast rate, corresponding to myofibrillar relaxation, was increased from 17.3±2.0 to 30.9±3.7 s −1 (n=4) by caffeine but was unaffected by CGP 48506 (16.6±1.7 and 14.4±2.3 s −1 in the absence and presence of drug, respectively; n=5). Thus, myofibril relaxation need not be slowed by Ca 2+ -sensitizing agents but can even be accelerated. Despite similarities in their effects on myofibril Ca 2+ sensitivity, caffeine and CGP 48506 affect the myofibrils at least partly via different mechanisms.