The positive force–frequency relationship is maintained in absence of sarcoplasmic reticulum function in rabbit, but not in rat myocardium

Abstract

Myocardial calcium handling differs between species, mainly in the relative contribution between the sources for activator calcium. To investigate the role of the myofilaments and intracellular calcium decline in governing the relaxation phase of cardiac muscle, and to elucidate additional determinants of relaxation other than the sarcoplasmic reticulum (SR) at various frequencies within the in vivo range, the present study was performed by altering the calcium handling in rat and rabbit. Trabeculae, iontophoretically loaded with bis-fura-2 to monitor cytoplasmic calcium levels, were subjected to ryanodine and cyclopiazonic acid to inhibit SR function. Simultaneous force and [Ca(2+)](i) measurements were obtained at 1-4 Hz in rabbit and at 4-8 Hz in rat before and after SR inhibition. Inhibition of the SR resulted in increased diastolic and peak calcium levels as well as decreased developed force in both species. Calcium transient amplitude decreased in rat, but increased in rabbit after SR inhibition. Time to peak tension, time from peak tension to 50% relaxation, time to peak calcium, and time from peak calcium to 50% calcium decline were all prolonged. Results suggest that L-type calcium channel current is responsible for increases in calcium with increasing frequency, and that the SR amplifies this effect in response to increased L-type current. The response of the myofilaments to alterations in calcium handling plays a critical role in the final determination of force, and may differ between species. These results imply the balance between force relaxation and calcium decline is significantly different in larger mammals, necessitating a critical re-evaluation of how myocardial relaxation is governed, specifically regarding frequency-dependent activation.