Alterations in the force‐frequency relationship by tert‐ butylbenzohydroquinone, a putative SR Ca2+ pump inhibitor, in rabbit and rat ventricular muscle

Abstract 1. The effects of 2,5 di-(tert-butyl)-1,4-benzohydroquinone (TBQ), a putative inhibitor of the sarcoplasmic reticulum (SR) Ca2+ pump, on twitch tension, time course and SR Ca2+ content have been studied at different stimulation frequencies (0.5-3 Hz) in isolated preparations from the rabbit and rat right ventricle, at 37 degrees C. 2. At 0.5Hz, 30 microM TBQ induced a marked negative inotropic effect in both species (-57% in the rabbit and -68% in the rat) and decreased the rate of rise and fall of twitch tension. In parallel, SR Ca2+ content (assessed by rapid cooling contractures) was depressed in the rabbit by 42%. The force-frequency relationship (positive for the rabbit and negative for the rat) was significantly attenuated. In the rabbit, this alteration was shown to rely on insufficient SR Ca2+ reloading with increasing frequencies. 3. Exposure of TBQ-treated preparations to 8 mM extracellular Ca2+ or 5 microM isoprenaline were effective in reloading the SR with Ca2+ whereas 20 mM caffeine emptied this compartment. 4. In the rabbit ventricle, increase in stimulation frequency shortened control twitch time course by decreasing both the time to peak tension (TTP) and the time to half relaxation (t1/2). TBQ did not differentially affect the pattern for t1/2 but significantly attenuated the frequency-induced decrease of TTP. 5. In rabbit ventricular muscle, the action potential duration increased between 0.5 and 3 Hz whether or not TBQ was present. However, TBQ induced a small but significant additional action potential shortening. 6. TBQ decreased twitch tension in the rat ventricle between 0.5 and 3 Hz but the negative staircase was not differentially affected by the SR Ca2+ pump inhibitor. In control conditions and in the presence of 30 microM TBQ, t1/2 was frequency-independent but TBQ consistently increased this parameter (by approximately 29%). 7. These data argue in favour of a specific and partial inhibition of the SR Ca2+ pump by 30 microM TBQ in the rabbit and rat ventricle and emphasise the importance of SR Ca2+ uptake in the force-frequency phenomenon.