Cross-Bridge-Dependent Change in Ca2+ Sensitivity is Involved in the Negative Inotropic Effect of Nifedipine in Aequorin-Injected Ferret Ventricular Muscles

Abstract

We hypothesized that the negative inotropic effect of nifedipine (Nif) on cardiac ventricular muscle is partly due to the cross-bridge-dependent decrease of Ca2+ sensitivity of the myofilaments as well as the decrease in Ca2+ influx. We used aequorin-injected ferret papillary muscles and measured the slope of the extra-Ca(2+)-tension relation which expresses the change in the Ca2+ sensitivity through the feedback from the cross-bridges. Twitch tension was decreased significantly by 0.5 micromol/L Nif accompanying a significant reduction of the Ca2+ transient peak. When Nif (0.2-0.5 micromol/L) was added to the solution with 8 mmol/L Ca2+, the slope of the extra-Ca2+-tension relation became steeper in a concentration-dependent manner, which was similar to the change in the slope when the concentration of Ca2+ was decreased from 8 to 1 mmol/L in the absence of Nif. BAY-K 8644 (0.3 micromol/L), a dihydropyridine receptor agonist, showed the opposite effect on the slope of the extra-Ca2+-tension relation to that observed in Nif. However, 2,3-butanedione monoxime (3 mmol/L), an inhibitor of the active cross-bridges, antagonized the effect of BAY-K 8644. Nif exerts its negative inotropic effect on cardiac muscle by suppressing Ca2+ binding to troponin C via the inhibition of the L-type Ca2+ channel, and by the cross-bridge-dependent decrease in the Ca2+ sensitivity, as in low extracellular Ca2+ concentration.