Mechanism of release of calcium from sarcoplasmic reticulum of guinea‐pig cardiac cells.

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Abstract
1. The mechanisms that control release of Ca2+ from the sarcoplasmic reticulum (SR) of guinea-pig ventricular cells were studied by observing intracellular calcium concentration ([Ca2=]i transients) and membrane currents in voltage-clamped guinea-pig ventricular myocytes perfused internally with Fura-2. 2. Sarcolemmal Ca2+ current was identified through the use of tetrodotocin (TTX) and Ca2+ channel antagonists (verapamil) and agonists (Bay K86440. 3. Changes in [Ca2+]i attributable to release of Ca2+ from the SR were identified through the use of ryanodine, which abolishes the ability of the SR to release Ca2+. Ryanodine-sensitive increases in [Ca2+]i could be elicited either by depolarization or by repolarization (from depolarizing pulses to relatively positive membrane potentials). 4. At appropriate voltages, it is the initial fast change in [Ca2+]i elicited by either depolarization or repolarization that is abolished by ryanodine, and is defined here as ryanodine sensitive. 5. The amplitude of the ryanodine-sensitive [Ca2+]i transient elicited by depolarization had a bell-shaped dependence on membrane potential with a maximum of about 500 nM at 10 mV, and with the upper minimum between 60 and 70 mV. Verapamil-sensitive current activated over approximately the same potential range as the [Ca2+]i transient, with a peak amplitude at 10 mV, and a reversal potential of 65 mV. 6. When a holding potential of -68 mV and TTX (30 .mu.M) were used, the most negative pulse potential at which activation of an inward current occurred was -49 mV while changes in [Ca2+)i occurred at -43 mV. 7. Ryanodine-sensitive increased in [Ca2+]i elicited by repolarization (tail transients) were maximal for repolarization to 0 mV. Smaller changes in 7(Ca2+]i than maximal were elicited by repolarization to both more positive and more negative potentials than 0 mV. The peak amplitude of the verapamil-sensitive tail currents elicited by repolarization increased continuously as the membrane was repolarized to potential more negative than 60 mV. 8. Increasing depolarizing duration beyond 10-20 ms did not increase the amplitude of the [Ca2+]i transient, but prolonged it. 9. The experimental results are compared to the predictions of two theories on the mechanism of excitation-contraction coupling: Ca2+-induced release of Ca2+ (CICR), as it has been formulated from data in skinned cardiac cells, and a charge-coupled release mechanism (CCRM), as it has been formulated to explain excitation-contraction coupling in skeletal muscle. 10. Some of the results are clearly no consistent with certain features of a charge-coupled release mechanism. None of the results is clearly inconsistent with the theory of Ca2+-induced release of Ca2+.

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