Since 1981, when Mullins published his provocative book proposing that the Na-Ca exchanger is electrogenic, it has been shown, first by computer simulation by Noble and later by experiment by various investigators, that inward iNaCa triggered by the Ca2+ transient is responsible for the low plateau of the atrial action potential and contributes to the high plateau of the ventricular action potential. Reduction or complete block of inward iNaCa by buffering intracellular Ca2+ with EGTA or BAPTA, by blocking SR Ca2+ release or by substituting extracellular Na+ with Li+ can result in a shortening of the action potential. The effect of block of outward iNaCa or complete block of both inward and outward iNaCa on the action potential has not been investigated experimentally, because of the lack of a suitable blocker, and remains a goal for the future. An increase in the intracellular Na+ concentration (after the application of cardiac glycoside or an increase in heart rate) or an increase in extracellular Ca2+ are believed to lead to an outward shift in iNaCa at plateau potentials and a shortening of the action potential. Changes in the Ca2+ transient are expected to result in changes in inward iNaCa and thus the action potential. This may explain the shortening of the premature action potential as well as the prolongation of the action potential when a muscle is allowed to shorten during the action potential. Inward iNaCa may play an important role in both normal and abnormal pacemaker activity in the heart.

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The mechanisms underlying electrical restitution (recovery of action potential duration after a preceding beat) were investigated in ferret ventricular cells. The time to 80% recovery (t80) of action potential duration was ∼204 ms. At a holding potential of −80 mV, the Ca2+ current (ICa) reactivated and the delayed rectifier K+ current (IK) deactivated very rapidly (t80: ∼32 and ∼93 ms, respectively). The kinetics of both currents are too fast to account for electrical restitution alone. The putative inward Na+−Ca2+ exchange current (INa‐Ca) produced by the Na+−Ca2+ exchanger in response to the intracellular Ca2+ transient reprimed (t80: 189 ms) with the same time course as mechanical restitution (recovery of contraction) and with a similar time course to electrical restitution. Substantial reduction of inward INa‐Ca, by buffering intracellular Ca2+ with the acetyl methyl ester form of BAPTA, shortened the action potential and greatly altered the electrical restitution curve. Subsequent addition of nifedipine (to block ICa) or 4–aminopyridine (4–AP) (to block the transient outward current, ITO) further altered the electrical restitution curve. Any time‐dependent current that contributes to the action potential is likely to affect the time course of electrical restitution. Although ICa:, IK and ITO were previously thought to be the only currents involved in electrical restitution, we conclude that inward INa‐Ca also plays an important role.

The inotropic effects of ACh and adenosine on ferret ventricular cells were investigated with the action potential-clamp technique. Under current clamp, both agonists resulted in action potential shortening and a decrease in contraction. Under action potential clamp, both agonists failed to decrease contraction substantially. In the absence of agonist, application of the short action potential waveform (recorded previously in the presence of agonist) also resulted in a decrease in contraction. Under action potential clamp, application of ACh resulted in a Ba2+-sensitive outward current with the characteristics of muscarinic K+ current ( I K,ACh); the presence of the muscarinic K+ channel was confirmed by PCR and immunocytochemistry. In the absence of agonist, on application of the short ACh action potential waveform, the decrease in contraction was accompanied by loss of the inward Na+/Ca2+exchange current ( I NaCa). ACh also inhibited the background inward K+ current ( I K,1). It is concluded that ACh activates I K,ACh, inhibits I K,1, and indirectly inhibits I NaCa; this results in action potential shortening, decrease in contraction, and, as a result of the inhibition of I K,1, minimum decrease in excitability.

1. Inward Na+-Ca2+ exchange current (iUNca) 3. Replacing extracellular Nae with Li+ or buffering intracellular Ca2P caused a significant shortening of the action potential (at -65 mV, 44 + 2% with Li+ and 20 + 2% with BAPTA AM). The shortening can be explained by changes in iNaca. 4. The action potential clamp technique was used to measure the BAPTA-sensitive current (putative iNaca) and the Ca2P current (iCa; measured using nifedipine) during the action potential. Under control conditions, the inward BAPTA-sensitive current makes approximately the same contribution as ica during much of the action potential plateau. These results suggest an important role for inward iNaca in the ferret ventricular action potential.