Inactivation of ICa-L is the major determinant of use-dependent facilitation in rat cardiomyocytes

Two models have been proposed to explain facilitation of the L-type calcium current (I(Ca-L)). A positive feedback model proposes that calcium released during a conditioning pulse (I(1)) facilitates the subsequent pulse (I(2)) via calmodulin/calmodulin kinase II (CaMKII) mechanisms. The negative feedback model proposes that the calcium release of each pulse feeds back on itself via calcium-dependent inactivation. The relative physiological roles were evaluated in rat ventricular myocytes. Paired pulses (450 ms interpulse interval) elicited facilitation (I(2) of 872 ± 145 versus I(1) of 777 ± 132 pA, P 0.01). Evidence for the negative feedback mechanism includes: (a) ryanodine (0.3 mm) eliminated facilitation, surprisingly by increasing the amplitude of I(1) more than that of I(2) (1039 ± 216 and 977 ± 186 pA) and eliminated the difference in T(0.37) between I(2) and I(1) (33.1 ± 4.5 versus 32.5 ± 4.6 ms); (b) an outward I(2), which does not trigger sarcoplasmic reticulum (SR) Ca(2+) release, eliminated facilitation even when it was conditioned by an inward I(1); (c) facilitation decayed as the I(1)–I(2) interval lengthened (time constant (τ) = 16.9 ± 1.4 s); (d) thapsigargin (0.1 μm) slowed this decay (τ= 43.8 ± 11.7 s) whereas isoproterenol accelerated it (τ<= 5.6 ± 1.4 s, P < 0.01) and T(0.37) paralleled this decay; and (e) the magnitude of I(Ca-L) was negatively correlated with the sodium-calcium exchange current (I(Na/Ca)) elicited by the SR-Ca(2+) release. In conclusion, Ca(2+)-dependent inactivation of I(Ca-L) is the major mechanism underlying facilitation.