BAY K 8644 modifies Ca2+ cross signaling between DHP and ryanodine receptors in rat ventricular myocytes

The amplification factor of dihydropyridine (DHP)/ryanodine receptors was d efined as the amount of Ca2+ released from the sarcoplasmic reticulum (SR) relative to the influx of Ca2+ through L-type Ca2+ channels in rat ventricu lar myocytes. The amplification factor showed steep voltage dependence at p otentials negative to -10 mV but was less dependent on voltage at potential s positive to this value. In cells dialyzed with 0.2 mM cAMP in addition to 2 mM fura 2, the Ca2+-channel agonist (-)-BAY K 8644 enhanced Ca2+-channel current (I-Ca), shifted the activation curve by -10 mV, and significantly delayed its inactivation. Surprisingly, BAY K 8644 reduced the amplificatio n factor by 50% at all potentials, even though the caffeine-releasable Ca2 stores were mostly intact at holding potentials of -90 mV. In contrast, br ief elevation of extracellular Ca2+ activity from 2 to 10 mM enhanced both I-Ca and intracellular Ca2+ transients in the absence or presence of BAY K 8644 but had no significant effect on the amplification factor. BAY K 8644 abolished the direct dependence of the rate of inactivation of I-Ca on the release of Ca2+ from the SR. These findings suggest that the gain of the Ca 2+-induced Ca2+ release in cardiac myocytes is regulated by the gating kine tics of cardiac L-type Ca2+ channels via local exchange of Ca2+ signals bet ween DHP and ryanodine receptors and that BAY K 8644 suppresses the amplifi cation factor through attenuation of the Ca2+-dependent inactivation of Ca2 + channels.