1. L-type Ca2+ channels play an important role in vital cell functions such
as muscle contraction and hormone secretion. Both a voltage-dependent and
a Ca2+-dependent process inactivate these channels. Here we present evidenc
e that inhibition of the mitochondrial Ca2+ import mechanism in rat (Spragu
e-Dawley) ventricular myocytes by ruthenium red (RR), by RON or by carbonyl
cyanide m-chlorophenylhydrazone (CCCP) decreases the magnitude of electric
ally evoked transient elevations of cytosolic Ca2+ concentration ([Ca2+](c)
). These agents were most effective at stimulus rates greater than 1 Hz.
2. RR and CCCP also caused a significant delay in the recovery from inactiv
ation of L-type Ca2+ currents (I-Ca). This suggests that sequestration of c
ytosolic Ca2+, probably near the, mouth of L-type Ca2+ channels, into mitoc
hondria. during cardiac contractile cycles, helps to remove the Ca2+-depend
ent inactivation of L-type Ca2+ channels.
3. We conclude that impairment of mitochondrial Ca2+ transport has no impac
t on either L-type Ca2+ currents or SR Ca2+ release at low stimulation freq
uencies (e.g. 0.1 Hz); however, it causes a depression of cytosolic: Ca2+ t
ransients attributable to an impaired recovery of L-type Ca2+ currents from
inactivation at high stimulation frequencies (e.g. 3 Hz). The impairment o
f mitochondrial Ca2+ uptake and subsequent effects on Ca2+ transients at hi
gh frequencies at room temperature could be physiologically relevant since
the normal heart rate of rat is around 5 Hz at body temperature. The role o
f mitochondria in clearing Ca2+ in the micro-domain near L-type Ca2+ channe
ls could be impaired during high frequencies of heart beats such as in vent
ricular tachycardia, explaining, at least in part, the reduction of muscle
contractility.