Effects of the Na(+)-Ca(2+) exchange (NCX) inhibitor
KB-R7943 on electrical and contractile function were examined in guinea pig ventricular myocytes exposed to
ischemia and reperfusion. Action potentials and transmembrane currents were recorded with
microelectrodes; contractions were measured with an edge detector. Cells were exposed to simulated
ischemia (
hypoxia,
hypercapnia,
hyperkalemia,
acidosis,
lactate accumulation, no
glucose) for 20 min and reperfused with
Tyrode's solution. Experiments were conducted at 37 degrees C in the absence or presence of
KB-R7943. Low concentrations of
KB-R7943 (0.1 microM) had little impact on changes in contractions, membrane potential, or Ca(2+) current induced by
ischemia and reperfusion. However, higher concentrations of
KB-R7943 (0.5 and 1.0 microM) reduced the magnitude of Ca(2+) current and promoted action potential abbreviation in both
ischemia and reperfusion. High concentrations of
KB-R7943 also promoted post-ischemic contractile dysfunction (stunning) in reperfusion. In the absence of
KB-R7943, the arrhythmogenic transient inward current (I(TI)) plus aftercontractions occurred upon reperfusion, and some cells exhibited irreversible cell injury (hypercontracture). Higher concentrations of
KB-R7943 (0.5 and 1.0 micoM) did not affect the occurrence or magnitude of I(TI) and aftercontractions and did not affect the occurrence of hypercontracture. In contrast, 0.1 microM
KB-R7943 virtually abolished I(TI), aftercontractions and hypercontracture. Thus, low concentrations of
KB-R7943 protected against
ischemia and
reperfusion injury, but higher concentrations of
drug actually exacerbated detrimental effects of
ischemia and reperfusion. These results suggest that inhibition of I(TI) may contribute to the antiarrhythmic effects of
KB-R7943 on reperfusion-induced arrhythmias.