Potassium channel activators differentially modulate the effect of sodium channel blockade on cardiac conduction.

AIMS: Diminished repolarization reserve contributes to the arrhythmogenic substrate in many disease states. Pharmacological activation of K(+) channels has been suggested as a potential antiarrhythmic therapy in such conditions. Having previously demonstrated that I(K1) and I(Kr) can modulate cardiac conduction, we tested here the effects of pharmacological I(KATP) and I(Ks) activation on cardiac conduction and its dependence on the sodium current (I(Na)). METHODS AND RESULTS: Bath electrocardiograms (ECGs) recorded from Langendorff-perfused guinea pig ventricles revealed QRS prolongation during I(KATP) activation by pinacidil but not during I(Ks) activation by R-L3 relative to control. In contrast, when I(Na) was partially blocked by flecainide, R-L3 but not pinacidil prolonged the QRS relative to flecainide alone. Conduction velocity (θ) was quantified by optical mapping during epicardial pacing. Both longitudinal (θ(L)) and transverse (θ(T)) θ were reduced by pinacidil (by 10 ± 1 and 9 ± 3%, respectively) and R-L3 (by 11 ± 2% and 15 ± 4%, respectively). Flecainide decreased θ(L) by 33 ± 4% and θ(T) by 36 ± 5%. Whereas pinacidil did not further slow θ relative to flecainide alone, R-L3 decreased both θ(L) and θ(T). CONCLUSION: Pharmacological activation of I(KATP) and I(Ks) slows cardiac conduction; however, they demonstrate diverse effects on θ dependence on I(Na) blockade. These findings may have significant implications for the use of K(+) channel activators as antiarrhythmic drugs and for patients with Na(+) channel abnormalities or being treated with Na(+) channel blockers.

Energetic study of cardioplegic hearts under ischaemia/reperfusion and [Ca(2+)] changes in cardiomyocytes of guinea-pig: mitochondrial role.

AIM: To study the role of mitochondria in the recovery of guinea-pig hearts exposed to high-K(+)-cardioplegia (CPG) and ischaemia/reperfusion (I/R) METHODS: We measured contractility and heat release in perfused guinea-pig hearts and cytosolic and mitochondrial Ca(2+) by epifluorescence and confocal microscopy in isolated cardiomyocytes loaded with Fluo-4 or Rhod-2. RESULTS: In hearts, CPG increased the postischaemic contractile recovery, and this was potentiated by the mNCX blocker clonazepam and the mKATP opener diazoxide, which also prevented the fall in muscle economy. Moreover, CPG prevented the stunning induced by ouabain, which was reduced by clonazepam. In cardiomyocytes, CPG increased fluorescent signals of cytosolic and mitochondrial Ca(2+), while the addition of a mNCX blocker (CGP37157) increased cytosolic but reduced mitochondrial [Ca(2+)]. Ouabain in CPG increased cytosolic Ca(2+) and resting heat, but the addition of CGP37157 reduced them, as well as mitochondrial Ca(2+). CONCLUSIONS: CPG, diazoxide and clonazepam improve postischaemic recovery, respectively, by increasing the Ca(2+) cycling and by reducing the mitochondrial Ca(2+) uptake either by uniporter or by mNCX. The mitochondria compete with the leaky sarcoplasmic reticulum (SR) as sink of Ca(2+) in guinea-pig hearts, affecting the postischaemic contractility. CPG also prevented the ouabain-induced dysfunction by avoiding the Ca(2+) overload. Ouabain reduced the synergism between CPG and clonazepam suggesting that [Na(+)]i and SR load influence the mNCX role.