We investigated the effects of the
ATP-dependent K+ channel antagonist
glyburide and the
ATP-dependent K+ channel agonist
pinacidil in a Langendorff-perfused rabbit isolated heart subjected to a period of global
hypoxia. A class III
antiarrhythmic drug,
E-4031, also was studied in this model. These studies aimed to define the mechanism of action of putative profibrillatory actions of
pinacidil and the mechanism for the antifibrillatory effect of the class III
antiarrhythmic drug,
E-4031, in the hypoxic heart. After stabilization and determination of baseline functional parameters under normoxic perfusion conditions (95% O2/5% CO2), hearts were subjected to global
hypoxia by switching to a 95% N2/5% CO2 saturated perfusion medium for a period of 12 min. After the hypoxic period, normoxia was re-established by switching to the
oxygen-
carbon dioxide saturated
buffer medium for a period of 40 min. The
oxygen tension of the perfusion
buffer was reduced from approximately 400 mm Hg to below 50 mm Hg during the hypoxic period. All hearts subjected to
hypoxia had reduced function: the left ventricular developed pressure and +/- dP/dt were reduced significantly. Myocardial tissue
ATP concentrations were reduced (> 50%) in hearts subjected to
hypoxia. Under conditions of hypoxic/reoxygenation and in the presence of a low (2.5 mM)
potassium concentration ([K+]0),
pinacidil (1.25 microM) facilitated the induction of
ventricular fibrillation (80% fibrillation in the presence of
pinacidil vs. 20% in the absence of
pinacidil).
Glyburide (10 microM) and
E-4031 (1 and 10 microM) significantly reduced the incidence of
ventricular fibrillation associated with
pinacidil (20% fibrillation in the presence of
hypoxia,
pinacidil, and
glyburide or 10 microM
E-4031). Opening of the
ATP-dependent K+ channel by
pinacidil under normoxia and low K+ also facilitated the induction of
ventricular fibrillation (60%
ventricular fibrillation).
Pinacidil failed to induce
ventricular fibrillation under either normoxic or conditions of hypoxic/reoxygenation when the [K+]0 was increased to 5.1 mM. The results of this study demonstrate that K+ channel activators facilitate the induction of
ventricular fibrillation under both normoxic conditions and conditions of hypoxic/reoxygenation when the perfusion
buffer K+ concentration is reduced.