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Actions of pinacidil at a reduced potassium concentration: a direct cardiac effect possibly involving the ATP-dependent potassium channel.

Abstract：

: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.

journal_name

J Cardiovasc Pharmacol

journal_title

Journal of cardiovascular pharmacology

authors

Chi L,Black SC,Kuo PI,Fagbemi SO,Lucchesi BR

doi

10.1097/00005344-199302000-00001

subject

Has Abstract

pub_date

1993-02-01 00:00:00

pages

179-90

issue

eissn

0160-2446

issn

1533-4023

journal_volume

pub_type

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Actions of pinacidil at a reduced potassium concentration: a direct cardiac effect possibly involving the ATP-dependent potassium channel.