The phosphoinositide 3-kinase inhibitor LY294002 enhances cardiac myocyte contractility via a direct inhibition of Ik,slow currents

doi:10.1016/j.cardiores.2004.01.029

Cardiovascular Research 2004 62(3):509-520; doi:10.1016/j.cardiores.2004.01.029
© 2004 by European Society of Cardiology

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The phosphoinositide 3-kinase inhibitor LY294002 enhances cardiac myocyte contractility via a direct inhibition of I_k,slow currents

Hui Sun, Gavin Y. Oudit, Rafael J. Ramirez, Danny Costantini and Peter H. Backx^*

Department of Physiology and Medicine, Heart & Stroke/Richard Lewar Centre and Division of Cardiology, University Health Network, University of Toronto Fitzgerald Building, 150 College St., Toronto, Ontario, Canada M5S 3E2

^* Corresponding author. Tel.: +1-416-946-8112, +1-416-528-4003; fax: +1-416-946-8380. Email address: p.backx{at}utoronto.ca

Objective: Phosphoinositide 3-kinase (PI3K) is a key componentin regulating myocardial growth, survival and contractility.LY294002 and wortmannin are two PI3K inhibitors used widelyto establish the role of PI3K. The goal of this study was toexamine the effects of acute application of LY294002 and wortmanninon cardiac myocyte contractility and underlying machanisms.Methods: Patch-clamp, indo-1 epifluorescence and video-edgedetection techniques were used to measure outward K⁺ currents,action potentials (AP), Ca²⁺ transients and shortening of myocytesisolated from mouse left ventricular free wall. Results: Infield-stimulated myocytes, LY294002 (10 µmol/l) increasedCa²⁺ transient amplitude by 23%, and cell shortening amplitudeby 60% in the absence or presence of wortmannin, while wortmanninalone had no effect. LY294002 (but not wortmannin) prolongedAP duration by specifically inhibiting slowly inactivating K⁺currents (i.e., the 4-aminopyrydine-sensitive I_k,slow1 and thetetraethylammonium-sensitive I_k,slow2), leading to an increasein sarcoplasmic reticular Ca²⁺ levels. It appeared that theAP prolongation was responsible for elevated contractility sinceAP-clamp of myocytes with prolonged APs (recorded in LY294002-treatedmyocytes) induced a 29% increase in cell shortening comparedwith control APs, while LY294002 application did not increasecontractility in voltage-clamp studies using either step orAP depolarizations. Conclusions: The putative PI3K inhibitorLY294002 increases Ca²⁺ release and myocyte contractility viadirect inhibition of cardiac I_k,slow and AP prolongation, thuslimiting the usefulness of this agent in the analyses of therole of PI3K in heart function.

KEYWORDS Phosphoinositide 3-kinase; LY294002; Cardiac myocyte contractility; Ca²⁺ transient; Action potential; I_k,slow currents

Time for primary review 25 days

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