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(Circulation Research. 2007;101:1274.)
© 2007 American Heart Association, Inc.

Cellular Biology

Altered Heart Rate and Sinoatrial Node Function in Mice Lacking the cAMP Regulator Phosphoinositide 3-Kinase-

Robert A. Rose, M. Golam Kabir, Peter H. Backx

From the Departments of Physiology and Medicine (R.A.R., P.H.B.), Division of Cardiology at the University Health Network (R.A.R., P.H.B.), and Heart and Stroke/Richard Lewar Centre of Excellence (R.A.R., M.G.K., P.H.B.), University of Toronto, Ontario, Canada.

Correspondence to Dr Peter H. Backx, University of Toronto, Heart & Stroke/ Richard Lewar Centre, Room 68, Fitzgerald Building, 150 College St, Toronto, Ontario, Canada M5S 3E2. E-mail p.backx{at}utoronto.ca

Ablation of the enzyme phosphoinositide 3-kinase (PI3K) (PI3K^–/–) in mice increases cardiac contractility by elevating intracellular cAMP and enhancing sarcoplasmic reticulum Ca²⁺ handling. Because cAMP is a critical determinant of heart rate, we investigated whether heart rate is altered in mice lacking PI3K. Heart rate was similar in anesthetized PI3K^–/– and wild-type (PI3K^+/+) mice. However, IP injection of atropine (1 mg/kg), propranolol (1 mg/kg), or both drugs in combination unmasked elevated heart rates in PI3K^–/– mice, suggesting altered sinoatrial node (SAN) function. Indeed, spontaneous action potential frequency was 35% greater in SAN myocytes isolated from PI3K^–/– mice compared with PI3K^+/+ mice. These differences in action potential frequency were abolished by intracellular dialysis with the cAMP/protein kinase A antagonist Rp-cAMP but were unaffected by treatment with ryanodine to inhibit sarcoplasmic reticulum Ca²⁺ release. Voltage-clamp experiments demonstrated that elevated action potential frequencies in PI3K^–/– SAN myocytes were more strongly associated with cAMP-dependent increases in L-type Ca²⁺ current (I_Ca,L) than elevated hyperpolarization-activated current (I_f). In contrast, I_Ca,L was not increased in working atrial myocytes, suggesting distinct subcellular regulation of L-type Ca²⁺ channels by PI3K in the SAN compared with the working myocardium. In summary, PI3K regulates heart rate by the cAMP-dependent modulation of SAN function. The effects of PI3K ablation in the SAN are unique from those in the working myocardium.

Key Words: ion channels • electrophysiology • action potentials • arrhythmia