Altered heart rate and Sinoatrial node function in mice lacking the cAMP regulator phosphoinositide 3-kinase-gamma

作者：Rose Robert A; Kabir M Golam; Backx Peter H^*

来源：Circulation Research, 2007, 101(12): 1274-1282.

DOI：10.1161/CIRCRESAHA.107.158428

• ion channels
• electrophysiology
• action potentials
• arrhythmia

Ablation of the enzyme phosphoinositide 3-kinase (PI3K) gamma ( PI3K gamma(-/-)) in mice increases cardiac contractility by elevating intracellular cAMP and enhancing sarcoplasmic reticulum Ca(2+) handling. Because cAMP is a critical determinant of heart rate, we investigated whether heart rate is altered in mice lacking PBK gamma. Heart rate was similar in anesthetized PI3K gamma(-/-) and wild-type (PI3K gamma(-/-)) mice. However, IP injection of atropine ( 1 mg/kg), propranolol ( 1 mg/ kg), or both drugs in combination unmasked elevated heart rates in PI3K gamma(-/-) mice, suggesting altered sinoatrial node (SAN) function. Indeed, spontaneous action potential frequency was approximate to 35% greater in SAN myocytes isolated from PI3K gamma(-/-) mice compared with PI3K gamma(-/-) 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 Ca(2+) release. Voltage-clamp experiments demonstrated that elevated action potential frequencies in PI3K gamma(-/-) SAN myocytes were more strongly associated with cAMP-dependent increases in L-type Ca(2+) current (I(Ca, L)) than elevated hyperpolarization- activated current ( If). In contrast, ICa, L was not increased in working atrial myocytes, suggesting distinct subcellular regulation of L-type Ca(2+) channels by PI3K gamma in the SAN compared with the working myocardium. In summary, PI3K gamma regulates heart rate by the cAMP-dependent modulation of SAN function. The effects of PI3K gamma ablation in the SAN are unique from those in the working myocardium.

• 出版日期2007-12-7