Altered heart rate and Sinoatrial node function in mice lacking the cAMP regulator phosphoinositide 3-kinase-γ
Altered heart rate and Sinoatrial node function in mice lacking the cAMP regulator phosphoinositide 3-kinase-γ
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DOI：
10.1161/circresaha.107.158428
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发表时间：
2007-12-07
影响因子：
20.1
通讯作者：
Backx, Peter H.
中科院分区：
文献类型：
--
作者：
Rose, Robert A.;Kabir, M. Golam;Backx, Peter H.
在小鼠中，酶磷酸肌醇3-激酶（PI 3 K）γ（PI 3 K γ（-/-））的消融通过升高细胞内cAMP和增强肌浆网Ca 2+处理来增加心肌收缩力。由于cAMP是心率的关键决定因素，我们研究了缺乏PBK γ的小鼠的心率是否改变。麻醉的PI 3 K γ（-/-）和野生型（PI 3 K γ（-/-））小鼠的心率相似。然而，IP注射阿托品（1 mg/kg）、普萘洛尔（1 mg/ kg）或两种药物联合给药暴露了PI 3 K γ（-/-）小鼠的心率升高，表明窦房结（SAN）功能改变。事实上，与PI 3 K γ（-/-）小鼠相比，从PI 3 K γ（-/-）小鼠分离的SAN肌细胞中的自发动作电位频率大约高35%。这些动作电位频率的差异被废除的cAMP/蛋白激酶A拮抗剂RP-cAMP的细胞内透析，但不受治疗与ryanodine抑制肌浆网Ca 2+释放。电压钳实验表明，在PI 3 K γ（-/-）SAN心肌细胞中，动作电位频率升高与L型Ca 2+电流（I-Ca，I-L）的cAMP依赖性增加的相关性比超极化激活电流（If）升高更强。相反，伊卡，L在工作心房肌细胞中没有增加，表明与工作心肌相比，SAN中PI 3 K γ对L型Ca 2+通道的亚细胞调节不同。总之，PI 3 K γ通过cAMP依赖性调节SAN功能来调节心率。SAN中PI 3 K伽马消融的效果与工作心肌中的效果不同。
Ablation of the enzyme phosphoinositide 3-kinase (PI3K) gamma ( PI3K gamma(-/-)) 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 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 Ca2+ 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 Ca2+ current (I-Ca,I- 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 Ca2+ 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.