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β2 adrenergic receptor activation governs cardiac repolarization and arrhythmogenesis in a guinea pig model of heart failure.

Wang Y, Yuan J, Qian Z, Zhang X, Chen Y, Hou X, Zou J - Sci Rep (2015)

Bottom Line: These effects could be prevented by the selective β2-AR antagonist, ICI118551.Salbutamol prolonged APD90 and reduced Ikr in guinea pig HF myocytes.However, the antagonists of Gi protein (PTX) and PDE III (amrinone) showed opposite effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

ABSTRACT
β2-AR activation increases the risk of sudden cardiac death (SCD) in heart failure (HF) patients. Non-selective β-AR blockers have greater benefits on survival than selective β1-AR blockers in chronic HF patients, indicating that β2-AR activation contributes to SCD in HF. This study investigated the role of β2-AR activation on repolarization and ventricular arrhythmia (VA) in the experimental HF model. The guinea pig HF was induced by descending aortic banding. The effective refractoriness period (ERP), corrected QT (QTc) and the incidence of VA were examined using Langendorff and programmed electrical stimulation. Ikr and APD were recorded by the whole cell patch clamp. Selective β2-AR agonist salbutamol significantly increased the incidence of VA, prolonged QTc and shortened ERP. These effects could be prevented by the selective β2-AR antagonist, ICI118551. Salbutamol prolonged APD90 and reduced Ikr in guinea pig HF myocytes. The antagonists of cAMP (Rp-cAMP) and PKA (KT5720) attenuated Ikr inhibition and APD prolongation induced by salbutamol. However, the antagonists of Gi protein (PTX) and PDE III (amrinone) showed opposite effects. This study indicates that β2-AR activation increases the incidence of VA in the experimental HF model via activation of Gs/cAMP/PKA and/or inhibition of Gi/PDE pathways.

No MeSH data available.


Related in: MedlinePlus

Salbutamol (Sal) significantly prolonges QTc in HF guinea pigs.(A) Representative ECG traces from control (left), salbutamol (10 μM, middle) and salbutamol plus ICI118551 (ICI, 1 μM, right) treated hearts from Control (upper) and HF guinea pigs (lower). (B) Bar graphs summarize the rate-corrected QT from Con and HF guinea pigs before and after administration of Sal (10 μM) or Sal plus ICI (1 μM) (*p < 0.05, HF vs. Con, n = 6). (C) Bar graphs show the Sal-induced percentage difference of prolongation of QTc from Control () and HF () guinea pigs (*p < 0.05, n = 6).
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f2: Salbutamol (Sal) significantly prolonges QTc in HF guinea pigs.(A) Representative ECG traces from control (left), salbutamol (10 μM, middle) and salbutamol plus ICI118551 (ICI, 1 μM, right) treated hearts from Control (upper) and HF guinea pigs (lower). (B) Bar graphs summarize the rate-corrected QT from Con and HF guinea pigs before and after administration of Sal (10 μM) or Sal plus ICI (1 μM) (*p < 0.05, HF vs. Con, n = 6). (C) Bar graphs show the Sal-induced percentage difference of prolongation of QTc from Control () and HF () guinea pigs (*p < 0.05, n = 6).

Mentions: In the control hearts, the selective β2-AR agonist salbutamol slightly prolonged QTc compared to the control group (262.2 ± 7.29 ms vs 240.8 ± 6.07 ms, n = 6, p < 0.05) (Fig. 2B). However, salbutamol significantly broadened QTc of HF hearts compared to HF hearts perfused without salbutamol (293.5 ± 6.60 ms vs. 258.7 ± 6.65 ms, n = 6, p < 0.01) (Fig. 2B). The percentage increase in QTc was significantly larger in the HF hearts than in the control hearts (13.52 ± 1.72% vs. 8.87 ± 0.84%, n = 6, p < 0.05) (Fig. 2C). To determine if β2-AR mediated QTc broadening was induced by salbutamol, the hearts were perfused with selective β2-AR antagonist ICI118551 for 30 min prior to salbutamol. ICI118551 significantly limited QTc prolongation induced by salbutamol in the control (239.7 ± 7.29 ms vs. 262.2 ± 7.29 ms, n = 6, p < 0.05) (Fig. 2B) and HF groups (264.5 ± 9.29 ms vs 293.5 ± 6.60 ms, n = 6, p < 0.05) (Fig. 2B).


β2 adrenergic receptor activation governs cardiac repolarization and arrhythmogenesis in a guinea pig model of heart failure.

Wang Y, Yuan J, Qian Z, Zhang X, Chen Y, Hou X, Zou J - Sci Rep (2015)

Salbutamol (Sal) significantly prolonges QTc in HF guinea pigs.(A) Representative ECG traces from control (left), salbutamol (10 μM, middle) and salbutamol plus ICI118551 (ICI, 1 μM, right) treated hearts from Control (upper) and HF guinea pigs (lower). (B) Bar graphs summarize the rate-corrected QT from Con and HF guinea pigs before and after administration of Sal (10 μM) or Sal plus ICI (1 μM) (*p < 0.05, HF vs. Con, n = 6). (C) Bar graphs show the Sal-induced percentage difference of prolongation of QTc from Control () and HF () guinea pigs (*p < 0.05, n = 6).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4286790&req=5

f2: Salbutamol (Sal) significantly prolonges QTc in HF guinea pigs.(A) Representative ECG traces from control (left), salbutamol (10 μM, middle) and salbutamol plus ICI118551 (ICI, 1 μM, right) treated hearts from Control (upper) and HF guinea pigs (lower). (B) Bar graphs summarize the rate-corrected QT from Con and HF guinea pigs before and after administration of Sal (10 μM) or Sal plus ICI (1 μM) (*p < 0.05, HF vs. Con, n = 6). (C) Bar graphs show the Sal-induced percentage difference of prolongation of QTc from Control () and HF () guinea pigs (*p < 0.05, n = 6).
Mentions: In the control hearts, the selective β2-AR agonist salbutamol slightly prolonged QTc compared to the control group (262.2 ± 7.29 ms vs 240.8 ± 6.07 ms, n = 6, p < 0.05) (Fig. 2B). However, salbutamol significantly broadened QTc of HF hearts compared to HF hearts perfused without salbutamol (293.5 ± 6.60 ms vs. 258.7 ± 6.65 ms, n = 6, p < 0.01) (Fig. 2B). The percentage increase in QTc was significantly larger in the HF hearts than in the control hearts (13.52 ± 1.72% vs. 8.87 ± 0.84%, n = 6, p < 0.05) (Fig. 2C). To determine if β2-AR mediated QTc broadening was induced by salbutamol, the hearts were perfused with selective β2-AR antagonist ICI118551 for 30 min prior to salbutamol. ICI118551 significantly limited QTc prolongation induced by salbutamol in the control (239.7 ± 7.29 ms vs. 262.2 ± 7.29 ms, n = 6, p < 0.05) (Fig. 2B) and HF groups (264.5 ± 9.29 ms vs 293.5 ± 6.60 ms, n = 6, p < 0.05) (Fig. 2B).

Bottom Line: These effects could be prevented by the selective β2-AR antagonist, ICI118551.Salbutamol prolonged APD90 and reduced Ikr in guinea pig HF myocytes.However, the antagonists of Gi protein (PTX) and PDE III (amrinone) showed opposite effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

ABSTRACT
β2-AR activation increases the risk of sudden cardiac death (SCD) in heart failure (HF) patients. Non-selective β-AR blockers have greater benefits on survival than selective β1-AR blockers in chronic HF patients, indicating that β2-AR activation contributes to SCD in HF. This study investigated the role of β2-AR activation on repolarization and ventricular arrhythmia (VA) in the experimental HF model. The guinea pig HF was induced by descending aortic banding. The effective refractoriness period (ERP), corrected QT (QTc) and the incidence of VA were examined using Langendorff and programmed electrical stimulation. Ikr and APD were recorded by the whole cell patch clamp. Selective β2-AR agonist salbutamol significantly increased the incidence of VA, prolonged QTc and shortened ERP. These effects could be prevented by the selective β2-AR antagonist, ICI118551. Salbutamol prolonged APD90 and reduced Ikr in guinea pig HF myocytes. The antagonists of cAMP (Rp-cAMP) and PKA (KT5720) attenuated Ikr inhibition and APD prolongation induced by salbutamol. However, the antagonists of Gi protein (PTX) and PDE III (amrinone) showed opposite effects. This study indicates that β2-AR activation increases the incidence of VA in the experimental HF model via activation of Gs/cAMP/PKA and/or inhibition of Gi/PDE pathways.

No MeSH data available.


Related in: MedlinePlus