尾₂-Adrenergic and M₂-muscarinic receptors decrease basal t-tubular L-type Ca²⁺ channel activity and suppress ventricular contractility in heart failure

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• 作者：Toshihide Kashihara ; Masamichi Hirose ; Hisashi Shimojo ; Tsutomu Nakada ; Simmon Gomi ; Minoru Hongo ; Mitsuhiko Yamada
• 关键词：Heart failure ; L-type Ca2+ channels ; Protein phosphatase ; 尾2-adrenergic receptor ; M2-muscarinic receptor ; A1-adenosine receptor
• 刊名：European Journal of Pharmacology
• 出版年：5 February, 2014
• 年：2014
• 卷：724
• 期：Complete
• 页码：122-131
• 全文大小：1840 K

文摘

L-type Ca²⁺ channels (LTCC) play a crucial role in cardiac excitation-contraction coupling. We previously found that in failing ventricular myocytes of mice chronically treated with isoproterenol, basal t-tubular (TT) LTCC activity was halved by activation of protein phosphatase (PP)2A whereas basal surface sarcolemmal (SS) LTCC activity was doubled by inhibition of PP1. Interestingly, chronic treatment of these mice with pertussis toxin almost completely normalized TT and SS LTCC densities and cardiac contractility. In the present study, we therefore sought to identify the G_i/o protein-coupled receptors in cardiac myocytes (i.e. 尾₂-adrenergic, M₂-muscarinic and A₁-adenosine receptors) that are responsible for these abnormalities in heart failure by chronically administrating mice a selective antagonist of each receptor (ICI118,551, atropine and 8-cyclopentyl-1,3-dipropilxanthine (DPCPX), respectively) with isoproterenol. Compared with mice treated with isoproterenol alone, mice treated with isoproterenol plus ICI118,551 or atropine, but not DPCPX showed significantly lower lung weight/tibial length, higher fractional shortening, lower left ventricular end-diastolic pressure and higher dP/dt_max and dP/dt_min. In addition, ventricular myocytes of mice treated with isoproterenol plus ICI118,551 or atropine, but not DPCPX exhibited significantly higher TT and lower SS LTCC current densities than those of mice treated with isoproterenol alone due to normalization of the PP activities. These results indicate that 尾₂-adrenergic, M₂-muscarinic, but not A₁-adenosine receptors contribute to reduced ventricular contractility at least partially by decreasing basal TT LTCC activity in heart failure. Therefore, antagonists of 尾₂-adrenergic and/or M₂-muscarinic receptors can be good adjuncts to 尾₁-adrenergic receptor antagonists in the treatment of heart failure.