Atropine augments cardiac contractility by inhibiting cAMP-specific phosphodiesterase type 4
Atropine augments cardiac contractility by inhibiting cAMP-specific phosphodiesterase type 4
复制标题
阿托品通过抑制 cAMP 特异性磷酸二酯酶 4 型增强心肌收缩力
DOI：
10.1038/s41598-017-15632-x
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发表时间：
2017
影响因子：
4.6
通讯作者：
Nikolaev VO
中科院分区：
文献类型：
--
作者：
Perera RK;Fischer TH;Wagner M;Dewenter M;Vettel C;Bork NI;Maier LS;Conti M;Wess J;El- Armouche A;Hasenfuß G;Nikolaev VO
阿托品是一种临床上相关的抗胆碱能药物，它可以阻断副交感神经递质乙酰胆碱对心率的抑制作用，从而导致心动过速。然而，阿托品的许多心脏作用不能仅仅用它对毒扁豆碱受体的拮抗来充分解释。在表达Förster共振能量转移(FRET)的cAMP生物传感器的分离的小鼠心肌细胞中，我们证实阿托品抑制了乙酰胆碱诱导的cAMP减少。出乎意料的是，即使在没有乙酰胆碱的情况下，在百日咳毒素使G蛋白失活后，或者在M2或M1/3受体敲除小鼠的心肌细胞中，阿托品也增加了用β肾上腺素能激动剂异丙肾上腺素预先升高的cAMP水平。利用FRET方法和体外磷酸二酯酶(PDE)活性测定，我们证明阿托品是一种变构PDE 4(PDE4)抑制剂。在人心房心肌和野生型和M2或M1/3受体敲除的完整小鼠的朗宁多夫心脏中，阿托品分别导致收缩能力和心率的增加。在体内，PDE4D的阿托品依赖的心率增加的延长被钝化，但在野生型或PDE4B基因敲除的小鼠中没有。我们认为，阿托品对PDE4的抑制至少部分是该药物诱发心动过速和致心律失常的原因。
Atropine is a clinically relevant anticholinergic drug, which blocks inhibitory effects of the parasympathetic neurotransmitter acetylcholine on heart rate leading to tachycardia. However, many cardiac effects of atropine cannot be adequately explained solely by its antagonism at muscarinic receptors. In isolated mouse ventricular cardiomyocytes expressing a Förster resonance energy transfer (FRET)-based cAMP biosensor, we confirmed that atropine inhibited acetylcholine-induced decreases in cAMP. Unexpectedly, even in the absence of acetylcholine, after G-protein inactivation with pertussis toxin or in myocytes from M2- or M1/3-muscarinic receptor knockout mice, atropine increased cAMP levels that were pre-elevated with the β-adrenergic agonist isoproterenol. Using the FRET approach andin vitrophosphodiesterase (PDE) activity assays, we show that atropine acts as an allosteric PDE type 4 (PDE4) inhibitor. In human atrial myocardium and in both intact wildtype and M2or M1/3-receptor knockout mouse Langendorff hearts, atropine led to increased contractility and heart rates, respectively.In vivo, the atropine-dependent prolongation of heart rate increase was blunted in PDE4D but not in wildtype or PDE4B knockout mice. We propose that inhibition of PDE4 by atropine accounts, at least in part, for the induction of tachycardia and the arrhythmogenic potency of this drug.