β3-adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca2+ current
β3-adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca2+ current
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DOI：
10.1172/jci32519
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发表时间：
2008-09-01
影响因子：
15.9
通讯作者：
Fischmeister, Rodolphe
中科院分区：
文献类型：
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作者：
Skeberdis, V. Arvydas;Gendvilliene, Vida;Fischmeister, Rodolphe
β(3)-肾上腺素能受体（β (3)-AR）的激活在人类心室产生负性肌力效应。在这里，我们探讨了[β (3)-AR在人类心房中的作用。出乎意料的是，β (3)-AR激活增加了人心房组织的收缩性，并刺激了离体人心房肌细胞（HAMs）中的l型Ca2+通道电流（I-Ca,I-L）。右心房组织标本来自57例因先天性缺陷、冠状动脉疾病、瓣膜置换术或心脏移植而接受心脏手术的患者。使用全细胞膜片钳技术和机电力传感器记录I-Ca、I-L和等距收缩。与异丙肾上腺素相比，两种选择性β (3)-AR激动剂SR58611和BRL37344以及β (3)-AR部分激动剂CGP12177能以纳米摩尔的效力刺激ham中的I-Ca，I-L，其疗效为60%-90%。β (3)-AR激动剂也能增加收缩力，但其疗效远低于异丙肾上腺素（约为10%）。用β (3)- ar拮抗剂L-748,337、β (1)/ β (2)- ar拮抗剂纳多洛尔和β (1)-/ β (2)- ar拮抗剂布萘洛尔证实β (3)- ars(而不是β (1)-/ β (2)- ars)参与了这些作用。β (3)-AR效应涉及cAMP/PKA途径，因为PKA抑制剂H89阻断了I-Ca，I-L刺激，而磷酸二酯酶抑制剂3-异丁基-1-甲基黄嘌呤（IBMX）强烈增强了正性肌力效应。因此，与心室组织不同，β (3)- ar通过camp依赖性途径与l型Ca2+通道和心房组织的收缩性正偶联。
beta(3)-adrenergic receptor (beta(3)-AR) activation produces a negative inotropic effect in human ventricles. Here we explored the role of [beta(3)-AR in the human atrium. Unexpectedly, beta(3)-AR activation increased human atrial tissue contractility and stimulated the L-type Ca2+ channel current (I-Ca,I-L) in isolated human atrial myocytes (HAMs). Right atria] tissue specimens were obtained from 57 patients undergoing heart surgery for congenital defects, coronary artery diseases, valve replacement, or heart transplantation. The I-Ca,I-L and isometric contraction were recorded using a whole-cell patch-clamp technique and a mechanoelectrical force transducer. Two selective beta(3)-AR agonists, SR58611 and BRL37344, and a beta(3)-AR partial agonist, CGP12177, stimulated I-Ca,I-L in HAMs with nanomolar potency and a 60%-90% efficacy compared with isoprenaline. The beta(3)-AR agonists also increased contractility but with a much lower efficacy (similar to 10%) than isoprenaline. The beta(3)-AR antagonist L-748,337, beta(1)/beta(2)-AR antagonist nadolol, and beta(1)-/beta(2)-/beta(3)-AR antagonist bupranolol were used to confirm the involvement Of beta(3)-ARs (and not beta(1)-/beta(2)-ARs) in these effects. The beta(3)-AR effects involved the cAMP/PKA pathway, since the PKA inhibitor H89 blocked I-Ca,I-L stimulation and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) strongly increased the positive inotropic effect. Therefore, unlike in ventricular tissue, beta(3)-ARs are positively coupled to L-type Ca2+ channels and contractility in human atrial tissues through a cAMP-dependent pathway.