North Shore Heart Research Group, Kolling Institute of Medical Research, University of Sydney, Australia.
Circulation. 2010 Dec 21;122(25):2699-708. doi: 10.1161/CIRCULATIONAHA.110.964619. Epub 2010 Dec 6.
inhibition of L-type Ca(2+) current contributes to negative inotropy of β(3) adrenergic receptor (β(3) AR) activation, but effects on other determinants of excitation-contraction coupling are not known. Of these, the Na(+)-K(+) pump is of particular interest because of adverse effects attributed to high cardiac myocyte Na(+) levels and upregulation of the β(3) AR in heart failure.
we voltage clamped rabbit ventricular myocytes and identified electrogenic Na(+)-K(+) pump current (I(p)) as the shift in holding current induced by ouabain. The synthetic β(3) AR agonists BRL37344 and CL316,243 and the natural agonist norepinephrine increased I(p). Pump stimulation was insensitive to the β(1)/β(2) AR antagonist nadolol and the protein kinase A inhibitor H-89 but sensitive to the β(3) AR antagonist L-748,337. Blockade of nitric oxide synthase abolished pump stimulation and an increase in fluorescence of myocytes loaded with a nitric oxide-sensitive dye. Exposure of myocytes to β(3) AR agonists decreased β(1) Na(+)-K(+) pump subunit glutathionylation, an oxidative modification that causes pump inhibition. The in vivo relevance of this was indicated by an increase in myocardial β(1) pump subunit glutathionylation with elimination of β(3) AR-mediated signaling in β(3) AR(-/-) mice. The in vivo effect of BRL37344 on contractility of the nonfailing and failing heart in sheep was consistent with a beneficial effect of Na(+)-K(+) pump stimulation in heart failure.
the β(3) AR mediates decreased β(1) subunit glutathionylation and Na(+)-K(+) pump stimulation in the heart. Upregulation of the receptor in heart failure may be a beneficial mechanism that facilitates the export of excess Na(+).
L 型钙电流的抑制导致β（3）肾上腺素能受体（β（3）AR）激活的负性肌力作用，但对兴奋-收缩偶联的其他决定因素的影响尚不清楚。在这些因素中，钠-钾泵特别引人关注，因为高心肌细胞钠离子水平和心力衰竭时β（3）AR 的上调会产生不良影响。
我们对兔心室肌细胞进行电压钳位，并通过哇巴因诱导的保持电流变化来鉴定生电性钠-钾泵电流（I（p））。合成的β（3）AR 激动剂 BRL37344 和 CL316,243 以及天然激动剂去甲肾上腺素增加了 I（p）。泵刺激对β（1）/β（2）AR 拮抗剂纳多洛尔和蛋白激酶 A 抑制剂 H-89 不敏感，但对β（3）AR 拮抗剂 L-748,337 敏感。一氧化氮合酶阻断消除了泵刺激，并增加了用一氧化氮敏感染料负载的细胞的荧光。β（3）AR 激动剂暴露降低了β（1）钠-钾泵亚基的谷胱甘肽化，这是一种导致泵抑制的氧化修饰。β（3）AR（-/-）小鼠中消除β（3）AR 介导的信号转导导致心肌β（1）泵亚基谷胱甘肽化增加，表明这与体内的相关性。在绵羊中，BRL37344 对正常和衰竭心脏收缩性的体内作用与心力衰竭时钠-钾泵刺激的有益作用一致。
β（3）AR 在心脏中介导β（1）亚基谷胱甘肽化减少和钠-钾泵刺激。心力衰竭时受体的上调可能是促进多余钠离子输出的有益机制。
