Schoner Wilhelm, Scheiner-Bobis Georgios
Institute of Biochemistry and Endocrinology, Justus-Liebig-University Giessen, Giessen, Germany.
Am J Cardiovasc Drugs. 2007;7(3):173-89. doi: 10.2165/00129784-200707030-00004.
Cardiac glycosides have been used for decades to treat congestive heart failure. The recent identification of cardiotonic steroids such as ouabain, digoxin, marinobufagenin, and telocinobufagin in blood plasma, adrenal glands, and hypothalamus of mammals led to exciting new perspectives in the pathology of heart failure and arterial hypertension. Biosynthesis of ouabain and digoxin occurs in adrenal glands and is under the control of angiotensin II, endothelin, and epinephrine released from cells of the midbrain upon stimulation of brain areas sensing cerebrospinal Na(+) concentration and, apparently, the body's K(+) content. Rapid changes of endogenous ouabain upon physical exercise may favor the economy of the heart by a rise of intracellular Ca(2)(+) levels in cardiac and atrial muscle cells. According to the sodium pump lag hypothesis, this may be accomplished by partial inhibition of the sodium pump and Ca(2+) influx via the Na(+)/Ca(2+) exchanger working in reverse mode or via activation of the Na(+)/K(+)-ATPase signalosome complex, generating intracellular calcium oscillations, reactive oxygen species, and gene activation via nuclear factor-kappaB or extracellular signal-regulated kinases 1 and 2. Elevated concentrations of endogenous ouabain and marinobufagenin in the subnanomolar concentration range were found to stimulate proliferation and differentiation of cardiac and smooth muscle cells. They may have a primary role in the development of cardiac dysfunction and failure because (i) offspring of hypertensive patients evidently inherit elevated plasma concentrations of endogenous ouabain; (ii) such elevated concentrations correlate positively with cardiac dysfunction, hypertrophy, and arterial hypertension; (iii) about 40% of Europeans with uncomplicated essential hypertension show increased concentrations of endogenous ouabain associated with reduced heart rate and cardiac hypertrophy; (iv) in patients with advanced arterial hypertension, circulating levels of endogenous ouabain correlate with BP and total peripheral resistance; (v) among patients with idiopathic dilated cardiomyopathy, high circulating levels of endogenous ouabain and marinobufagenin identify those individuals who are predisposed to progressing more rapidly to heart failure, suggesting that endogenous ouabain (and marinobufagenin) may contribute to toxicity upon digoxin therapy. In contrast to endogenous ouabain, endogenous marinobufagenin may act as a natriuretic substance as well. It shows a higher affinity for the ouabain-insensitive alpha(1) isoform of Na(+)/K(+)-ATPase of rat kidney tubular cells and its levels are increased in volume expansion and pre-eclampsia. Digoxin, which is synthesized in adrenal glands, seems to counteract the hypertensinogenic action of ouabain in rats, as do antibodies against ouabain, for example, (Digibind) and rostafuroxin (PST 2238), a selective ouabain antagonist. It lowers BP in ouabain- and adducin-dependent hypertension in rats and is a promising new class of antihypertensive medication in humans.
几十年来，强心苷一直用于治疗充血性心力衰竭。最近在哺乳动物的血浆、肾上腺和下丘脑等部位发现了哇巴因、地高辛、海蟾蜍精和远华蟾毒精等强心甾体，这为心力衰竭和动脉高血压的病理学研究带来了令人兴奋的新视角。哇巴因和地高辛在肾上腺中生物合成，并受血管紧张素II、内皮素和肾上腺素的调控，这些物质在刺激感知脑脊液Na(+)浓度以及显然还有机体K(+)含量的脑区时从中脑细胞释放出来。体育锻炼时内源性哇巴因的快速变化可能通过提高心肌细胞和心房肌细胞内的Ca(2+)水平而有利于心脏的能量代谢。根据钠泵滞后假说，这可能是通过部分抑制钠泵以及Ca(2+)通过反向工作的Na(+)/Ca(2+)交换体流入，或者通过激活Na(+)/K(+)-ATP酶信号体复合物来实现的，后者会产生细胞内钙振荡、活性氧物种，并通过核因子-κB或细胞外信号调节激酶1和2激活基因。已发现亚纳摩尔浓度范围内的内源性哇巴因和海蟾蜍精浓度升高会刺激心肌细胞和平滑肌细胞的增殖和分化。它们可能在心脏功能障碍和衰竭的发生发展中起主要作用，原因如下：(i)高血压患者的后代显然遗传了内源性哇巴因血浆浓度升高；(ii)这种升高的浓度与心脏功能障碍、肥厚和动脉高血压呈正相关；(iii)约40%无并发症的原发性高血压欧洲人显示内源性哇巴因浓度升高，且与心率降低和心脏肥厚有关；(iv)在晚期动脉高血压患者中，内源性哇巴因的循环水平与血压和总外周阻力相关；(v)在特发性扩张型心肌病患者中，内源性哇巴因和海蟾蜍精的高循环水平可识别出那些更容易快速进展为心力衰竭的个体，这表明内源性哇巴因（和海蟾蜍精）可能会导致地高辛治疗时出现毒性。与内源性哇巴因不同，内源性海蟾蜍精也可能作为一种利钠物质起作用。它对大鼠肾小管细胞中哇巴因不敏感的Na(+)/K(+)-ATP酶α(1)亚型具有更高的亲和力，并且在容量扩张和先兆子痫时其水平会升高。在肾上腺中合成的地高辛似乎能抵消哇巴因在大鼠中的升压作用，例如抗哇巴因抗体（Digibind）和选择性哇巴因拮抗剂罗斯他福辛（PST 2238）也是如此。它能降低大鼠中哇巴因和内收蛋白依赖性高血压的血压，是一种有前景的新型人类抗高血压药物。
