Krep H H, Graves S W, Price D A, Lazarus M, Ensign A, Soszynski P A, Hollenberg N K
Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
Am J Hypertens. 1996 Jan;9(1):39-46. doi: 10.1016/0895-7061(95)00260-x.
The possibility that a circulating sodium pump inhibitor contributes to the pathogenesis of volume-dependent hypertension via an action on vascular smooth muscle (VSM) is supported by multiple lines of investigation, but remains controversial. We had two goals in this study. The first was to compare the pattern of contractile response of rabbit aorta induced by two candidates, ouabain and a labile sodium pump inhibitor that we have identified in the peritoneal dialysate of volume-expanded hypertensive patients with chronic renal failure. Our second goal was to examine the ability of Digibind, a Fab fragment of antisera directed against digoxin, to reverse VSM contraction induced by both agents. Ouabain induced a concentration-dependent contraction, which was delayed in onset, was gradual, and reached a stable plateau after many hours. The labile sodium pump inhibitor induced a qualitatively similar series of responses. Digibind rapidly reversed the contractile responses to both sodium pump inhibitors, with a rate of relaxation that matched that induced by physical removal of the pump inhibitor from the bath. For ouabain, the Digibind:ouabain stoichiometry was highly predictable. When Digibind was present in a molar concentration equivalent to that of ouabain, or less, it had no effect. When the Digibind concentration was twice that of ouabain, complete relaxation occurred. Although the concentration:VSM response relationship for ouabain was steep, the concentration:effect interaction with Digibind was even more steep. The molar concentration of Digibind required to reverse the effects of the labile endogenous inhibitor from peritoneal dialysate was consistently lower than that for ouabain, which is compatible with either greater potency of the labile factor in VSM or greater affinity for Digibind. These findings are compatible with a role for one or more endogenous sodium pump inhibitors as the determinant of vascular smooth muscle tone in the volume-sensitive hypertension of renal disease.
循环中的钠泵抑制剂通过作用于血管平滑肌（VSM）而导致容量依赖性高血压发病的可能性，得到了多项研究的支持，但仍存在争议。我们在本研究中有两个目标。第一个目标是比较两种物质诱导兔主动脉收缩反应的模式，这两种物质分别是哇巴因和一种不稳定的钠泵抑制剂，后者是我们在慢性肾衰竭容量扩张型高血压患者的腹膜透析液中鉴定出来的。我们的第二个目标是研究地高辛特异性抗体Fab片段（Digibind）逆转这两种物质诱导的VSM收缩的能力。哇巴因诱导出浓度依赖性收缩，起效延迟，收缩过程渐进，数小时后达到稳定平台期。这种不稳定的钠泵抑制剂诱导出了一系列定性相似的反应。Digibind迅速逆转了对两种钠泵抑制剂的收缩反应，其舒张速率与通过从浴槽中物理去除泵抑制剂所诱导的舒张速率相匹配。对于哇巴因，Digibind与哇巴因的化学计量关系具有高度可预测性。当Digibind的摩尔浓度等于或低于哇巴因时，它没有效果。当Digibind浓度是哇巴因的两倍时，完全舒张发生。尽管哇巴因的浓度与VSM反应关系陡峭，但与Digibind的浓度效应相互作用甚至更陡峭。逆转腹膜透析液中不稳定内源性抑制剂作用所需的Digibind摩尔浓度始终低于哇巴因，这与不稳定因子在VSM中具有更高效力或对Digibind具有更高亲和力相符。这些发现与一种或多种内源性钠泵抑制剂在肾病容量敏感性高血压中作为血管平滑肌张力决定因素的作用相符。
