Elijovich Fernando, Laffer Cheryl L, Schiffrin Ernesto L, Gavras Haralambos, Amador Elias
Center for Hypertension and Cardiovascular Medicine, Lenox Hill Hospital, New York, New York 10021, USA.
J Hypertens. 2004 Mar;22(3):573-82. doi: 10.1097/00004872-200403000-00021.
To investigate whether endothelin and aldosterone participate in the increased prevalence and severity of nephrosclerosis in human low-renin hypertension, analogous to observations in experimental hypertension.
Comparison of endothelin, aldosterone and their relationships with proteinuria, in hypertensive patients with high aldosterone : renin ratios (HARR group, n = 14) or normal aldosterone : renin ratios (NARR group, n = 15).
Urine protein and radioimmunoassay measurements of plasma renin activity, endothelin and aldosterone were carried out in individuals taking their usual diet, and after salt loading and salt depletion.
Compared with the NARR group, patients in the HARR group had higher blood pressure, greater salt sensitivity of their blood pressure, significantly greater urine protein and lower serum potassium concentrations, lower renin activities [0.14 +/- 0.03 ng AngiotensinI (AI)/l per s compared with 0.76 +/- 0.16 ng AI/l per s; P < 0.005], blunted renin-aldosterone responses to salt loading and salt depletion, enhanced catecholamine responses to salt depletion, and increased plasma endothelin (5.1 +/- 0.5 fmol/ml compared with 3.7 +/- 0.3 fmol/ml; P < 0.03). In the HARR group, endothelin and aldosterone concentrations were highly correlated, and both correlated with blood pressure and urine protein. In contrast, in the NARR group, endothelin and aldosterone did not correlate between them or with blood pressure, and only endothelin, not aldosterone, correlated with urine protein. Multivariate regression confirmed that the interaction between aldosterone and endothelin was the major predictor of urine protein in the HARR group (r = 0.442), whereas endothelin, renin and their interaction were predictors in the NARR group (r = 0.467).
Our results concur with experimental evidence for participation of endothelin in renal damage of angiotensin-dependent hypertension and for that of an endothelin-aldosterone interaction in low-renin hypertension. We propose that combined pharmacological antagonism of endothelin and aldosterone may confer renal protection beyond blood pressure reduction in patients with low-renin hypertension, a population at high risk for hypertensive nephrosclerosis.
研究内皮素和醛固酮是否像在实验性高血压中观察到的那样，参与人类低肾素性高血压患者肾硬化患病率的增加和病情的加重。
比较醛固酮:肾素比值高的高血压患者（高醛固酮:肾素比值组，n = 14）或醛固酮:肾素比值正常的高血压患者（正常醛固酮:肾素比值组，n = 15）的内皮素、醛固酮及其与蛋白尿的关系。
对正常饮食、盐负荷及限盐后的个体进行尿蛋白检测以及血浆肾素活性、内皮素和醛固酮的放射免疫测定。
与正常醛固酮:肾素比值组相比，高醛固酮:肾素比值组患者血压更高，血压对盐的敏感性更强，尿蛋白显著更多，血清钾浓度更低，肾素活性更低[分别为0.14±0.03 ng血管紧张素I（AI）/（升·秒）与0.76±0.16 ng AI/（升·秒）；P < 0.005]，肾素-醛固酮对盐负荷及限盐的反应迟钝，儿茶酚胺对限盐的反应增强，血浆内皮素升高（分别为5.1±0.5 fmol/ml与3.7±0.3 fmol/ml；P < 0.XX）。在高醛固酮:肾素比值组中，内皮素和醛固酮浓度高度相关，且二者均与血压和尿蛋白相关。相反，在正常醛固酮:肾素比值组中，内皮素与醛固酮之间以及它们与血压之间均无相关性，仅内皮素与尿蛋白相关，醛固酮与尿蛋白无关。多变量回归分析证实，醛固酮与内皮素之间的相互作用是高醛固酮:肾素比值组尿蛋白的主要预测因素（r = 0.442），而在内皮素、肾素及其相互作用是正常醛固酮:肾素比值组尿蛋白的预测因素（r = 0.467）。
我们的结果与内皮素参与血管紧张素依赖性高血压肾损害以及内皮素-醛固酮相互作用参与低肾素性高血压的实验证据一致。我们提出，对于低肾素性高血压患者（高血压肾硬化的高危人群），联合使用内皮素和醛固酮的药理学拮抗剂可能在降低血压之外还能提供肾脏保护作用。
