Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients.
Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients.
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DOI：
10.1161/hypertensionaha.112.194787
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Vongpatanasin W
中科院分区：
文献类型：
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作者：
Raheja P;Price A;Wang Z;Arbique D;Adams-Huet B;Auchus RJ;Vongpatanasin W
我们实验室最近的研究表明，氯噻酮触发交感神经系统的持续激活，并促进高血压患者的胰岛素抵抗，独立于血清钾。氯噻酮这些不良反应的潜在机制尚不清楚，但啮齿动物中越来越多的证据表明血管紧张素和醛固酮过量在诱导交感神经过度活跃和胰岛素抵抗中的作用。因此，我们在17名未经治疗的I期高血压受试者中进行了研究，使用随机交叉设计，在基线时，单独使用氯噻酮（25 mg/天），氯噻酮+螺内酯，氯噻酮+厄贝沙坦12周后测量交感神经活性（SNA）。我们发现，单独使用氯噻酮可使24小时动态血压（ABP）从135±3/84±2降至124±2/78±2 mm Hg，并显著增加SNA（从41±3 vs 49±4爆发/分钟，p < 0.01）。在氯噻酮基础上加用螺内酯可使SNA值恢复至基线水平（42±3次爆发/min，p = NS），而在相同受试者中加用厄贝沙坦不能改变SNA对氯噻酮的反应（52±2次爆发/min，p < 0.01），尽管ABP降低相似（分别为121±2/75±2和121±2/75±2 mmHg）。氯噻酮单独使用也增加胰岛素抵抗指数，与螺内酯联合使用时未观察到。总之，我们的研究表明螺内酯在减弱氯噻酮诱导的交感神经激活和胰岛素抵抗方面具有有益作用，与血压降低无关。由于交感神经过度活跃和胰岛素抵抗导致心血管疾病患者预后不良，因此氯噻酮与盐皮质激素受体拮抗剂联合治疗可能比氯噻酮单药治疗高血压患者更可取。
Recent studies from our laboratory indicate that chlorthalidone triggers persistent activation of the sympathetic nervous system and promotes insulin resistance in hypertensive patients, independent of serum potassium. Mechanisms underlying these adverse effects of chlorthalidone remain unknown but increasing evidence in rodents suggests the role of angiotensin and aldosterone excess in inducing both sympathetic overactivity and insulin resistance. Accordingly, we conducted studies in 17 subjects with untreated stage I hypertension, measuring sympathetic nerve activity (SNA) at baseline, after 12 weeks of chlorthalidone alone (25 mg/day), chlorthalidone plus spironolactone, and chlorthalidone plus irbesartan, using randomized crossover design. We found that chlorthalidone alone decreased 24-hour ambulatory BP (ABP) from 135±3/84±2 to 124±2/78±2 mm Hg and significantly increased SNA from baseline (from 41±3 vs 49±4 bursts/min, p < 0.01). Addition of spironolactone to chlorthalidone returned SNA value to baseline (42±3 bursts/min, p = NS) while addition of irbesartan failed to alter the SNA response to chlorthalidone in the same subjects (52±2 bursts/min, p < 0.01) despite similar reduction in ABP (121±2/75±2 and 121±2/75±2 mmHg, respectively). Chlorthalidone alone also increased indices of insulin resistance, which was not observed when used in combination with spironolactone. In conclusion, our study demonstrates beneficial effects of spironolactone in attenuating both chlorthalidone-induced sympathetic activation and insulin resistance in humans, independent of BP reduction. Because sympathetic overactivity and insulin resistance contributes to the poor prognosis in patients with cardiovascular disease, combination therapy of chlorthalidone with mineralocorticoid receptor antagonists may constitute a preferable regimen than chlorthalidone alone in hypertensive patients.