From the Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, Miller School of Medicine, University of Miami, FL (R.A.P., D.A., E.V.C., B.J.M., R.R., E.A., A.B.A.).
University of Miami Clinical and Translational Science Institutes, FL (R.A.P.).
Hypertension. 2021 Feb;77(2):447-460. doi: 10.1161/HYPERTENSIONAHA.120.15933. Epub 2021 Jan 4.
The thiazide-sensitive sodium-chloride cotransporter (NCC;SLC12A3) is central to sodium and blood pressure regulation. Metabolic syndrome induces NCC upregulation generating sodium-sensitive hypertension in experimental animal models. We tested the role of NCC in sodium sensitivity in hypertensive humans with metabolic syndrome. Conversely, oral potassium induces NCC downregulation producing potassium-induced natriuresis. We determined the time course and magnitude of potassium-induced natriuresis compared with the natriuresis following hydrochlorothiazide (HCTZ) as a reference standard. We studied 19 obese hypertensive humans with metabolic syndrome during 13-day inpatient confinement. We determined sodium sensitivity by change in 24-hour mean systolic pressure by automated monitor from days 5 (low sodium) to 10 (high sodium). We determined NCC activity by standard 50 mg HCTZ sensitivity test (day 11). We determined potassium-induced natriuresis following 35 mmol KCl (day 13). We determined (1) whether NCC activity was greater in sodium-sensitive versus sodium-resistant participants and correlated with sodium sensitivity and (2) time course and magnitude of potassium-induced natriuresis following 35 mmol KCl directly compared with 50 mg HCTZ. NCC activity was not greater in sodium-sensitive versus sodium-resistant humans and did not correlate with sodium sensitivity. Thirty-five-millimoles KCl produced a rapid natriuresis approximately half that of 50 mg HCTZ with a greater kaliuresis. Our investigation tested a key hypothesis regarding NCC activity in human hypertension and characterized potassium-induced natriuresis following 35 mmol KCl compared with 50 mg HCTZ. In obese hypertensive adults with metabolic syndrome ingesting a high-sodium diet, 35 mmol KCl had a net natriuretic effect approximately half that of 50 mg HCTZ.
噻嗪类敏感的钠-氯共转运蛋白（NCC；SLC12A3）是钠和血压调节的核心。代谢综合征诱导 NCC 上调，在实验动物模型中产生钠敏感型高血压。我们在患有代谢综合征的高血压人类中测试了 NCC 在钠敏感性中的作用。相反，口服钾诱导 NCC 下调，产生钾诱导的钠排泄。我们确定了钾诱导的钠排泄与氢氯噻嗪（HCTZ）作为参考标准的钠排泄之间的时间过程和幅度。我们在 13 天的住院期间研究了 19 名患有代谢综合征的肥胖高血压患者。我们通过自动监测仪从第 5 天（低钠）到第 10 天（高钠）确定 24 小时平均收缩压的变化来确定钠敏感性。我们通过标准的 50mg HCTZ 敏感性试验（第 11 天）确定 NCC 活性。我们在第 13 天测定 35mmol KCl 后的钾诱导的钠排泄。我们确定（1）NCC 活性在钠敏感型与钠抵抗型参与者中是否更大，并与钠敏感性相关，（2）直接比较 35mmol KCl 后钾诱导的钠排泄的时间过程和幅度与 50mg HCTZ。NCC 活性在钠敏感型与钠抵抗型人群中没有更大，并且与钠敏感性不相关。35mmol KCl 产生了大约是 50mg HCTZ 的一半的快速钠排泄，并有更大的尿钾排泄。我们的研究检验了关于人类高血压中 NCC 活性的一个关键假设，并描述了与 50mg HCTZ 相比，35mmol KCl 后钾诱导的钠排泄。在摄入高钠饮食的患有代谢综合征的肥胖成年高血压患者中，35mmol KCl 具有大约是 50mg HCTZ 的一半的净排钠作用。
