Jackson Edwin K, Zhang Yumeng, Cheng Dongmei
From the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA.
Hypertension. 2017 Mar;69(3):484-493. doi: 10.1161/HYPERTENSIONAHA.116.08623. Epub 2017 Jan 30.
Tissue nonspecific alkaline phosphatase (TNAP) contributes to the production of adenosine by the kidney, and A-receptor activation enhances renovascular responses to norepinephrine. Therefore, we hypothesized that TNAP regulates renovascular responsiveness to norepinephrine. In isolated, perfused rat kidneys, the TNAP inhibitor l-p-bromotetramisole (0.1 mmol/L) decreased renal venous levels of 5'-AMP (adenosine precursor) and adenosine by 61% (<0.0384) and 62% (=0.0013), respectively, at 1 hour into treatment and caused a 10-fold rightward shift of the concentration-response relationship to exogenous norepinephrine (<0.0001). Similarly, 2 other TNAP inhibitors, levamisole (1 mmol/L) and 2,5-dimethoxy-N-(quinolin-3-yl)benzenesulfonamide (0.02 mmol/L), also right shifted the concentration-response relationship to norepinephrine. The ability of TNAP inhibition to blunt renovascular responses to norepinephrine was mostly prevented or reversed by restoring A-adenosinergic tone with the A-receptor agonist 2-chloro-N-cyclopentyladenosine (100 nmol/L). All 3 TNAP inhibitors also attenuated renovascular responses to renal sympathetic nerve stimulation, suggesting that TNAP inhibition attenuates renovascular responses to endogenous norepinephrine. In control propranolol-pretreated rats, acute infusions of norepinephrine (10 μg/kg/min) increased mean arterial blood pressure from 95±5 mm Hg to a peak of 169±4 mm Hg and renovascular resistance from 12±2 mm Hg/mL/min to a peak of 55±12 mm Hg/mL/min; however, in rats also treated with intravenous l-p-bromotetramisole (30 mg/kg), the pressor and renovascular effects of norepinephrine were significantly attenuated (blood pressure: basal and peak, 93±7 and 146±6 mm Hg, respectively; renovascular resistance: basal and peak, 13±2 and 29±5 mm Hg/mL/min, respectively). TNAP inhibitors attenuate renovascular and blood pressure responses to norepinephrine, suggesting that TNAP participates in the regulation of renal function and blood pressure.
组织非特异性碱性磷酸酶（TNAP）有助于肾脏生成腺苷，且A受体激活可增强肾血管对去甲肾上腺素的反应。因此，我们推测TNAP调节肾血管对去甲肾上腺素的反应性。在离体灌注大鼠肾脏中，TNAP抑制剂l - 对溴四咪唑（0.1 mmol/L）在治疗1小时后，使肾静脉中5'-AMP（腺苷前体）和腺苷水平分别降低61%（<0.0384）和62%（=0.0013），并使对外源性去甲肾上腺素的浓度 - 反应关系向右移动10倍（<0.0001）。同样，另外两种TNAP抑制剂，左旋咪唑（1 mmol/L）和2,5 - 二甲氧基 - N -（喹啉 - 3 - 基）苯磺酰胺（0.02 mmol/L），也使对去甲肾上腺素的浓度 - 反应关系向右移动。通过用A受体激动剂2 - 氯 - N - 环戊基腺苷（100 nmol/L）恢复A - 腺苷能张力，大多可预防或逆转TNAP抑制减弱肾血管对去甲肾上腺素反应的能力。所有三种TNAP抑制剂也减弱了肾血管对肾交感神经刺激的反应，表明TNAP抑制减弱了肾血管对内源性去甲肾上腺素的反应。在对照的经普萘洛尔预处理的大鼠中，急性输注去甲肾上腺素（10 μg/kg/min）使平均动脉血压从95±5 mmHg升高至峰值169±4 mmHg，肾血管阻力从12±2 mmHg/mL/min升高至峰值55±12 mmHg/mL/min；然而，在同时静脉注射l - 对溴四咪唑（30 mg/kg）的大鼠中，去甲肾上腺素的升压和肾血管效应明显减弱（血压：基础值和峰值分别为93±7和146±6 mmHg；肾血管阻力：基础值和峰值分别为13±2和29±5 mmHg/mL/min）。TNAP抑制剂减弱肾血管和血压对去甲肾上腺素的反应，提示TNAP参与肾功能和血压的调节。
