Liclican Elvira L, Doumad Anabel B, Wang Jianjin, Li Jing, Falck John R, Stier Charles T, Carroll Mairéad A
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Hypertension. 2009 Dec;54(6):1284-90. doi: 10.1161/HYPERTENSIONAHA.108.123570. Epub 2009 Oct 12.
Adenosine-induced renovasodilation in Dahl rats is mediated via activation of adenosine(2A) receptors (A(2A)Rs) and stimulation of epoxyeicosatrienoic acid (EET) synthesis. Unlike Dahl salt-resistant rats, salt-sensitive rats exhibit an inability to upregulate the A(2A)R-EET pathway with salt loading; therefore, we examined the effect of in vivo inhibition of the A(2A)R-EET pathway on blood pressure and the natriuretic response to salt-loading in Dahl salt-resistant rats. N-Methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 20 mg/kg per day), an epoxygenase inhibitor, or ZM241385 (ZM; 5 mg/kg per day), an A(2A)R antagonist, was given daily as an IV bolus dose for 3 days before and after placing rats on high salt intake (2% saline). After 3 days of high salt, systolic blood pressure per 24 hours increased from 108+/-2 mm Hg to 136+/-5 mm Hg and 140+/-4 mm Hg when treated with MS-PPOH or ZM, respectively (P<0.001). Plasma levels of EETs and dihydroxyeicosatrienoic acids during salt loading and MS-PPOH (29.3+/-1.8 ng/mL) or ZM treatment (9.8+/-0.5 ng/mL) did not increase to the same extent as in vehicle-treated rats (59.4+/-1.7 ng/mL; P<0.001), and renal levels of EETs+dihydroxyeicosatrienoic acids were 2-fold lower with MS-PPOH or ZM treatment. On day 3 of the high salt intake, MS-PPOH- and ZM-treated rats exhibited a positive Na(+) balance, and plasma Na(+) levels were significantly increased (163.3+/-1.2 and 158.1+/-4.5 mEq/L, respectively) compared with vehicle-treated rats (142.1+/-1 mEq/L), reflecting a diminished natriuretic capacity. These data support a role for the A(2A)R-EET pathway in the adaptive natriuretic response to modulate blood pressure during salt loading.
腺苷诱导的 Dahl 大鼠肾血管舒张是通过激活腺苷（2A）受体（A（2A）Rs）和刺激环氧二十碳三烯酸（EET）合成来介导的。与 Dahl 盐抵抗大鼠不同，盐敏感大鼠在盐负荷时无法上调 A（2A）R-EET 途径；因此，我们研究了体内抑制 A（2A）R-EET 途径对 Dahl 盐抵抗大鼠血压和盐负荷时利钠反应的影响。环氧合酶抑制剂 N-甲基磺酰基-6-（2-炔丙氧基苯基）己酰胺（MS-PPOH；每天 20 mg/kg）或 A（2A）R 拮抗剂 ZM241385（ZM；每天 5 mg/kg）在大鼠摄入高盐（2%盐水）前后，每天静脉推注给药 3 天。高盐摄入 3 天后，与溶媒处理组大鼠相比，MS-PPOH 或 ZM 处理组大鼠每 24 小时的收缩压分别从 108±2 mmHg 升高到 136±5 mmHg 和 140±4 mmHg（P<0.001）。盐负荷及 MS-PPOH（29.3±1.8 ng/mL）或 ZM 处理期间，EETs 和二羟基二十碳三烯酸的血浆水平升高幅度不及溶媒处理组大鼠（59.4±1.7 ng/mL；P<0.001），且 MS-PPOH 或 ZM 处理组大鼠肾脏中 EETs+二羟基二十碳三烯酸水平降低了 2 倍。在高盐摄入的第 3 天，MS-PPOH 和 ZM 处理组大鼠呈现正钠平衡，与溶媒处理组大鼠相比（142.1±1 mEq/L），血浆钠水平显著升高（分别为 163.3±1.2 和 158.1±4.5 mEq/L），这反映了利钠能力减弱。这些数据支持 A（2A）R-EET 途径在盐负荷期间调节血压的适应性利钠反应中发挥作用。
