Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
Hypertens Res. 2012 Jun;35(6):654-60. doi: 10.1038/hr.2012.13. Epub 2012 Feb 2.
Previously, we demonstrated that angiotensin II type 2 (AT(2)) receptors have a role in natriuresis in obese Zucker rats (OZR). In the present study, we investigated the role of a novel, non-peptide agonist, C21, in natriuresis via AT(2) receptor activation in OZR. Infusion of C21 (1 and 5 μg kg(-1) min(-1)) into rats under anesthesia caused a dose-dependent increase in urine flow (UF) and urinary Na volume (U(Na)V). These effects of C21 were blocked by pre-infusion of the AT(2) receptor antagonist, PD123319, (50 μg kg(-1) min(-1)), suggesting involvement of the AT(2) receptor. Infusion of C21 (5 μg kg(-1) min(-1)) significantly increased the fractional excretion of sodium without changing the glomerular filtration rate or blood pressure, suggesting a tubular effect. Similarly, C21 infusion increased the fractional excretion of lithium, suggesting a proximal tubular effect. Furthermore, we tested the effect of C21 on natriuresis after blocking two main, distal-nephron Na transporters, the epithelial Na channels (ENaC), with amiloride (AM, 3 mg kg(-1) body wt), and the NaCl cotransporters (NCC), with bendroflumethiazide (BFTZ, 7 mg kg(-1) body wt). Infusion of AM + BFTZ caused significant increases in both diuresis and natriuresis, which were further increased by infusion of C21 (5 μg kg(-1) min(-1)). Natriuresis in response to C21 was associated with increases in urinary NO and cGMP levels. The data indicate that the AT(2) receptor agonist, C21, promotes natriuresis via AT(2) receptor activation and that this effect is potentially based in the proximal tubules and linked to the nitric oxide/cyclic guanosine monophosphate pathway. The natriuretic response to C21 may have therapeutic significance by improving kidney function in obesity.
先前，我们已经证明血管紧张素 II 型 2（AT(2)）受体在肥胖 Zucker 大鼠（OZR）的利钠作用中发挥作用。在本研究中，我们通过麻醉下 OZR 中 AT(2)受体激活研究了新型非肽激动剂 C21 在利钠中的作用。C21（1 和 5 μg kg(-1) min(-1)）输注可引起尿流量（UF）和尿钠排泄量（U(Na)V）的剂量依赖性增加。C21 的这些作用被 AT(2)受体拮抗剂 PD123319（50 μg kg(-1) min(-1)）的预输注阻断，表明 AT(2)受体的参与。C21（5 μg kg(-1) min(-1)）输注显著增加了钠的分数排泄而不改变肾小球滤过率或血压，表明存在肾小管作用。同样，C21 输注增加了锂的分数排泄，表明存在近端肾小管作用。此外，我们测试了 C21 在阻断两种主要的远端肾单位 Na 转运体后对利钠的作用，上皮 Na 通道（ENaC）用阿米洛利（AM，3 mg kg(-1)体重）和 NaCl 协同转运体（NCC）用苯氟噻嗪（BFTZ，7 mg kg(-1)体重）。AM + BFTZ 输注引起利尿和利钠的显著增加，而 C21（5 μg kg(-1) min(-1)）输注进一步增加了这两者。C21 引起的利钠作用与尿中 NO 和 cGMP 水平的增加有关。数据表明，AT(2)受体激动剂 C21 通过 AT(2)受体激活促进利钠，并且这种作用可能基于近端肾小管，并与一氧化氮/环鸟苷单磷酸途径相关。C21 的利钠反应可能通过改善肥胖症患者的肾功能而具有治疗意义。
