Systemic activation of the calcium sensing receptor produces acute effects on vascular tone and circulatory function in uremic and normal rats: Focus on central versus peripheral control of vascular tone and blood pressure by cinacalcet
Systemic activation of the calcium sensing receptor produces acute effects on vascular tone and circulatory function in uremic and normal rats: Focus on central versus peripheral control of vascular tone and blood pressure by cinacalcet
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DOI：
10.1124/jpet.107.123901
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发表时间：
2007-10-01
影响因子：
3.5
通讯作者：
Reinhart, Glenn A.
中科院分区：
文献类型：
--
作者：
Fryer, Ryan M.;Segreti, Jason A.;Reinhart, Glenn A.
钙敏感受体 (CaR) 激活会降低血清甲状旁腺激素 (PTH) 和 Ca2+，并且尽管平均动脉血压 (MAP) 长期降低，但可能会在大鼠中产生急性高血压，我们假设这种效应是由多个血管床收缩介导的。对大鼠进行5/6肾切除术（NX）或不进行手术（正常）； 7至8周时，尿毒症动物被麻醉并用仪器记录MAP和局部血流（颈动脉、肠系膜和后肢）。西那卡塞[N-(1-萘-1-基乙基)3-[3-(三氟甲基)苯基]-丙-1-胺； 1、3和10毫克/公斤； 30分钟/剂量]输注超过90分钟。在NX大鼠中，西那卡塞剂量依赖性地降低离子钙（iCa(2+)），引起PTH减少90%，并产生剂量依赖性的MAP自限性增加（每次输注结束时从119 +/- 6到129 +/- 5、142 +/- 4和145 +/- 3 mm Hg）。在 1 mg/kg 剂量下，颈动脉血管阻力 (CVR) 和肠系膜血管阻力 (MVR) 分别比基线增加 16 +/- 6 % 和 18 +/- 6%。后肢血管阻力 (HVR) 也呈上升趋势 (13 +/- 8%)。 3 mg/kg 时，CVR (38 +/- 10%)、MVR (40 +/- 8%) 和 HVR (39 +/- 14%) 的增加加剧；在 10 毫克/千克时，数值保持在或接近这些水平。西那卡塞对正常大鼠的作用与 NX 相似，并且在低剂量时通过六甲铵的神经节阻断而减弱，但在高剂量时仍然显着升高。因此，CaR 激活会急剧增加尿毒症和非尿毒症大鼠的 MAP，这种反应通过中枢和外周作用机制与多个血管床中的血管收缩同时发生。此外，随后的机制研究表明，西那卡塞产生的 MAP 增加可能是由于血液 iCa(2+) 减少后，强直性 NO 合酶依赖性 NO 产生减少而介导的。
Calcium-sensing receptor (CaR) activation decreases serum parathyroid hormone (PTH) and Ca2+ and, despite long-term reductions in mean arterial blood pressure ( MAP), may produce acute hypertension in rats, an effect we hypothesized was mediated by constriction of multiple vascular beds. Rats were subjected to 5/6 nephrectomy (NX) or no surgery ( Normal); at 7 to 8 weeks, uremia animals were anesthetized and instrumented to record MAP and regional blood flow ( carotid, mesenteric, and hindlimb). Cinacalcet [N-(1-naphthalen-1-ylethyl)3-[ 3-( trifluoromethyl)phenyl]-propan-1-amine; 1, 3, and 10 mg/kg; 30 min/dose] was infused over 90 min. In NX rats, cinacalcet dose-dependently decreased ionized calcium (iCa(2+)), elicited a 90% reduction in PTH, and produced dose-dependent selflimiting increases in MAP ( from 119 +/- 6 to 129 +/- 5, 142 +/- 4, and 145 +/- 3 mm Hg at the end of each infusion). At 1 mg/kg, carotid vascular resistance (CVR) and mesenteric vascular resistance (MVR) increased to 16 +/- 6 and 18 +/- 6% above baseline, respectively. Hindlimb vascular resistance (HVR) also trended upward (13 +/- 8%). At 3 mg/ kg, increases in CVR (38 +/- 10%), MVR (40 +/- 8%), and HVR (39 +/- 14%) were exacerbated; at 10 mg/ kg, values remained at or near these levels. The effects of cinacalcet in Normal rats were similar to NX and were attenuated by ganglionic blockade with hexamethonium at low doses but remained significantly elevated at higher doses. Thus, CaR activation acutely increases MAP in uremic and nonuremic rats, responses that occur in parallel to vasoconstriction in multiple vascular beds through both a central and peripheral mechanism of action. Moreover, subsequent mechanistic studies suggest that increases in MAP produced by cinacalcet may be mediated by reduced tonic NO synthase-dependent NO production subsequent to reductions in blood iCa(2+).