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背景咪唑啉受体是重要的抗高血压药物作用位点,以往的研究认为胍丁胺是咪唑啉受体的内源性配体,但胍丁胺的中枢心血管效应及其机制研究不清楚。目的通过侧脑室注射的方法观察胍丁胺的中枢心血管效应及其机制,并探讨胍丁胺是否是咪唑啉受体的内源性配体。方法雄性SD大鼠70只,腹腔注射氨基甲酸乙酯1.0g/kg实施麻醉、气管插管、右侧股动、静脉插管,固定于立体定位仪。其中29只大鼠随机分为对照组、胍丁胺组(5、10、20μmol)和可乐定组(1.0μmol),以人工脑脊液为对照,给药后观察大鼠血压和心率变化。其余41只大鼠随机分为:①咪唑克生(咪唑啉受体阻断剂)+胍丁胺组;②MK-801[N-甲基-D-天门冬氨酸(NMDA)受体拮抗剂]+胍丁胺组;③可乐定+胍丁胺组;④人工脑脊液+胍丁胺组;⑤咪唑克生+可乐定组;⑥MK-801+可乐定组;⑦人工脑脊液+可乐定组。先分别侧脑室注射咪唑克生等阻断剂,10min后待血压平稳再分别侧脑室注射胍丁胺或可乐定,观察给药后大鼠的血压和心率变化。结果侧脑室注射胍丁胺5μmol[平均动脉压(MBP):给药前(113±5)比给药后(105±13)mmHg],10μmol[MBP:给药前(103±7)比给药后(72±9)mmHg](均P<0.05),胍丁胺均可显著降低麻醉大鼠血压,并减慢心率;侧脑室注射1.0μmol可乐定具有相似的心血管效应[MBP:给药前(92±8)比给药后(78±19)mmHg,P<0.05]。侧脑室注射等量人工脑脊液对麻醉大鼠的血压和心率不产生显著性作用。预先给予咪唑克生(1.0μmol)、NMDA受体拮抗剂MK-801(0.5μmol)或可乐定(1.0μmol)单独给药能显著减弱侧脑室注射胍丁胺的心血管效应;同时预先给予咪唑克生(1.0μmol)、NMDA受体拮抗剂MK-801(0.5μmol)也能有效减弱侧脑室注射可乐定产生的心血管效应。结论侧脑室注射胍丁胺产生的降低血压、减慢心率的作用可能是作用于咪唑啉受体产生,并且由NMDA受体介导的;可乐定能阻断胍丁胺的中枢心血管效应。
Background Imidazoline receptors are important sites of antihypertensive drugs. Previous studies suggested that agmatine is the endogenous ligand for imidazolinium receptors, but the central cardiovascular effects and mechanism of agmatine are not well understood . Objective To observe the central cardiovascular effects of agmatine by intracerebroventricular injection and to investigate whether agmatine is an endogenous ligand for imidazoline receptors. Methods Seventy male Sprague Dawley rats were anesthetized by intraperitoneal injection of urethane 1.0 g / kg, intubated, right femoral and venous catheter were fixed in stereotaxic instrument. 29 rats were randomly divided into control group, agmatine group (5, 10, and 20 micromol) and clonidine group (1.0 micromol). Artificial cerebrospinal fluid was used as control. After administration, the changes of blood pressure and heart rate were observed. The remaining 41 rats were randomly divided into: (1) midazolam (imidazolinone receptor blocker) + agmatine group; (2) MK-801 [N-methyl-D-aspartate (NMDA) receptor antagonist ] + Agmatine group; (3) clonidine + agmatine group; (4) artificial cerebrospinal fluid + agmatine group; (5) midazolam + clonidine group; (6) MK-801 + clonidine group; The first intracerebroventricular injection of imidazole and other blockers, to be stable until 10 minutes after intravenous agmatine or clonidine intraventricular injection were observed after administration of blood pressure and heart rate changes. Results Intraventricular injection of agmatine 5 μmol [mean arterial pressure (MBP): (113 ± 5) before administration (105 ± 13) mmHg] and 10 μmol [MBP: (72 ± 9) mmHg] (all P <0.05), and agmatine significantly reduced blood pressure and heart rate in anesthetized rats. Cerebral ventricular injection of 1.0 μmol clonidine had similar cardiovascular effects [MBP: Before treatment (92 ± 8) than after administration (78 ± 19) mmHg, P <0.05]. Intracerebroventricular injection of an equal amount of artificial cerebrospinal fluid did not produce a significant effect on blood pressure and heart rate in anesthetized rats. Administration of imidazocin (1.0 μmol), NMDA receptor antagonist MK-801 (0.5 μmol), or clonidine (1.0 μmol) alone significantly attenuated the cardiovascular effects of agmatine administration to the lateral ventricle. Simultaneous administration of imidazole Keratomileusis (1.0μmol), and NMDA receptor antagonist MK-801 (0.5μmol) also effectively attenuated the cardiovascular effects of intracerebroventricular injection of clonidine. Conclusions Intraventricular injection of agmatine may reduce the blood pressure and decrease the heart rate. It may be mediated by NMDA receptors and clonidine can block the central cardiovascular effects of agmatine.