Department of Anesthesiology, Lewis Katz School of Medicine, Temple University.
Department of Chemistry and Physics, Chestnut Hill College, Philadelphia, PA.
J Neurosurg Anesthesiol. 2018 Oct;30(4):359-367. doi: 10.1097/ANA.0000000000000463.
This study examines the direct effects of 3 noncompetitive N-methyl-D-aspartate receptor antagonists, phencyclidine (PCP), (+)MK-801, and (-)MK-801, on bovine middle cerebral arteries (BMCA). Rings of BMCA were mounted in isolated tissue chambers equipped with isometric tension transducers to obtain pharmacologic dose-response curves. In the absence of endogenous vasoconstrictors, the 3 N-methyl-D-aspartate antagonists each produced direct constriction of BMCA. The thromboxane A2 receptor antagonist SQ-29,548, the TxA2 synthase inhibitor furegrelate, the calcium antagonist nimodipine, and calcium-deficient media all inhibited maximal phencyclidine or (+)MK-801-induced constriction. Direct constriction by PCP or (+)MK-801 was independent of the presence of endothelium. When BMCA were preconstricted with potassium-depolarizing solution, PCP, (+)MK-801, and (-)MK-801 each produced only concentration-dependent relaxation. When BMCA were preconstricted with the stable TxA2 analog U-46,619 and exposed to increasing concentrations of PCP, (+)MK-801, or (-)MK-801, tension increased. Thromboxane A2 may contract BMCA by acting as a potassium channel blocker; iberiotoxin and tetraethylammonium both constrict BMCA. In Ca-deficient media containing either potassium or U-46,619, phencyclidine and (+)MK-801 each produced competitive inhibition of subsequent Ca-induced constriction. In additional experiments, arterial strips were mounted in isolated tissue chambers to directly measure calcium uptake, using Calcium as a radioactive tracer. Both phencyclidine and (+)MK-801 blocked potassium-stimulated or U-46,619-stimulated Ca uptake into arterial strips. These results suggest that phencyclidine and (+)MK-801 have 2 separate actions on BMCA. They may constrict arterial rings by releasing TxA2 from cerebrovascular smooth muscle, and relax arterial rings by acting as calcium antagonists.
这项研究考察了 3 种非竞争性 N-甲基-D-天冬氨酸受体拮抗剂，苯环利定（PCP）、（+）MK-801 和（-）MK-801，对牛大脑中动脉（BMCA）的直接影响。将 BMCA 环安装在配备等长张力换能器的分离组织室中，以获得药理剂量反应曲线。在没有内源性血管收缩剂的情况下，这 3 种 N-甲基-D-天冬氨酸拮抗剂都导致 BMCA 直接收缩。血栓烷 A2 受体拮抗剂 SQ-29,548、血栓烷 A2 合酶抑制剂 furegrelate、钙拮抗剂尼莫地平以及缺钙介质均抑制最大程度的苯环利定或（+）MK-801 诱导的收缩。PCP 或（+）MK-801 引起的直接收缩与内皮的存在无关。当 BMCA 用低钾去极化溶液预收缩时，PCP、（+）MK-801 和（-）MK-801 各自仅产生浓度依赖性舒张。当 BMCA 用稳定的血栓烷 A2 类似物 U-46,619 预收缩并暴露于逐渐增加的 PCP、（+）MK-801 或（-）MK-801 浓度时，张力增加。血栓烷 A2 可能通过作为钾通道阻滞剂收缩 BMCA； Iberiotoxin 和四乙铵都收缩 BMCA。在含有钾或 U-46,619 的缺钙介质中，苯环利定和（+）MK-801 各自对随后的 Ca 诱导收缩产生竞争性抑制。在其他实验中，将动脉条安装在分离的组织室中，使用放射性示踪剂钙来直接测量钙摄取。苯环利定和（+）MK-801 均阻断钾刺激或 U-46,619 刺激的动脉条中 Ca 的摄取。这些结果表明，苯环利定和（+）MK-801 对 BMCA 有 2 种不同的作用。它们可能通过从脑血管平滑肌释放血栓烷 A2 来收缩动脉环，并且通过作为钙拮抗剂来舒张动脉环。
