Multiple Actions of Phencyclidine and (+)MK-801 on Isolated Bovine Cerebral Arteries.

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 Ca2+-deficient media containing either potassium or U-46,619, phencyclidine and (+)MK-801 each produced competitive inhibition of subsequent Ca2+-induced constriction. In additional experiments, arterial strips were mounted in isolated tissue chambers to directly measure calcium uptake, using 45Calcium as a radioactive tracer. Both phencyclidine and (+)MK-801 blocked potassium-stimulated or U-46,619-stimulated 45Ca 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. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved

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