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

Wendling, Woodrow W., MD, PhD*; Chen, Dong, MBBS, MS*; Wendling, Karen S., PhD; Kamel, Ihab R., MD*

Journal of Neurosurgical Anesthesiology: October 2018 - Volume 30 - Issue 4 - p 359–367
doi: 10.1097/ANA.0000000000000463
Laboratory Investigation

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.

*Department of Anesthesiology, Lewis Katz School of Medicine, Temple University

Department of Chemistry and Physics, Chestnut Hill College, Philadelphia, PA

The authors have no funding or conflicts of interest to disclose.

Address correspondence to: Woodrow W. Wendling, MD, PhD, Department of Anesthesiology, Lewis Katz School of Medicine, Temple University, 3401 North Broad Street, Philadelphia, PA 19140 (e-mail: woodrow.wendling@temple.edu).

Received February 18, 2017

Accepted August 29, 2017

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