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

Woodrow W. Wendling, Dong Chen, Karen S. Wendling, Ihab R Kamel

Research output: Contribution to journalArticle

Abstract

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 A 2 receptor antagonist SQ-29,548, the TxA 2 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 TxA 2 analog U-46,619 and exposed to increasing concentrations of PCP, (+)MK-801, or (-)MK-801, tension increased. Thromboxane A 2 may contract BMCA by acting as a potassium channel blocker; iberiotoxin and tetraethylammonium both constrict BMCA. In Ca 2+ -deficient media containing either potassium or U-46,619, phencyclidine and (+)MK-801 each produced competitive inhibition of subsequent Ca 2+ -induced constriction. In additional experiments, arterial strips were mounted in isolated tissue chambers to directly measure calcium uptake, using 45 Calcium as a radioactive tracer. Both phencyclidine and (+)MK-801 blocked potassium-stimulated or U-46,619-stimulated 45 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 TxA 2 from cerebrovascular smooth muscle, and relax arterial rings by acting as calcium antagonists.

Original languageEnglish (US)
Pages (from-to)359-367
Number of pages9
JournalJournal of Neurosurgical Anesthesiology
Volume30
Issue number4
DOIs
StatePublished - Oct 1 2018
Externally publishedYes

Fingerprint

Phencyclidine
Cerebral Arteries
Dizocilpine Maleate
Middle Cerebral Artery
Constriction
Calcium
Potassium
Thromboxanes
varespladib methyl
Potassium Channel Blockers
Radioactive Tracers
Nimodipine
Tetraethylammonium
Vasoconstrictor Agents
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Transducers
Endothelium
Smooth Muscle

Keywords

  • calcium channel blockers
  • cattle
  • cerebral arteries
  • dizocilpine maleate
  • phencyclidine
  • potassium channel blockers
  • vascular smooth muscle

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Multiple Actions of Phencyclidine and (+)MK-801 on Isolated Bovine Cerebral Arteries. / Wendling, Woodrow W.; Chen, Dong; Wendling, Karen S.; Kamel, Ihab R.

In: Journal of Neurosurgical Anesthesiology, Vol. 30, No. 4, 01.10.2018, p. 359-367.

Research output: Contribution to journalArticle

Wendling, Woodrow W. ; Chen, Dong ; Wendling, Karen S. ; Kamel, Ihab R. / Multiple Actions of Phencyclidine and (+)MK-801 on Isolated Bovine Cerebral Arteries. In: Journal of Neurosurgical Anesthesiology. 2018 ; Vol. 30, No. 4. pp. 359-367.
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AB - 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 A 2 receptor antagonist SQ-29,548, the TxA 2 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 TxA 2 analog U-46,619 and exposed to increasing concentrations of PCP, (+)MK-801, or (-)MK-801, tension increased. Thromboxane A 2 may contract BMCA by acting as a potassium channel blocker; iberiotoxin and tetraethylammonium both constrict BMCA. In Ca 2+ -deficient media containing either potassium or U-46,619, phencyclidine and (+)MK-801 each produced competitive inhibition of subsequent Ca 2+ -induced constriction. In additional experiments, arterial strips were mounted in isolated tissue chambers to directly measure calcium uptake, using 45 Calcium as a radioactive tracer. Both phencyclidine and (+)MK-801 blocked potassium-stimulated or U-46,619-stimulated 45 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 TxA 2 from cerebrovascular smooth muscle, and relax arterial rings by acting as calcium antagonists.

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