Evidence of a Direct Constrictor Action of MK-801 and Its Modulation by the Endothelium in Cerebral Arteries

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Abstract
The effects of MK-801 on the cerebral arteries and the possible involvement of the endothelium in such a response were examined using two experimental approaches: in vivo, by recording cerebral blood flow (CBF) in the unanestheized goat, and in vitro, by recording isometric tension in goat and human cerebral arteries. Injection of increasing doses (3, 10, 30, and 100 µg) of MK-801 directly into the cerebroarterial supply elicited decreases in CBF and increases in cerebral vascular resistance (CVR; for the highest dose tested CBF decreased by 16 ± 10% and CVR increased by 18 ± 10%, p& –1) reproduced that vasoconstrictor response (CBF decreased by 17 ± 9% and CVR increased by 46 ± 33%, p -6 to 3 × 10-4M) of MK-801 elicited concentration-related contractions of goat and human cerebral arteries at both resting and active tone (10-5M prostaglandin F2α). The MK-801-elicited contractile response in goat cerebral arteries at resting tone (maximum contraction of 7.7 ± 5.5% of the response to 50 mM KCl) was enhanced during the following treatments: endothelium deprivation (16.3 ± 4.1%, p -5 and 10–4 M NG-nitro-L-arginine (NOLAG, 16.9 ± 9.1 and 33.2 ± 16.6% respectively, p& -5M NOLAG + 10–4M L D-arginine (22.6 ± 7.1%, p -5M NOLAG + 10-4ML· arginine did not induce significant changes (11.0 ± 7.0%). These results demonstrate that: (1) MK-801 has a direct constrictor action on cerebral arteries, and (2) the endothelium plays a negative feedback role by counteracting the MK-801-elicited contractions through the release of nitric oxide or a nitric oxide-containing compound.

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