EVIDENCE OF A DIRECT CONSTRICTOR ACTION OF MK-801 AND ITS MODULATION BY THE ENDOTHELIUM IN CEREBRAL-ARTERIES

The effects of MK-801 on the cerebral arteries and the possible involv ement of the endothelium in such a response were examined using two ex perimental approaches: in vivo, by recording cerebral blood flow (CBF) in the unanesthetized goat, and in vitro, by recording isometric tens ion in goat and human cerebral arteries. Injection of increasing doses (3, 10, 30, and 100 mu g) of MK-801 directly into the cerebroarterial supply elicited decreases in CBF and increases in cerebral vascular r esistance (CVR; for the highest dose tested CBF decreased by 16 +/- 10 % and CVR increased by 18 +/- 10%, p < 0.05). Administration of MK-801 as a single intravenous bolus (0.2 mg kg(-1)) reproduced that vasocon strictor response (CBF decreased by 17 +/- 9% and CVR increased by 46 +/- 33%, p < 0.05), and it was followed by a phase of sustained tachyc ardia (26 +/- 15% increase in resting heart rate, p < 0.01) and hypert ension (34 +/- 17% increase in resting mean arterial blood pressure, p < 0.05). In the in vitro experiments, addition of cumulative concentr ations (10(-6) to 3 x 10(-4) M) of MK-801 elicited concentration-relat ed contractions of goat and human cerebral arteries at both resting an d active tone (10(-5) M prostaglandin F-2 alpha) The MK-801-elicited c ontractile response in goat cerebral arteries at resting tone (maximum contraction of 7.7 +/- 5.5% of the response to 50 mM KCl) was enhance d during the following treatments: endothelium deprivation (16.3 +/- 4 .1%, p < 0.05); 10(-5) and 10(-4) M N-G-nitro-L-arginine (NOLAG, 16.9 +/- 9.1 and 33.2 +/- 16.6% respectively, p < 0.05), and 10(-5) M NOLAG +/- 10(-4) M D-arginine (22.6 +/- 7.1%, p < 0.05). However, 10(-5) M NOLAG +/- 10(-4) M L-arginine did not induce significant changes (11.0 +/- 7.0%). These results demonstrate that: (1) MK-801 has a direct co nstrictor action on cerebral arteries, and (2) the endothelium plays a negative feedback role by counteracting the MK-801-elicited contracti ons through the release of nitric oxide or a nitric oxide-containing c ompound.