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Cocaine-induced cerebrovasospasm and its possible mechanism of action.

Experiments were designed to study the effects and mechanism of action of cocaine (COC) on cerebrovascular tissues. Acute exposure to COC (10(-9) to 5 x 10(-3) M) induced contractile responses in isolated canine basilar (BA) and middle cerebral arteries in a dose-dependent manner, but not in mesenteric arteries. The presence or absence of intact endothelium did not alter COC concentration-response curves. The sensitivity to COC was higher in BA (ED50 = 7.20 +/- 0.16 x 10(-5) M) than middle cerebral arteries (ED50 = 1.25 +/- 0.12 x 10(-4) M). Similar effects of COC were also noted in BA from piglets (ED50 = 0.99 +/- 0.25 x 10(-4) M) and sheep (ED50 = 1.34 +/- 0.31 x 10(-4) M). A variety of amine antagonists, an opiate antagonist and an N-MDA receptor antagonist failed to interfere with the COC-induced contractions. However, haloperidol, indomethacin, verapamil and excess [Mg++]0 (4.8 x 10(-3) M) as well as removal of [Ca++]0 completely prevented vasospasms induced by COC. Dopamine and COC resulted in very similar concentration-response curves on canine BA. COC stimulation failed to affect vascular release of thromboxane B2, prostaglandins or 6-Keto-prostaglandin F1 alpha. Interestingly, 10(-7) M COC rapidly elevated intracellular free Ca++ concentrations of cultured cerebral vascular muscle cells about 50% over initial resting levels. The data suggest that COC produces cerebrovasospasm, probably by a direct action on cerebral blood vessels via promoting Ca++ influx and/or intracellular Ca++ release in cerebral vascular muscle cells, which may be modulated by Mg++.