Cocaine-induced cerebrovasospasm and its possible mechanism of action

Abstract

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++.