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++.
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Department of Physiology, State University of New York, Health Science Center at Brooklyn.
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D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000098:blood supply; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003042:Cocaine / Q000633:toxicity*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004285:Dogs; D004298:Dopamine / Q000494:pharmacology; D018492:Dopamine Antagonists; D015777:Eicosanoids / Q000096:biosynthesis; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D012756:Sheep; D013552:Swine; D014700:Verapamil / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D018492:Dopamine Antagonists; D015777:Eicosanoids; D014700:Verapamil; D003042:Cocaine; D006220:Haloperidol; D002118:Calcium; D004298:Dopamine; D007213:Indomethacin