REPEATED COCAINE ADMINISTRATION REDUCES BRADYKININ-INDUCED DILATION OF PIAL ARTERIOLES

Using the acute cranial window technique in rabbits under surgical ane sthesia, we tested the vasoactivity of acetylcholine (ACh, 10(-8)-10(- 5) M), bradykinin (BK, 10(-8)-10(-5) M), and asphyxia (10% O-2, 9% CO2 , balance N-2) after subchronic pretreatment with cocaine. After repea ted administration of cocaine (20 mg . kg(-1). day(-1) sc x 7 days), t he BK-induced dilation of pial arterioles was reduced by 51%. Previous work showed that BK produces dilation of pial arterioles by a cycloox ygenase-dependent oxygen radical-mediated mechanism and that in rabbit s the BK-induced dilation is dependent on both vascular and nonvascula r cyclooxygenase. Selective blockade of vascular cyclooxygenase, in ad dition to cocaine treatment, did not produce any greater inhibition of the BK-induced dilation. The dilation in response to ACh and asphyxia was unaltered by cocaine. Levels of cerebrospinal fluid prostaglandin s suggest cocaine pretreatment may inhibit cerebral vascular prostagla ndin production. Together, cerebrospinal fluid prostaglandin and vasor eactivity data indicate cocaine pretreatment selectively inhibits the vascular cyclooxygenase-dependent mechanism mediating the BK-induced d ilation. This decreased response to BK in cocaine-treated rabbits may result from decreased oxygen radical production concomitant with decre ased vascular prostaglandin production. Alternatively, oxygen radical scavenging may be increased after cocaine treatment. We speculate that cocaine-induced alterations in cerebrovascular function and metabolis m map be related to the increased incidence of stroke reported to occu r in human cocaine users.