Repeated cocaine administration reduces bradykinin-induced dilation of pial arterioles.
Using the acute cranial window technique in rabbits under surgical anesthesia, we tested the vasoactivity of acetylcholine (ACh, 10(-8)-10(-5) M), bradykinin (BK, 10(-8)-10(-5) M), and asphyxia (10% O2, 9% CO2, balance N2) after subchronic pretreatment with cocaine. After repeated administration of cocaine (20 mg.kg-1.day-1 sc x 7 days), the BK-induced dilation of pial arterioles was reduced by 51%. Previous work showed that BK produces dilation of pial arterioles by a cyclooxygenase-dependent oxygen radical-mediated mechanism and that in rabbits the BK-induced dilation is dependent on both vascular and nonvascular cyclooxygenase. Selective blockade of vascular cyclooxygenase, in addition 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 prostaglandins suggest cocaine pretreatment may inhibit cerebral vascular prostaglandin production. Together, cerebrospinal fluid prostaglandin and vasoreactivity data indicate cocaine pretreatment selectively inhibits the vascular cyclooxygenase-dependent mechanism mediating the BK-induced dilation. This decreased response to BK in cocaine-treated rabbits may result from decreased oxygen radical production concomitant with decreased vascular prostaglandin production. Alternatively, oxygen radical scavenging may be increased after cocaine treatment. We speculate that cocaine-induced alterations in cerebrovascular function and metabolism may be related to the increased incidence of stroke reported to occur in human cocaine users.
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613, USA.
J R
JR
Copeland
K A
KA
Willoughby
R J
RJ
Police
E F
EF
Ellis
D015121:6-Ketoprostaglandin F1 alpha / Q000134:cerebrospinal fluid; D000109:Acetylcholine / Q000494:pharmacology; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000201:enzymology; D001237:Asphyxia / Q000503:physiopathology; D001241:Aspirin / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage* / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D010841:Pia Mater / Q000098:blood supply*; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D014665:Vasodilator Agents; D015121:6-Ketoprostaglandin F1 alpha; D000410:Alanine Transaminase; D003042:Cocaine; D000109:Acetylcholine; D001241:Aspirin; D001920:Bradykinin; D003345:Corticosterone