Cocaine constricts immature cerebral arterioles by a local anesthetic mechanism.
The effect of cocaine on cerebral arterioles was determined in newborn pigs and the mechanism of action was examined in terms of its local anesthetic and sympathomimetic properties. Forty-three newborn piglets were anesthetized, equipped with a closed cranial window, and the diameter of pial arterioles was measured by intravital microscopy. Increasing concentrations of cocaine (10(-7) M to 10(-3) M) applied onto the cortical surface resulted in a dose-dependent decrease in arteriolar diameter. Coadministration with phentolamine, an alpha-adrenoceptor antagonist, did not inhibit the contractile response to cocaine even though phentolamine blocked the constriction to topically applied norepinephrine. In contrast, coadministration of either tetrodotoxin (Na+ channel blocker), charybdotoxin (K+ channel blocker), or quinacrine (phospholipase A2 inhibitor), or pretreatment with indomethacin (cyclooxygenase inhibitor) attenuated vasoconstriction induced by cocaine. Topically applied lidocaine (10(-7) M to 10(-3) M), a local anesthetic without sympathomimetic properties, caused a dose-dependent constriction similar to cocaine, whereas topically applied nomifensine and desipramine (each 10(-7) M to 10(-3) M), inhibitors of dopamine and norepinephrine re-uptake, respectively, did not constrict cerebral arterioles. These results indicate that cocaine constricts cerebral arterioles by its local anesthetic properties rather than its sympathomimetic properties. The mechanism appears to involve an alteration in the flux of Na+ or K+ or prostanoid metabolism.
Albuquerque
M L
ML
Department of Anesthesiology, Children's Hospital of Philadelphia, PA.
Kurth
C D
CD
D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D002536:Cerebral Arteries / Q000187:drug effects; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006400:Hematocrit; D006863:Hydrogen-Ion Concentration; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D013552:Swine; D013566:Sympathomimetics / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000779:Anesthetics, Local; D013566:Sympathomimetics; D014662:Vasoconstrictor Agents; D003042:Cocaine