Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

August 1998

Abstract

An in vitro model was used to assess the effect of cocaine and its metabolites on the umbilical artery. Objectives were to pharmacologically confirm the presence of adrenergic innervation using tyramine, evaluate the ability of cocaine, benzoylecgonine, norcocaine and cocaethylene to potentiate vasoconstriction by serotonin and norepinephrine, examine the ability of ketanserin to block the enhanced vasoconstriction produced by cocaine, and determine displacement of 3 H-ketanserin by serotonin, norepinephrine, tyramine and mianserin. The vasoconstrictive effect of tyramine (100 μM) was enhanced in the presence of cocaine by 257%. Vasoconstrictive effects of serotonin and norepinephrine were significantly enhanced by cocaine by 28%, and 64% respectively; producing significant increases in the cumulative response. Norcocaine significantly augmented the maximum response to norepinephrine by 54%. Benzoylecgonine significantly decreased the maximum response to serotonin by 36% as well as the cumulative response. Ketanserin (0.03 μM) completely attenuated the vasoconstrictive potentiation of serotonin and norepinephrine by cocaine; shifting the EC50 for serotonin to the right 10-fold in the presence of ketanserin and cocaine. Ketanserin shifted the EC15 for norepinephrine with cocaine to the right 205-fold. Maximum response to norepinephrine with cocaine was depressed 54% by ketanserin. Serotonin, tyramine, and mianserin were able to displace 3 H-ketanserin (3 nM) from the membrane fraction of the human umbilical artery. Indicating that serotonin2 receptors are involved in vasoconstrictive responses to serotonin and tyramine. Norepinephrine did not displace 3 H-ketanserin in the membrane fraction of the umbilical artery. These data suggest that enhanced vasoconstriction of norepinephrine and serotonin by cocaine and potentiation of the maximum response to norepinephrine by norcocaine in the human umbilical artery may be important components of perinatal cocaine toxicity. Ketanserin was able to suppress the umbilical artery constriction produced by cocaine, demonstrating its antidotal potential. The potentiation of the tyramine response by cocaine and the displacement of 3 H-ketanserin by tyramine indicate that tyramine may be producing its vasoconstrictive effect through serotonin2 in the umbilical artery.

Document Type

Dissertation - unrestricted

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