|SOFT - TIAFT 1998||Scientific Session 3||Thursday October 8, 1998|
|IN VITRO ASSESSMENT OF THE TOXICITY OF COCAINE AND ITS METABOLITES IN THE HUMAN UMBILICAL ARTERY|
|Tessa L. Long1, Peter J. Rice1, Frederick R. Jelovsek2, Kenneth E. Ferslew1|
Depts. of Pharmacology1 and Obstetrics & Gynecology2, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
|Cocaine toxicity has generally been attributed to its vasoconstrictive and sympathomimetic effects. Placental abruption, preterm birth, and low birth weight associated with cocaine abuse has been correlated with increased systolic/diastolic ratios in human umbilical artery blood flow. We used an in vitro model to assess the effect of cocaine and its metabolites on the umbilical artery. Our objectives were to pharmacologically confirm the presence of adrenergic innervation using tyramine, to evaluate the ability of cocaine, norcocaine and cocaethylene to potentiate vasoconstriction by 5-hydroxytrytamine (5HT) and norepinephrine (NE), and to examine the ability of ketanserin, a 5HT2 antagonist, to block the vasoconstrictive toxicity produced by cocaine.
Rings of umbilical arteries (3mm) were collected and perfused in isolated tissue baths under physiological conditions. Isometric contractions were measured in paired tissues following exposure to NE, 5HT, or tyramine in the presence and absence of cocaine, norcocaine, or cocaethylene (10µM). The rings were exposed to ketanserin (0.03µM) and the dose response curves for 5HT and NE were reconstucted in the presence of cocaine.
The vasoconstrictive effect of tyramine was enhanced in the presence of cocaine, suggesting that tyramine produces a direct postsynaptic effect on the tissue. The vasoconstrictive effects of 5HT and norepinephrine were significantly enhanced by cocaine. Norcocaine significantly augmented the maximum response to NE in our preparation. Ketanserin completely attenuated the potentiation of NE and 5HT by cocaine. These data suggest that enhanced vasoconstriction of NE and 5HT by cocaine and potentiation of the maximum response to NE by norcocaine in the human umbilical artery may be important components of perinatal cocaine toxicity. Furthermore, ketanserin was able to suppress the umbilical artery constriction produced by cocaine, demonstrating antidotal potential for this compound in acute perinatal cocaine toxicity.