Antagonism of cocaine-induced fetal anomalies by prazosin and diltiazem in mice.
Cocaine-induced uteroplacental and fetal vasoconstriction have been observed to cause fetal hypoxemia. The ability of cocaine to elevate norepinephrine (NE) levels has been proposed as one mechanism to explain the effect of cocaine on fetal development. Prazosin, a selective antagonist of alpha-1 adrenergic receptors, and diltiazem, a calcium channel blocker, were used to determine if antagonism of NE-induced vasoconstriction would reduce the effects of chronic cocaine administration on fetal development. The dose-response relationship of cocaine with fetal development was established in CF-1 mice by administering cocaine sc on days 5 to 18 of gestation followed by teratologic evaluation. Cocaine 2 mg/kg/day produced a significant incidence of fetal anomalies without significantly affecting food consumption or maternal and fetal weight gain. In subsequent experiments, prazosin (0.03, 0.3 mg/kg) or diltiazem (1.7, 5.1 mg/kg) were administered po 2 h prior to 2 mg/kg cocaine sc (gestation days 5 to 18) followed by teratologic evaluation. Diltiazem (5.1 mg/kg) produced a significant increase, whereas prazosin (0.3 mg/kg) produced a significant reduction, in the incidence of fetal anomalies compared with saline controls. While data from the pretreatment studies were inconclusive, comparisons between cocaine alone and the cocaine groups pretreated with the high doses of either prazosin or diltiazem seem worthy of further study with larger sample sizes.
Mahalik
M P
MP
Department of Physiology and Pharmacology, Philadelphia College of Osteopathic Medicine, Pennsylvania 19131-1696.
Hitner
H W
HW
D000014:Abnormalities, Drug-Induced / Q000517:prevention & control*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004110:Diltiazem / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005327:Fetal Resorption / Q000517:prevention & control; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011224:Prazosin / Q000494:pharmacology*; D011247:Pregnancy; D013723:Teratogens / Q000633:toxicity; D014661:Vasoconstriction / Q000187:drug effects
D013723:Teratogens; D004110:Diltiazem; D003042:Cocaine; D011224:Prazosin