Cardiovascular and respiratory actions of U50,488H in the unanaesthetized ovine foetus.
In an effort to evaluate the feasibility of kappa-opioid receptor agonists for use in pregnancy, we have investigated the actions of U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide) on cardiovascular and respiratory control in the unanaesthetized ovine foetus. Intravenous administration of U50,488H (1.0 mg/kg) to the foetus resulted in an immediate increase in foetal blood pressure (P < 0.0001) and heart rate (P < 0.0001) which lasted 15 min, followed by a prolonged loss of heart rate variability for up to 3 h. There was also a significant suppression of foetal breathing movements for 2-3 h (P < 0.008). Pretreatment with naloxone (12 mg/h) completely blocked the hypertensive and tachycardiac response to U50,488H, but was unable to prevent the loss of variation in heart rate or respiratory depression. These data suggest that U50,488H can exert direct cardiovascular and respiratory actions in the ovine foetus via both opioid and non-opioid mechanisms. The naloxone-insensitive suppression of foetal breathing would severely limit the use of U50,488H as an obstetrical analgesic.
Szeto
H H
HH
Department of Pharmacology, Cornell University Medical College, New York, NY 10021, USA. hhszeto@mail.med.cornell.edu
Wu
D
D
Cheng
P Y
PY
Soong
Y
Y
Taylor
C C
CC
Yee
J
J
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000502:physiology*; D006340:Heart Rate, Fetal / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D009270:Naloxone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011247:Pregnancy; D011759:Pyrrolidines / Q000494:pharmacology*; D015656:Respiratory Mechanics / Q000187:drug effects*; D012756:Sheep
D000959:Antihypertensive Agents; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer