Effect of Ro 61-1790, a selective endothelin-A receptor antagonist, on systemic and uterine hemodynamics and fetal oxygenation in sheep.
OBJECTIVE
Endothelin-1 is reportedly elevated in preeclampsia, and studies in our laboratory have shown that infusion of endothelin-1 produces increased mean arterial pressure, hemoconcentration, and proteinuria, while decreasing uterine blood flow. If a role in preeclampsia is confirmed for endothelin-1, therapeutic intervention may involve selective endothelin-A receptor blockers. Thus, this study was designed to determine the effects of Ro 61-1790, a selective endothelin-A receptor inhibitor, on mean arterial pressure, heart rate, and uteroplacental blood flow in pregnant and nonpregnant sheep.


METHODS
Seven pregnant and seven nonpregnant sheep were instrumented with indwelling femoral artery and vein catheters and bilateral uterine artery flow probes, allowing determination of mean arterial pressure, heart rate, and uteroplacental blood flow. After baseline administration, animals received intravenous Ro 61-1790 either 1 mg/kg or 3 mg/kg, and hemodynamic responses were monitored for 120 minutes.


RESULTS
Intravenous administration of Ro 61-1790 at 1 mg/kg had no effect on the parameters measured in either group studied. However, at 3 mg/kg, Ro 61-1790 caused an increase in total uterine blood flow in nonpregnant sheep from 22 +/- 6 mL/min to 51 +/- 15 mL/min. This occurred in the absence of significant changes in mean arterial pressure. In pregnant animals, administration of 3 mg/kg Ro 61-1790 decreased mean (+/- SEM) uteroplacental blood flow by 20% (from 771 +/- 130 mL/min to 621 +/- 110 mL/min) and increased uterine vascular resistance transiently. Administration of Ro 61-1790 had no significant effect on fetal mean arterial pressure, heart rate, or oxygenation.


CONCLUSIONS
These data suggest that endogenous endothelin-1 may play an important role in regulating uterine vascular tone in pregnant and nonpregnant sheep and that inhibition of endogenous endothelin-1 may lead to reductions in uteroplacental perfusion in pregnant animals.
McElvy
Sherrie
S
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Ohio 45267-0526, USA.
Greenberg
Suzanne
S
Baker
R Scott
RS
Khoury
Jane
J
Clark
Kenneth E
KE
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004146:Dioxanes / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D005260:Female; D005312:Fetal Blood / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D010100:Oxygen / Q000097:blood*; D010920:Placenta / Q000098:blood supply; D011247:Pregnancy; D011725:Pyridines; D011743:Pyrimidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D012756:Sheep; D013449:Sulfonamides; D013777:Tetrazoles; D014599:Uterus / Q000098:blood supply*; D014655:Vascular Resistance / Q000187:drug effects
D004146:Dioxanes; D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan; D010100:Oxygen