Chronic blockade of nitric oxide-synthase and endothelin receptors during pregnancy in the rat: effect on pregnancy outcome.
OBJECTIVE
To investigate the effects of endothelin-1 (ET-1) receptor antagonism and/or chronic blockade of nitric oxide (NO) production on pregnancy outcome in the rat.


METHODS
Pregnant or nonpregnant Wistar rats were either treated orally for up to 18 days with the NO-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), the ETA-/ETB-receptor antagonist bosentan (Roche Basel, Switzerland) or both, or received no treatment (controls). Blood pressure, body weight, and drug intake were measured at regular intervals. Pregnancy outcome and proteinurea were also determined. Analysis of variance and paired Student t test were used for statistical analysis.


RESULTS
Chronic L-NAME treatment increased systolic blood pressure by 69 and 64 mmHg in pregnant and virgin rats respectively (P < .05). Bosentan-blunted, L-NAME-induced hypertension at the beginning (P < .05), but not at the end of the treatment period in all rats examined. N omega-nitro-L-arginine methyl ester-treatment in pregnancy reduced the number of living fetuses at term (P < .05) and caused proteinurea (P < .05). Bosentan tended to reverse the effects of L-NAME on fetus number and proteinurea, but both effects failed to reach statistical significance.


CONCLUSIONS
The effects of chronic, NO-synthase-blockade on blood pressure in gravid rats can be reversed only temporarily by ETA-/ETB-antagonism, suggesting an involvement of endothelin-1 in the early phase of the L-NAME-induced, preeclampsia-like syndrome during pregnancy, although at later stages other mechanisms may come into play.
Wight
E
E
Department of Obstetrics and Gynecology, University Hospital Zürich, Switzerland.
Küng
C F
CF
Moreau
P
P
Takase
H
H
Lüscher
T F
TF
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D005260:Female; D005333:Fetus / Q000033:anatomy & histology / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000033:anatomy & histology / Q000187:drug effects; D011247:Pregnancy; D011256:Pregnancy Outcome; D011270:Pregnancy, Animal / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D019001:Nitric Oxide Synthase; D000077300:Bosentan; D019331:NG-Nitroarginine Methyl Ester