Long-term nitric oxide blockade in the pregnant rat: effects on blood pressure and plasma levels of endothelin-1.
OBJECTIVE
Abnormalities in the production of nitric oxide and endothelin-1 have been implicated in the development of preeclampsia. We postulated that long-term nitric oxide synthase inhibition with L-nitro-arginine methyl ester would induce sustained hypertension, a rise in plasma levels of endothelin-1, and fetal growth restriction.


METHODS
Conscious virgin and pregnant Sprague-Dawley rats received infusions of vehicle or L-nitro-arginine methyl ester (2.5 mg/kg/hr) for 11 days. Mean arterial pressure was assessed serially. On day 21 of gestation (or equivalent in virgin rats) plasma was collected for endothelin-1 levels; pup weight and litter size were determined. Data were analyzed with analysis of variance and regression techniques.


RESULTS
Mean arterial pressure was constant in virgin control rats (n = 7) but declined in pregnant control rats (n = 11) as gestation advanced. Nitric oxide synthase inhibition in virgin (n = 10) and pregnant (n = 11) rats caused sustained elevations in mean arterial pressure (165 +/- 7 vs 100 +/- 3 mm Hg, L-nitro-arginine methyl ester vs control virgin rats, p < 0.0001; 149 +/- 5 vs 91 +/- 2 mm Hg, L-nitro-arginine methyl ester vs control pregnant rats, p < 0.0001). L-nitro-arginine methyl ester induced a rise in plasma endothelin-1 levels in virgin (4.4 +/- 0.1 vs 3.5 +/- 0.1 pg/ml, L-nitro-arginine methyl ester vs control, p < 0.0001) and pregnant rats (3.0 +/- 0.1 vs 2.6 +/- 0.1 pg/ml, L-nitro-arginine methyl ester vs control, p < 0.0001). Pregnant rats had lower endothelin-1 levels than did virgin rats (p < 0.0001). Mean arterial pressure and endothelin-1 were significantly correlated in pregnant rats. L-nitro-arginine methyl ester decreased pup weight (2.4 +/- 0.4 vs 3.7 +/- 0.2 gm/pup/litter, L-nitro-arginine methyl ester vs control, p < 0.01) and litter size (6.6 +/- 1.3 vs 10.2 +/- 0.9 pups/litter, L-nitro-arginine methyl ester vs control, p < 0.05).


CONCLUSIONS
Long-term nitric oxide synthase blockade causes sustained hypertension, elevated levels of endothelin-1, and fetal growth restriction. Although the endocrine and pressor effects are not unique to pregnancy, this model clearly induces some of the changes seen in preeclampsia and may be useful for studying specific interventions.
Edwards
D L
DL
Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center Burns and Allen Research Institute, Los Angeles, California, USA.
Arora
C P
CP
Bui
D T
DT
Castro
L C
LC
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects; D019332:Endothelin-1 / Q000097:blood*; D005260:Female; D006973:Hypertension / Q000139:chemically induced; D008098:Litter Size / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000139:chemically induced; D011270:Pregnancy, Animal / Q000097:blood / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D019332:Endothelin-1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester