Perinatal nitric oxide synthase inhibition retards neonatal growth by inducing hypertrophic pyloric stenosis in rats.
Administration of the nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) during pregnancy has been shown to compromise fetal growth. This study was designed to determine whether aminoguanidine, a predominate inhibitor of inducible NOS, affects fetal outcome. In addition, we extended the prenatal administration of L-NAME into the postnatal period (14 d) to determine whether neonatal growth and maturation were also affected. L-NAME, but not aminoguanidine, compromises fetal and placental growth. When compared with control 14-d-old pups, postnatal L-NAME compromised neonatal growth, whether it was given directly (intraperitoneally) (39.7 +/- 1.1 versus 24.1 +/- 1.0 g) or indirectly (38.6 +/- 0.5 versus 22.2 +/- 1.2 g) via maternal breast milk. Neonatal growth retardation was asymmetric, with brain sparing, suggesting a nutritional origin. L-NAME administration resulted in growth retardation that extended into adulthood, without evidence of catch-up growth. Treated neonates displayed the hallmarks of hypertrophic pyloric stenosis. Significant increases in stomach weight/pup weight (9.9 +/- 0.3 versus 8.2 +/- 0.4 x 10(3)) and stomach volume/pup weight (12.0 +/- 0.6 versus 9.4 +/- 0.6 mL/100 g) with a concomitant decrease in small intestine weight/length (2.10 +/- 0.08 versus 3.18 +/- 0.13 g/100 cm) was noted in treated versus control pups (p < 0.05). Muscularis hypertrophy at the pyloric sphincter in the L-NAME-treated pups was noted by histology. Blood pressure was elevated in the L-NAME-treated pups (93 +/- 6 versus 60 +/- 5 mm Hg in control pups, p < 0.05). These findings are consistent with inhibition of neuronal and endothelial NOS activity. We conclude that NO, formed via the constitutive isoforms of NOS, is a critical determinant of fetal and neonatal growth and maturation.
Voelker
C A
CA
Department of Pediatrics, Tulane Medical Center, New Orleans, Louisiana 70112, USA.
Miller
M J
MJ
Zhang
X J
XJ
Eloby-Childress
S
S
Clark
D A
DA
Pierce
M R
MR
D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001835:Body Weight; D004195:Disease Models, Animal; D005314:Embryonic and Fetal Development / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006128:Growth; D006146:Guanidines / Q000494:pharmacology*; D006984:Hypertrophy / Q000139:chemically induced / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D011707:Pyloric Stenosis / Q000139:chemically induced / Q000503:physiopathology*; D051381:Rats
D006146:Guanidines; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester