Effects of sodium bicarbonate and ammonium chloride on the incidence of furosemide-induced fetal skeletal anomaly, wavy rib, in rats.
Furosemide produces fetal wavy ribs when administered to pregnant rats during late gestation. The compound is also known to produce metabolic alkalosis in laboratory animals and man. In order to evaluate the effect of furosemide on maternal blood pH, Crj:CD(SD) female rats received an oral administration of 150 or 200 mg/kg of furosemide by gavage on day 16 of gestation and were bled at 4 hr post-dose. Compared to an average pH of 7.39 in control females, there was a significant elevation in blood pH in these furosemide-treated females (average pH of 7.44 to 7.48). When 2% sodium bicarbonate was provided in the drinking water for females treated with 150 mg/kg of furosemide, there was a further rise in maternal blood pH (7.52) compared to females treated with furosemide alone. Associated with this elevation in maternal blood pH was a marked increase in the incidence of fetal wavy ribs (87.6% compared to 27.6%). When females treated with 200 mg/kg of furosemide were provided with 0.5% ammonium chloride, furosemide-induced maternal alkalosis was corrected (pH decreased to 7.35) and there was a reduction in the incidence of fetal wavy ribs (7.0% compared to 37.2%). In addition, maternal blood pH among individual females was positively correlated with the incidence of fetal wavy ribs (r = 0.714). These results suggest that maternal metabolic alkalosis is involved in the pathogenesis of furosemide-induced wavy ribs.
Nakatsuka
T
T
Development Research Laboratories, Banyu Pharmaceutical Co., Ltd., Saitama-ken, Japan.
Fujikake
N
N
Hasebe
M
M
Ikeda
H
H
D000471:Alkalosis / Q000139:chemically induced; D000643:Ammonium Chloride / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004347:Drug Interactions; D005260:Female; D005665:Furosemide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008297:Male; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012272:Ribs / Q000002:abnormalities*; D017693:Sodium Bicarbonate / Q000633:toxicity*; D013723:Teratogens / Q000633:toxicity*
D013723:Teratogens; D000643:Ammonium Chloride; D005665:Furosemide; D017693:Sodium Bicarbonate