Subject(s)
Dopamine beta-Hydroxylase/antagonists & inhibitors , Embryonic and Fetal Development/drug effects , Enzyme Inhibitors/toxicity , Fusaric Acid/toxicity , Adrenal Glands/drug effects , Adrenal Glands/metabolism , Analysis of Variance , Animals , Body Weight/drug effects , Brain/drug effects , Brain/metabolism , Cleft Palate/chemically induced , Corticosterone/blood , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Female , Fetal Resorption/chemically induced , Fusaric Acid/administration & dosage , Kidney/drug effects , Kidney/metabolism , Liver/drug effects , Liver/metabolism , Male , Maternal-Fetal Exchange , Mice , No-Observed-Adverse-Effect Level , Osteogenesis/drug effects , Pregnancy , Radioimmunoassay , Staining and LabelingABSTRACT
Dose-response of the teratogenic effect of caffeine (CA) and the potential role of facial hematomas in the pathogenesis of caffeine-induced cleft palate were investigated using CD1 mice treated with 150, 200, or 250 mg CA/kg i.p. on gestational day (GD) 12. Dimethylsulfoxide (DMSO; 20%) and arachidonic acid (AA, 200 mg/kg) were administered along with CA (200 mg/kg) to study their interaction with CA-induced teratogenesis and elevation in maternal glucocorticoids (MGC, measured by RIA) on GD 13 and 14. Dose-dependent increase in the incidence of cleft palate (CP) was noted in CA-exposed mice. High maternal deaths, an increased number of resorptions, gross facial hematomas (GFH), and club foot (CF) were produced only by the highest (250 mg/kg) dose of CA. Palates from all offspring with GFH were clefted at this dose level. None of the control or CA-treated nonclefted offspring had GFH or microscopic hematomas (MH). At 200 mg/kg of CA, DMSO in combination with CA actually increased CA-induced CP from 30% to 100% and also produced 100% GFH as compared to 0% by CA alone at this dose. Greater than 50% of clefted offspring without GFH, given either dose (200 or 250 mg/kg) of CA, had MH. Very high levels of MGC were present in CA-treated mice on GD 13 and 14. Although simultaneous administration of DMSO reduced the magnitude of CA-induced MGC elevations on GD 14, the MGC levels remained high for greater than 24 hours following CA exposure. Increase in maternal mortality and fetal resorptions, a decrease in the number of live pups and their body weights, and no change in the incidence of CP were seen when CA-treated mice were simultaneously exposed to AA. These results suggest a correlation between caffeine-induced FH and CP; a role for increased hematomagenic effects of DMSO in its potentiation of the cleft-palatogenic effect of caffeine; and absence of a role for AA-mediated effects of MGC in the causation of CA-induced CP and other malformations.
Subject(s)
Abnormalities, Drug-Induced/pathology , Arachidonic Acid/toxicity , Caffeine/toxicity , Dimethyl Sulfoxide/toxicity , Animals , Cleft Palate/chemically induced , Cleft Palate/pathology , Corticosterone/blood , Drug Synergism , Face/pathology , Female , Hematoma/chemically induced , Hematoma/pathology , Male , Mice , Mice, Inbred Strains , PregnancyABSTRACT
The impact of acute and chronic portal hypertension on the dynamics of intestinal microvascular fluid exchange was examined in anesthetized, fasted, sham-operated control rats with normal portal pressures (CON), during acute elevations in portal pressure (APH) in control rats, and in rats in which chronic portal hypertension (CPH) was produced by calibrated stenosis of the portal vein 10 days prior to the experiments. Although intestinal blood flow and vascular resistance were not altered by APH in control rats, CPH was associated with an increased intestinal blood flow and reduced intestinal vascular resistance when compared with CON and APH. Intestinal capillary pressure and lymph flow were elevated in APH and CPH relative to control values. However, the increase in both variables was greater in CPH. The capillary filtration coefficient was elevated only in CPH. The transcapillary oncotic pressure gradient was not altered by APH or CPH. Interstitial fluid pressure was increased from -1.1 mmHg in CON to 3.9 mmHg during APH and to 5.0 mmHg in CPH. The results of this study indicate that chronic elevations in portal venous pressure produce larger increments in intestinal capillary pressure and filtration rate than do acute elevations in portal venous pressure of the same magnitude. However, the potential edemagenic effects of elevated capillary pressure in both acute and chronic portal hypertension are opposed by increases in lymph flow and interstitial fluid pressure.
