Involvement of free radicals and histamine in the potentiating action of cigarette smoke exposure on ethanol-induced gastric mucosal damage in rats

Cigarette smoking has been associated with peptic ulcer diseases. We studied the effects of cigarette smoke exposure on ethanol-induced gastric mucosal damage and its relationship with vascular integrity and the possible role of free radicals and histamine. Male Sprague-Dawley rats were exposed to cigarette smoke followed by ethanol administration (70% v/v). Smoke exposure alone dose-dependently reduced basal blood flow and increased xanthine oxidase (XO) activity but superoxide dismutase (SOD) activity remained unaffected in gastric mucosa. Cigarette smoking followed by ethanol administration significantly potentiated mucosal lesion formation along with augmentation of the mucosal blood flow, vascular permeability and myeloperoxidase (MPO) activity. The potentiating effect of smoking on ethanol-induced gastric mucosal lesion and MPO activity was abolished by pretreatment with allopurinol, terfenadine or ranitidine. Terfenadine and ranitidine also reduced the increased mucosal blood flow and vascular permeability induced by smoking and ethanol combined. These findings suggested that cigarette smoke adversely affected the defense mechanisms of the gastric mucosa by reducing the mucosal blood flow which in turn led to ischemia and increased XO activity. Activation of XO together with histamine H1 and H2 receptors stimulation could lead to neutrophil aggregation and vascular damage. However, the potentiating action of cigarette smoke on ethanol ulceration is unlikely through reduction of SOD activity in gastric mucosa.     

Subcutaneous loperamide prevents gastric lesions induced by necrotizing agents in rats

The effects of subcutaneous loperamide on gastric lesions induced by necrotizing agents were investigated in the rat. Loperamide produced a dose-dependent increase of gastric fluid volume and inhibition of gastric lesions caused by 0.6 N HCl or absolute ethanol. Pretreatment with naloxone almost completely blocked both fluid pooling effect and mucosal protective effect of loperamide. Omeprazole reduced the acidity of the gastric fluid in rats treated with loperamide without significantly decreasing the fluid volume. Various volumes of acid, given orally immediately before 0.6 N HCl, volume-dependently prevented gastric lesions. We conclude that subcutaneous loperamide protects the gastric mucosa against necrotizing agents through luminal dilution of irritants, which is mediated by naloxone-sensitive opiate receptors.     

Assessment of hemodynamic changes in rat stomachs by laser Doppler velocimetry and reflectance spectrophotometry. Effects of ethanol and prostaglandin E2 under ischemic and congestive conditions

One of the ulcerogenic mechanisms by which ethanol induces mucosal lesions in the stomach is the depression of gastric mucosal blood flow (GMBF). The goal of this study was to determine whether lesion formation is the result of vascular ischemia alone or ischemia combined with congestion. The aims of this study were to answer this question by evaluating the relationship between GMBF, oxygen saturation (ISO2) and hemoglobin volume (IHb) in the gastric mucosa under the influences of ethanol and prostaglandin E2 (PGE2) in the ischemic and congestive states, using a laser Doppler flowmeter and tissue spectrum analyzer. Ligation of the gastric celiac artery or vein markedly decreased the GMBF and the ISO2 level. The former procedure also reduced but the latter increased the IHb level. Ethanol administration produced effects similar to venous ligation, i.e. vascular stasis with ischemia. There was a negative correlation between GMBF and severity of lesion formation after ethanol administration. However, at the lesion site all the hemodynamic parameters were significantly reduced, indicating that a necrotic condition had occurred. PGE2 preincubation (25 micrograms) elevated GMBF, ISO2 and IHb levels. It also alleviated the reduction of blood flow induced by ethanol and increased the recovery rate of GMBF and ISO2 after the release of arterial or venous ligation. It is concluded that the decrease in blood flow due to ethanol is probably caused by constriction of venules rather than arterioles inside the mucosa, and this effect could lead to vascular congestion. PGE2 probably dilates both arterioles and venules in the gastric mucosa and thereby increases the blood flow in the gastric mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antioxidants inhibit ethanol-induced gastric injury in the rat. Role of manganese, glycine, and carotene

BACKGROUND: Oxygen-derived radicals are implicated in the pathogenesis of tissue damage and ulcerogenesis. This study aimed to examine the effect of manganese, glycine, and carotene, oxygen radical scavengers, on ethanol-induced gastric lesions in the rat and on ethanol cytotoxicity in epithelial cell culture. METHODS: MnCl2 + glycine (12.5-50 mg/rat) were injected subcutaneously up to 6 h before oral administration of 1 ml of 96% ethanol, and 0.5 ml carrot juice or beta-carotene was given orally 30 min before the ethanol. Mucosal injury was evaluated 1 h later by gross and microscopic scoring. The effect of Mn2+ and carrot juice was also tested in monolayers of radiolabeled epithelial cells exposed to H2O2 + ethanol injury as expressed by the extent of the isotope leakage. RESULTS: Mn2+ and glycine pretreatment dose-dependently reduced ethanol-induced gastric lesion formation. Protection was maximal when treatment was applied 4 h before the insult. Gross damage was also markedly prevented by pretreatment with carotenes and dimethylthiourea (DMTU, 75 mg/kg intraperitoneally) but not by allopurinol. Mixtures of subtoxic concentrations of ethanol and H2O2 were highly lethal for epithelial cell monolayers. In this model, cell death was markedly attenuated by catalase, DMTU, Mn2+, and carrot juice. CONCLUSIONS: Ethanol-induced gastric mucosal damage may involve generation of oxygen-derived radicals, independent of the xanthine oxidase system. By acting as oxygen radical scavengers, Mn2+, glycine, and carotenes, like catalase and DMTU, provide significant gastroprotection.     

Mucosal lesions due to gastric distension in the rat

The pathogenesis of acute gastric mucosal lesions produced by distension of the rat stomach was studied. One hour of distension with 0.1 N HCl, but not saline, produced lesions in the glandular stomach in all rats. Histologic studies revealed marked thinning of the mucosa plus thrombus formation in the ulcerated area. Gastric distension with 8 ml HCl (per 100 g body weight) produced severe lesions, 4 ml minimal lesions and 2 ml no lesions. Intragastric pressure in the 8-ml group remained above 110 mm H2O for the first 10 min. Distension with 8 ml acid/100 g body weight for just 10 min resulted in significant lesion formation. Acid distension did not cause generalized disruption of the gastric mucosal barrier to H+ back-diffusion. It appears that an intragastric pressure of over 110 mm H2O for 10 min damages the mucosa by pressure (with thinning) and ischemia (with thrombosis), resulting in decreased resistance to acid peptic digestion and consequent acute lesion formation.     

Different effects of indomethacin and nabumetone on prostaglandin-mediated gastric responses to central vagal activation in rats

Intracisternal injection of a stable thyrotropin-releasing hormone (TRH) analog increases gastric prostaglandins release and mucosal resistance to injury through central vagal pathways. The effects of two nonsteroidal anti-inflammatory drugs, indomethacin (INDO) and nabumetone on intracisternal injection of various doses of TRH-induced gastric acid secretion and changes in mucosal resistance were investigated in urethane-anesthetized rats. Doses of INDO (5 mg/kg) and nabumetone (13.75 mg/kg) producing similar acute anti-inflammatory response in the carrageenin-induced paw edema were injected i.p. in all studies. INDO potentiated the acid secretion induced by intracisternal injection of TRH at 25, 50 and 200 ng by 5.1-, 1.9- and 1.4-fold, respectively, whereas nabumetone did not modify the secretory response to TRH. Moderate erosions were observed in 100% of rats treated with the combination of INDO and TRH (200 ng) whereas no erosions were observed when TRH or INDO were given alone or TRH in combination with nabumetone. TRH at 7 ng reduced mucosal damage induced by intragastric administration of ethanol (60%, 1 ml/kg) by 63%. The mucosal protective action of TRH was abolished by INDO but not altered by nabumetone pretreatment. These data indicate that at comparable anti-inflammatory doses, nabumetone, unlike INDO, neither blocks the protection against ethanol injury induced by low doses of TRH injected intracisternally nor potentiates the gastric acid secretion or lesions induced by higher dose of TRH. We speculate that these differences reflect reduced inhibition of gastric prostaglandins by nabumetone.     

Role of eicosanoids, nitric oxide, and afferent neurons in antacid induced protection in the rat stomach

The mechanism underlying the mucosal protective effect of antacids is still unclear. This study shows that in rats the aluminum containing antacid, hydrotalcit, induces dose dependent protection against gastric mucosal damage caused by ethanol or indomethacin which is considerably enhanced by acidification. Hydrotalcit did not increase gastric mucosal formation or the intraluminal release of prostaglandins, and did not prevent the increase in mucosal leukotriene C4 formation in response to ethanol. Pretreatment with indomethacin did not attenuate the protective effect of unmodified or acidified hydrotalcit. Furthermore, hydrotalcit significantly reduced the gastric damage caused by indomethacin even when it was administered up to 2 hours after the ulcerogen. In indomethacin treated rats, simultaneous administration of hydrotalcit did not affect the concentrations of indomethacin in serum or inflammatory exudates nor did it attenuate the inhibition of prostaglandin release into the exudates. In hydrotalcit treated rats there was no attenuation of the increase in sulphidopeptide leukotriene release or decrease in leukocyte influx into inflammatory exudates elicited by indomethacin administration. Functional ablation of afferent neurons and inhibition of endogenous nitric oxide partially antagonised the protective effect of unmodified, but not of acidified, hydrotalcit. It is concluded that (i) the protective effect of unmodified and acidified hydrotalcit is independent of the eicosanoid system; (ii) protection against indomethacin induced gastric lesions does not require treatment before dosing of the ulcerogen and does not interfere with absorption and anti-inflammatory actions of indomethacin; (iii) endogenous nitric oxide and afferent neurons contribute partly to the effect of unmodified, but not of acidified, hydrotalcit suggesting that different mechanisms mediate their mucosal protective activity.     

Protective action of capsaicin and chilli on haemorrhagic shock-induced gastric mucosal injury in the rat

Chilli and its pungent ingredient, capsaicin, have been shown to protect against experimental gastric mucosal injury induced by various necrotizing agents such as ethanol and aspirin and stress. We investigated the effect of capsaicin and long-term ingestion of chilli on haemorrhagic shock-induced gastric mucosal injury in the rat. Anaesthetized male Sprague-Dawley rats were subjected to haemorrhagic shock by withdrawing blood to reduce the mean arterial blood pressure to 30-40 mmHg with subsequent reinfusion of shed blood. This resulted in gastric mucosal injury with readily identifiable haemorrhagic lesions. Capsaicin (5 mg) administered prior to, but not after, haemorrhagic shock, significantly reduced the gastric mucosal injury in intact animals. Sensory ablation with capsaicin pretreatment (125 mg/kg bodyweight) abolished the gastroprotective effect afforded by capsaicin. Similarly, 4 week intake of chilli powder (360 mg daily) reduced the gastric mucosal injury in intact, but not in capsaicin-desensitized rats. Capsaicin and long-term chilli intake protected against haemorrhagic shock-induced gastric mucosal injury and the protection may be mediated by capsaicin-sensitive afferent neurons. Our studies are of potential significance in the context of stress ulcer disease in the human.     

Modulatory role of 5-HT3 receptors in gastric function and ethanol-induced mucosal damage in rat stomachs

The involvement of 5-hydroxytryptamine (5-HT) in gastric function and mucosal damage has been defined. 5-HT also potentiates lesion formation in animals. The current study investigated further whether these actions are mediated through 5-HT3 receptors in rats. Ondansetron, a 5-HT3 receptor antagonist, was given subcutaneously, 2 or 4 mg/kg, 30 min before the gastric parameters were measured. The higher dose of ondansetron, 4 mg/kg, significantly increased gastric mucosal blood flow (GMBF) and also basal acid and Na+ secretion. However, it did not affect pepsin output. 5-HT time dependently reduced GMBF and pepsin secretion, but not that of acid and Na+. These actions were not altered by ondansetron pretreatment. The drug, however, dose dependently reduced ethanol-induced gastric mucosal lesions in the 5-HT-treated animals. These findings indicate that 5-HT3 receptors regulate not only basal GMBF, but also acid and Na+ secretion in stomachs. However, the depressive action of 5-HT on GMBF and pepsin secretion is most likely not mediated through 5-HT3 receptors. Ondansetron also modulates the toxicities of ethanol in the stomach and this action is likely to be mediated through the preservation of GMBF.     

Effects of cimetidine on acute gastric mucosal injury induced by ischemia-reperfusion in rats

We investigated the effects of cimetidine on acute gastric mucosal injury induced by ischemia-reperfusion in rats. Under pentobarbital anesthesia, the celiac artery was clamped for 30 min and reperfused for 60 min. Cimetidine, famotidine and omeprazole caused a dose-dependent suppression in the total area of erosions that were induced by ischemia-reperfusion. Whereas, none of them inhibited the increase in thiobarbituric acid-reactive substances in the stomach, as an index of lipid peroxidation. The inhibitory effect of intraperitoneally administered cimetidine on mucosal damage was abolished by continuous luminal perfusion with HCl solution (pH 1.5, 1 ml/min) during ischemia-reperfusion, while luminal perfusion with the solution containing HCl and cimetidine (3 mmol/l) significantly reduced the total area of erosions compared to luminal perfusion with HCl solution alone. Cimetidine (3 mmol/l) inhibited hydroxyl radical-induced lipid peroxidation of human erythrocyte membranes by 60% in vitro. These results indicate that cimetidine possesses a protective effect against acute gastric mucosal injury induced by ischemia-reperfusion not only due to the suppression in gastric acid secretion, but also due to the antioxidant action when it is present at a high concentration in the intragastric environment.     

Antimicrobial activity and spectrum investigation of eight broad-spectrum beta-lactam drugs: a 1997 surveillance trial in 102 medical centers in the United States. Cefepime Study Group

Anti-inflammatory studies were conducted on rats or mice using a crude hydroalcoholic extract of the aerial parts of Turnera ulmifolia and it's partitioned fractions, i.e. the aqueous, ethyl acetate and ethanolic fractions. The hydroalcoholic extract and it's fractions (aqueous and ethanolic) inhibited carrageenan-induced edema. However, only the ethanolic fraction was used in the other experiments due to it's yield. The extract also inhibited the cotton pellet granuloma and the increase of vascular permeability induced by histamine, 5-hydroxytryptamine and prostaglandin E2, but not that produced by bradykinin. The extract or the fraction did not present analgesic activity in the writhing test using acetic acid and did not reduce croton oil-induced ear edema in mice. When the ethanolic fraction and LPS were administered i.p. to Balb/C mice 72 h before blood or peritoneal fluid collection, no changes were observed in the white or total blood cell counts in the peripheral blood. On the other hand, changes were observed in both total and differential cell counts in the peritoneal exudate since all doses of the fraction reduced the number of total leukocytes (mainly lymphocytes) obtained from the peritoneal exudate. In contrast to nonsteroidal anti-inflammatory drugs, the administration of the hydroalcoholic extract or the ethanolic fraction alone did not potentiate gastric mucosal lesions induced by aspirin. The extract and the fraction inhibited the appearance of gastric lesions induced by indomethacin, ethanol and pylorus ligature, but not those induced by stress. As also observed with carbenoxolone, the ethanolic fraction increased the wall mucus in hypothermical-restraint stress-induced gastric lesions. The anti-ulcerogenic effect of the extract and of the ethanolic fraction may be related to an increase of mucosal defensive factors, such as prostaglandin and mucus. The anti-inflammatory actions of the extract and the fraction may be due to an inhibitory effect on histamine and cyclooxygenase II, but not on cyclooxygenase I, because the extract and it's fraction present both anti-inflammatory and anti-ulcerogenic effects. The major substances present in the ethanolic fraction are flavonoids which will be isolated and identified.     

Effects of intravenous lansoprazole on acute gastric mucosal lesions and acid secretion

The effects of lansoprazole given intravenously on gastric mucosal lesions, gastric bleeding and acid secretion were investigated in rats in comparison with those of omeprazole, famotidine and ranitidine. Lansoprazole inhibited the formation of gastric mucosal lesions in rats induced by water-immersion stress or aspirin with ID50 values of 0.26 and 0.99 mg/kg, respectively, and also inhibited gastric bleeding induced by hemorrhagic shock or water-immersion stress with ID50 values of 0.46 and 1.22 mg/kg, respectively. Lansoprazole was more potent than omeprazole, famotidine and ranitidine in inhibiting gastric mucosal lesions and hemorrhagic shock- or stress-induced bleeding. Famotidine and ranitidine showed negligible inhibition of water-immersion stress-induced gastric bleeding. Lansoprazole strongly inhibited water-immersion stress-stimulated acid secretion in rats, whereas famotidine and ranitidine did not show a potent inhibitory effect. These results indicate that lansoprazole exerts prominent inhibitory actions against the formation of gastric mucosal lesions and gastric bleeding by inhibiting acid secretion, and they show that it is superior to histamine H2-receptor antagonists in inhibiting stress-induced gastric bleeding.     

Sucralfate attenuates gastric mucosal lesions and increased vascular permeability induced by ischaemia and reperfusion in rats

Recent evidence suggests that oxygen-derived free radicals are involved in mediating gastric microvascular and parenchymal cell injuries induced by ischaemia and reperfusion. Therefore, the effect of the locally acting anti-ulcer drug, sucralfate, was studied on ischaemia and reperfusion (e.g. induced gastric lesions, intraluminal bleeding, changes in vascular permeability and non-protein sulfhydryl levels in the rat stomach). Allopurinol was used as a known standard antioxidant drug. Rats were subjected to 30 min of gastric ischaemia in the presence of 100 mmol/L hydrochloric acid and reperfusion periods of 15, 30 or 60 min duration. The gastric lesions were assessed microscopically under an inverted microscope. The vascular permeability was quantified by measuring the extravasated Evans blue in the stomach. There were significantly greater numbers of gastric lesions, intraluminal bleeding and leakage of Evans blue during all reperfusion periods as compared with those of ischaemia, with maximum effects occurring at 60 min following reperfusion. Pretreatment with sucralfate (31.25-250 mg/kg, p.o.) or allopurinol (12.5-50 mg/kg, i.p.) 30 min before the procedure, dose-dependently reduced the gastric lesions, intraluminal bleeding, and decreased the vascular permeability induced by ischaemia and reperfusion. Furthermore, sucralfate dose-dependently reverses the ischaemia and reperfusion-induced depletion of mucosal non-protein sulfhydryl levels and inhibited the superoxide radical production in both cell-free xanthine-xanthine oxidase and in the stimulated polymorphonuclear cellular systems. These results suggest that the protection produced by sucralfate against gastric injury may be due to its antioxidant effects.     

The effect of dopamine and PGI2 on indomethacin and alcohol-induced gastric lesions in rats of various ages in relation to gastric vascular permeability and HCl secretion

Gastric lesions induced by indomethacin (20 mg.kg-1 i.p.) and ethanol (1 ml 95% intragastrically) were studied in rats after a 24 hour fast. The size of gastric lesions was correlated with gastric HCl secretion and with gastric vascular permeability (determined from the Evan's blue concentration in the gastric tissue after its i.v. administration). These parameters were also studied in rats pretreated with either PGI2 (5 micrograms.kg-1) or dopamine (0.5 mg.kg-1). It was found that in 12-months old rats the gastric lesions were significantly higher compared with the 3-month old group. PGI2 and dopamine significantly decreased gastric lesions in the 3-month rats but not in 12-month old rats. Both indomethacin and ethanol increased gastric vascular permeability in both age groups. It was observed that the decrease of gastric lesions after pretreatment with PGI2 and dopamine in the 3-month old rats was followed with decreased gastric vascular permeability and HCl secretion. On the other hand the increased susceptibility of the gastric mucosa due to indomethacin in the 12-month old rats was followed by a decrease of HCl secretion. PGI2 or dopamine had any effect on the 12-month old rats. These results show that susceptibility of gastric mucosa to PGI2 and dopamine is dependent on age. (Fig. 3, Ref. 31.)     

Potassium channels participate in gastric mucosal protection in rats with partial portal vein ligation

Glybenclamide, an adenosine triphosphate-dependent potassium (K+(ATP)) channel blocker, lowered portal pressure and attenuated the hyperdynamic splanchnic circulation in rats with partial portal vein ligation (PPVL). The purpose of this report was to confirm these observations and to test the hypothesis that glybenclamide could reduce acidified ethanol-induced gastric mucosal injury in rats with PPVL. Gastric mucosal blood flow (hydrogen gas clearance), systemic blood pressure, and portal pressure were monitored in rats with PPVL or sham operation (SO). Intravenous glybenclamide (20 mg/kg) or vehicle was administered, followed by intragastric acidified ethanol (0.15 N HCl and 15% ethanol). The area of gastric mucosal lesions was assessed by image analysis. In contrast to published findings, there was no significant elevation of portal pressure after glybenclamide administration in rats with PPVL. Glybenclamide did not alter the gastric mucosal hyperemia in these rats. Glybenclamide significantly increased mucosal injury. The data are consistent with the hypothesis that K+(ATP) channels play a role in protecting the gastric mucosa in rats with PPVL.     

Alpha-fetoprotein and chromosome aberrations: what else? Results of a prospective study concerning 15,533 pregnancies

Gastric lesions induced by indomethacin (20 mg.kg-1 i.p.) were studied in rats after a 24 hour fast. The size of the lesions was correlated with gastric vascular permeability (determined from the Evans blue concentration in the stomach tissue after its i.v administration) and with the rate of gastric emptying (determined from the phenol red concentration after its intragastric application). These changes were correlated with the prevention of gastric lesions by allopurinol (50 mg.kg-1) after a single dose or once daily for 3 days before indomethacin and by a single dose (15,000 U.kg-1) of superoxide dismutase (SOD). Indomethacin significantly increases the rate of gastric emptying concomitantly with gastric vascular permeability. The pretreatment of animals with allopurinol and SOD inhibits gastric lesions as well as gastric vascular permeability without changing gastric emptying which was increased after indomethacin administration. The inhibition of gastric lesion formation and gastric vascular permeability was more marked in rats pretreated with allopurinol for 3 days when compared with rats treated with a single dose of allopurinol only. These results support the suggestion that oxygen-derived free radicals contribute to the pathogenesis of indomethacin-induced gastric lesions.     

Role of nitric oxide in pathogenesis of gastric mucosal damage induced by compound 48/80 in rats

We examined the effects of various nitric oxide synthase (NOS) inhibitors on development of gastric lesions induced by compound 48/80 (48/80) in rats and investigated the roles of NO and inducible NOS (iNOS) in inflammatory gastric responses. Animals were given 48/80 (1 mg/kg, i.p.) once daily for 4 days, and the stomachs were examined for lesions 24 h after the final administration. NOS inhibitors such as L-NAME, L-NMMA, aminoguanidine or dexamethasone were administered for 4 days during 48/80 treatment. The repeated administration of 48/80 caused damage in the stomach with severe edema in the submucosa. These lesions induced by 48/80 were dose-dependently prevented by concurrent administration of L-NAME. The protective effect of L-NAME on 48/80-induced gastric lesions was mimicked by L-NMMA, aminoguanidine as well as dexamethasone, and significantly antagonized by co-administration of L-arginine but not by D-arginine. Acid secretion was slightly decreased after 48/80 treatment, but was significantly augmented by the combined administration of L-NAME with 48/80. The mucosal MPO activity, TBA reactants and vascular permeability in the stomach were all increased after 48/80 treatment, but these changes were also significantly mitigated by co-administration of L-NAME. The Ca(2+)-independent NOS activity in the mucosa was increased four times during 48/80 treatment, and this change was also inhibited by dexamethasone. These results suggest that: 1) the repeated administration of 48/80 induced inflammatory gastric lesions in the rat stomach; 2) the pathogenic mechanism of these lesions involves endogenous NO produced by iNOS, in addition to oxyradical formation; and 3) the deleterious role of NO during 48/80 treatment may be accounted for by a cytotoxic action of peroxynitrite, which is formed in the presence of NO and superoxide radicals.     

In situ detection of myocardial infarction in pig by measurements of aspartate aminotransferase (ASAT) activity in the interstitial fluid

Recent studies have suggested that the fetal dysmorphogenesis in diabetic pregnancies is associated with an increase in embryonic oxygen-free radicals. This excess of oxygen-free radicals may result from either overproduction or decreased clearance by the enzymatic scavenging mechanism. However, there are no in vivo data on the activity of embryonic oxygen-free radical scavenging enzymes. The purpose of the current study is to investigate whether this increase in embryonic oxygen-free radicals is the result of a change in the activity of the fetal oxygen-free radical scavenging/antioxidant enzymes during pregnancy complicated by maternal diabetes in an in vivo rat model. Thirty-six Sprague-Dawley rats were randomly assigned to one of two study groups: nondiabetic control and an untreated diabetic group. On day 12, fetuses were examined for crown-rump lengths, somite numbers, and external anomalies. The activity of fetal oxygen-free radical scavenging enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT), were determined. The untreated diabetic group of rats had a significantly higher mean blood glucose level than that of the nondiabetic controls and also a significantly lower weight gain, higher resorption rate, smaller embryonic size with lower total protein content, and a approximately 6-fold increase in the rate of fetal neural tube defects compared to the nondiabetic controls. Superoxide dismutase activity was significantly reduced in the embryos with neural tube defects regardless of maternal diabetic status (2.25 +/- 0.83 vs. 1.17 +/- 0.04 u/mg protein; P < 0.05). Glutathione peroxidase and catalase activity were significantly reduced in malformed versus normal-formed embryos of nondiabetic mothers (GPX-2.68 +/- 1.15 vs. 4.46 +/- 1.12 mu/mg protein, CAT -1.67 +/- 0.53 vs 2.49 +/- 0.61 u/mg protein respectively; P < 0.01). However, overall catalase activity was increased in embryos of diabetic mothers as compared to controls. Two-way analysis of variance identified fetal malformations as the variance associated with reduced fetal SOD activity, whereas maternal diabetes was associated with the increase in fetal catalase activity. Neither neural tube defect nor maternal diabetes was found to be the variable affecting fetal GPX activity, Fetal oxygen-free radical scavenging enzymes respond differently to the adverse environment created by maternal diabetes during pregnancy. Defects in embryonic SOD and catalase activity, regardless of maternal diabetic status, may reduce the ability of the fetus to clear free oxygen radicals, thereby exposing it to an increased oxidative load that may cause fetal dysmorphogenesis. The diabetic state of the mothers did not decrease embryonic activity of any of the scavenging enzymes. Therefore, although excess oxidative load, as observed in diabetes, may cause tissue injury and embryopathy, the mechanism does not appear to be a diabetes-induced reduction in the action of the scavenging enzymes.