Induction of bone loss by bile duct ligation in rats.

Metabolic bone loss is the most common complication of chronic liver disease. However, there is little information available about bone loss in rats with a ligated bile duct, a biliary-type of experimental cirrhosis model. Therefore, in this study, the effect of bile duct ligation (BDL) on bone mineral density (BMD) and plasma insulin-like growth factor-I (IGF-I) levels was examined in rats. Two weeks after BDL operation, the rats with a ligated bile duct showed a pronounced and significant decrease in both trabecular and cortical BMD of the femur. In these rats, decreases in food intake and plasma IGF-I levels plus elevated levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and bilirubin were also observed. When the effect of dietary restriction (30% or 50%) over 2 weeks was then investigated in normal rats, 50% food restriction resulted in a significant decrease in femoral trabecular bone density although BMD was unchanged by 30% dietary restriction. The plasma levels of IGF-I were also decreased in food-restricted rats. Thus, the decrease in femoral bone density in 50% food-restricted rats was less potent compared with BDL rats; nevertheless, the decrease in plasma levels of IGF-I was almost equally potent in both BDL and food-restricted rats. Overall, this study showed that BDL operation resulted in a pronounced bone loss in rats, but also that this bone loss might not be merely due to the decreases in food intake and plasma IGF-I levels. These results suggest that BDL in rats is a useful experimental cirrhosis model for evaluating the bone loss associated with chronic liver disease.

Intravenous injection of oligodeoxynucleotides to the NF-kappaB binding site inhibits hepatic metastasis of M5076 reticulosarcoma in mice.

We have developed synthetic double-stranded oligodeoxynucleotides (ODN) as 'decoy' cis elements that block the binding of nuclear factors to promoter regions of targeted genes, resulting in the inhibition of gene transactivation in vivo. In the present study, we employed decoy ODN targeting the transcription factor nuclear factor-kappaB (NF-kappaB) binding cis-elements to hepatic metastasis of murine reticulosarcoma M5076 in mice. Intravenous inoculation of M5076 into mice caused a marked increase in gene expression of interleukin-1beta, tumor necrosis factor-alpha and intercellular adhesion molecule-1 in the liver, whereas intravenous treatment with NF-kappaB decoy ODN reduced M5076-induced transactivation of these genes. Treatment with NF-kappaB decoy ODN, but not scrambled decoy ODN, significantly inhibited hepatic metastasis of M5076 in mice, and furthermore the combined treatment of NF-kappaB decoy ODN with an anti-cancer drug resulted in complete inhibition of hepatic metastasis in half of the mice, without affecting myelosuppression induced by the anti-cancer drug. Here, NF-kappaB decoy ODN inhibited hepatic metastasis of M5076 in mice possibly through a decrease in transactivation of important NF-kappaB-driven genes and also potentiated the anti-metastatic effect of an anti-cancer drug, demonstrating the first successful in vivo therapy for cancer metastasis using NF-kappaB decoy ODN as a novel molecular decoy approach.

Adenosine A1 receptor blockade reverses dysmotility induced by ischemia-reperfusion in rat colon.

This study was designed to assess whether adenosine A1 receptor antagonists [(R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-piperidin-2-yl acetic acid (FK352) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)] reverse dysmotility induced by ischemia-reperfusion in the rat colon. The gene of adenosine A1 receptor was expressed in the colon. Clamping (30 min) of the colonic marginal vessels was followed by reperfusion, and the propulsive colonic motility was evaluated. Propulsion was significantly slowed by ischemia-reperfusion, while FK352 and DPCPX abolished this delay. In contrast, the non-selective adenosine receptor antagonist, 8-phenyltheophylline, failed to affect the dysmotility. Thus, adenosine A1 receptor antagonists have potent therapeutic potential against ischemia-reperfusion-induced dysmotility in the colon.

Stimulation of choleresis by insulin-like growth factor-I in rats.

Insulin-like growth factor-I (IGF-I) is an endogenous growth factor which is mainly produced in the liver. The functions of IGF-I can be summarized as growth-promoting and insulin-like metabolic actions. In the present study, the effect of IGF-I on bile flow and bile acid secretion was investigated in rats. In normal rats bile flow was significantly increased by single exogenous administration of IGF-I, and by 1 week treatment of IGF-I, both bile flow and bile acid secretion were significantly increased. Moreover, to further understand the relationship between IGF-I and bile acid secretion, hypophysectomized rats were next used. We found that the decreases in bile flow and bile acid secretion observed in rats after hypophysectomy, as well as the decrease in the endogenous level of IGF-I in the blood, were partially reversed by 1 week exogenous IGF-I treatment. Overall, this study showed that IGF-I stimulates choleresis associated with an elevation of bile acid secretion in both normal and hypophysectomized rats when exogenously administered, suggesting the importance of IGF-I in the stimulation of choleresis in vivo.

Molecular identification and pharmacological characterization of adenosine receptors in the guinea-pig colon.

The aim of this study is to elucidate the role of adenosine in the motor function of the guinea-pig distal colon.2 To determine whether adenosine A(1) receptors and A(2B) receptors are expressed in the guinea-pig colon, we employed the reverse transcription-polymerase chain reaction (RT - PCR). The gene expression of A(1) receptor and A(2B) receptor was found for the first time in the guinea-pig proximal and distal colon.3 Adenosine A(1) agonist N(6)-cyclopentyladenosine (CPA), and A(1)/A(2) agonist 5'-N-ethylcarboxamidoadenosine (NECA) concentration-dependently inhibited neurogenic responses to electrical field stimulation (EC(50)=1.07x10(-8) and 2.12x10(-8) M) in the longitudinal muscle, but A(2A) agonist 2-p-(2-carboxyethyl)phenylethylamino-5'-N-ethycarboxamido-ad enosine (CGS21680) had only a slight inhibitory effect (25.9%, 1 microM). A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 10 nM: A(1) selective concentration) antagonized responses to CPA and NECA. Furthermore, the affinity order of antagonists at inhibiting the effect NECA was: DPCPX>8-phenyltheophylline (8-PT: A(1)/A(2) antagonist).3 In the presence of tetrodotoxin (TTX, 0.3 microM), CPA and NECA relaxed myogenic precontraction induced by KCl (50 mM) (EC(50)=1.26x10(-5) and 1.04x10(-5) M, respectively), but CGS21680 (1 microM) did not cause any relaxation. DPCPX did not affect responses to CPA and NECA at a concentration of 10 nM, but a higher concentration (1 microM) of DPCPX and 10 microM of 8-PT antagonized those responses.5 These data lead us to the hypothesis that adenosine may mediate relaxation through two different inhibitory receptor subtypes; A(1) receptors on the enteric neuron and A(2B) receptor on the smooth muscle in the guinea-pig distal colon.

FR145715, a novel histamine H2 receptor antagonist, with specific anti-Helicobacter pylori activities.

The pharmacological profile of N-[3-[2-[N'-(2-methoxyethyl)guanidino]thiazol-4yl]benzyl-ace tamide (FR145715), a novel histamine H2 receptor antagonist, was examined in both in vitro and in vivo models using experimental animals in comparison with ranitidine. In isolated guinea-pig atria, FR145715 antagonized the effect of histamine on heart rate with approximately three times more potent activity than ranitidine. In in vivo experiments, intraduodenal FR145715 dose-dependently inhibited spontaneous gastric acid secretion in rats (Shay's rats), with a ED50 value of 18.4 mg/kg, which was comparable to that of ranitidine (30.5 mg/kg). FR145715 also inhibited histamine-stimulated acid secretion in stomach-perfused anaesthetized rats (Schild's rats), when given intravenously and intraduodenally with ED50 values of 0.59 and 2.72 mg/kg, respectively. Ranitidine displayed more potent activity having respective ED50 values of 0.10 and 0.17 mg/kg. In Heidenhain pouch dogs, intravenous and oral FR145715 dose-dependently inhibited gastrin-stimulated acid secretion with respective ED50 values of 0.12 and 0.32 mg/kg, which were similar to those of ranitidine (0.09 and 0.33 mg/kg). In gastric ulcer models, FR145715 dose-dependently inhibited water immersion restraint stress- and acidified aspirin-induced gastric lesions with ED50 values of 3.2 and 15.1 mg/kg (p.o.), respectively. The comparative compound, ranitidine, also showed beneficial effects on stress-induced gastric ulcers with an ED50 value of 1.5 mg/kg (p.o.). However, it failed to inhibit acidified aspirin-induced gastric ulcers. FR145715 inhibited HCl-induced gastric lesions in rats, while pre-treatment with indomethacin abolished its beneficial effects, suggesting that FR145715 has a so-called cytoprotective effect which is dependent on endogenous prostaglandin production. In addition to its atypical profile as a histamine H2 receptor antagonist, FR145715 exhibited strong anti-microbial activities against strains of Helicobacter pylori (H. pylori) with a mean minimal inhibitory concentration value of 0.32 microg/ml. Moreover, FR145715 showed no anti-microbial effects on 25 other bacteria examined. In addition, in vivo experiments using gnotobiotic piglets infected with H. pylori, FR145715 (16 mg/kg, t.i.d.) completely eliminated the organism with reduced intensity of inflammation, when treated orally for 10 days. These data demonstrate that FR145715 is a novel histamine H2 receptor antagonist having potent and selective anti-H. pylori activities as well as cytoprotective properties. The present data suggest that FR145715 might be useful for the patients suffering from ulcer relapse, since the drug might be able to eradicate H. pylori in the stomach, which is considered a key factor to cause ulcer recurrence in humans.

Assessment of radiotherapeutic effect on brain tumors by dynamic susceptibility contrast MR imaging: a preliminary report.

PURPOSE: The purpose of this study was to assess tumor vascularity of the brain by dynamic susceptibility contrast (DSC) MR imaging and to determine whether this method is clinically useful for monitoring radiation effects on brain tumors. We, furthermore, compared DSC MR imaging with single-photon emission computed tomography (SPECT) using technetium-99m diethylene-triamine-pentaacetic acid human serum albumin (99mTc-HSA-D) in the assessment of tumor vascularity in a limited numbers of cases. METHODS: Twelve patients with various kinds of brain tumors were studied. DSC MRI was performed on all patients before and after radiation therapy. SPECT using 99mTc-HSA-D was also performed in five patients. The rate of change in tumor blood volume in response to radiation therapy was evaluated with DSC MRI and SPECT. The rate of change in tumor volume in response to radiation was also measured. RESULTS: Ten patients were successfully studied. The rate of change in tumor blood volume correlated well between DSC MRI and SPECT. There was no significant correlation between the rates of change for tumor blood volume and tumor volume. Changes in tumor vascularity preceded the reduction in tumor volume seen following radiotherapy. CONCLUSION: DSC MRI provides information regarding radiation effects on tumor vessels that is not available with conventional MRI.

Intratumoral injection of oligonucleotides to the NF kappa B binding site inhibits cachexia in a mouse tumor model.

Cancer cachexia, characterized by anorexia, weight loss and progressive tissue wasting, has been postulated to be mediated by various cytokines. However, the precise mechanism of cachexia induction is not fully explained. We have developed synthetic double-stranded oligodeoxynucleotides (ODN) as 'decoy' cis-elements that block the binding of nuclear factors to promoter regions of targeted genes, resulting in the inhibition of gene transactivation in vivo as well as in vitro. This novel molecular strategy could be useful for treating a broad range of human diseases including cancer. In this study, we injected decoy ODN targeting the transcriptional factor, NF-kappa B (NF kappa B) binding cis-elements, which are essential for transactivation of gene expression of cytokines, directly into tumors of adenocarcinoma colon26 in mice, in order to examine whether or not cachexia is alleviated by inhibiting the action of cytokines. Tumor growth was not affected by transfection of NF kappa B decoy ODN as compared with scrambled decoy ODN. Nevertheless, transfection of NF kappa B decoy, but not scrambled decoy, ODN resulted in attenuation of the reductions in body weight, epididymal fat, gastrocnemius muscle mass and food intake, which were induced by the tumor presence. Interleukin 6 mRNA in the tumor was also markedly decreased by the transfection of NF kappa B decoy ODN. It is known that the transcriptional factor E2F plays a pivotal role in the coordinated transactivation of cell cycle regulatory genes. Therefore, we hypothesized that the introduction of synthetic double-stranded DNA with high affinity for E2F in vivo as 'decoy' cis-elements might inhibit the tumor growth of colon26, resulting in turn in inhibition of cachexia induction. However, injection of E2F decoy ODN failed to inhibit tumor growth and cachexia induction, as compared with mismatched decoy ODN. Overall, the present study demonstrated that cachexia induced by adenocarcinoma colon26 was inhibited by blocking of NF kappa B, using a novel molecular decoy strategy, without an effect on tumor growth, and also that tumor growth and cachexia induction in the colon26 model were not affected by E2F decoy ODN. These results suggest that cytokines regulated by NF kappa B may play a pivotal role in the induction of cachexia by colon26, providing a new therapeutic strategy for cancer cachexia.

[Assessment of radiotherapy effects on brain tumors by dynamic susceptibility contrast MR imaging].

Dynamic susceptibility contrast MR imaging(DSC MRI) was performed on eleven patients with brain tumors before and after radiotherapy. Their confirmed diagnoses were as follows: hemangioendothelioma(n = 1), meningioma(n = 1), low grade astrocytoma(n = 1), glioblastoma(n = 2), and brain metastasis(n = 6). The purpose of this study is to determine whether this technique is clinically useful for monitoring radiotherapeutic effect on brain tumors. Region of interest(ROI) analyses were performed on both the brain tumor and the contralateral normal area to evaluate the therapeutic effect semiquantitatively. The calculated subtraction images, rCBV maps, were also produced for the visual evaluation of the change of tumor vascular beds. The results showed that DSC MRI was clinically useful because of the capability to offer additional functional information.

FR149175, a beta 3-adrenoceptor-selective agonist, is a possible therapeutic agent for non-insulin-dependent diabetes mellitus.

We examined whether FR149175 (ethyl-[(S)-8-[(R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-6,7,8,9 - tetrahydro-5H-benzocyclohepten-2-yloxy]acetate monohydrochloride monohydrate), a selective agonist for the beta 3-adrenoceptor, is a possible therapeutic agent for non-insulin-dependent diabetes mellitus (NIDDM). FR149175 had hypoglycemic effects with an increase in the level of plasma insulin in normal rats. In Zucker fatty rats, an animal model of NIDDM, repeated administration of the drug improved hyperinsulinemia and showed a tendency to decrease the area under the curve (AUC) for plasma glucose levels in the glucose tolerance test. Moreover, FR149175 decreased plasma triglyceride, free fatty acid and total cholesterol levels in the rats. Body weight gain in the rat was suppressed by FR149175 as well. These results suggest that FR149175 has antiobesity and antidiabetic effects and that this drug may be useful for treating NIDDM.

Alterations of lactate (+lipid) concentration in brain tumors with in vivo hydrogen magnetic resonance spectroscopy during radiotherapy.

RATIONALE AND OBJECTIVES: The authors determine whether assessment of the relative lactate(+lipid) concentration ([r-Lac(+lip)]) obtained from hydrogen magnetic resonance (MR) spectroscopy is useful for predicting the outcome of radiotherapy on brain tumors. METHODS: Fifty-one hydrogen MR spectroscopic studies were performed in eight patients with primary or metastatic brain tumor before and during radiotherapy. The r-Lac(+lip) calculated as the ratio of lactate(+lipid) peak area to total water was compared before and during radiotherapy in each case. The change of tumor volume measured on magnetic resonance images also was compared. RESULTS: The r-Lac(+lip) substantially decreased in the radiosensitive cases (three lymphomas and one brain cancer) but did not decrease, even at the end of therapy, in the radioresistant cases (two brain cancers and two glioblastomas). CONCLUSION: Assessment of r-Lac(+lip) may adjunctively contribute to the early prediction of the radiotherapeutic effect on brain tumors.

Combined blockade of 5-HT3- and 5-HT4-serotonin receptors inhibits colonic functions in conscious rats and mice.

We have already reported that 5-hydroxytryptamine3 (5-HT3) receptor antagonists failed to modify 5-HT-accelerated colonic transit in conscious rats, but the 5-HT3 and 5-HT4 receptor dual antagonist FK1052 prevented the enhancement. In this study, the inhibitory effect on the stimulated colonic transit was not also observed with 5-HT4 receptor antagonists (SDZ205-557 and SB204070) in freely moving rats with chronic cannulas implanted into the proximal colon. In contrast, combined antagonism by simultaneous administration of ondansetron and the 5-HT4 receptor antagonist exerted a drastic inhibitory effect on the propulsive motility. Furthermore, we examined the effect of 5-HT receptor antagonists on 5-HT-induced fluid secretion in mice. Although none of these selective 5-HT receptor antagonists (YM060 and ondansetron as 5-HT3 receptor antagonist, SB204070 as 5-HT4 receptor antagonist) by itself produced a great inhibition of the 5-HT-induced diarrhea, the combination of a 5-HT3 receptor antagonist and a 5-HT4 receptor antagonist markedly reduced the diarrhea. These data suggest that 5-HT-accelerated colonic motility and 5-HT-evoked fluid secretion are mediated by both 5-HT3 and 5-HT4 receptors and that the pathways activated by these receptors may collaborate.

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.

Difference between normal and WHHL rabbits in susceptibility to the adrenal toxicity of an acyl-CoA:cholesterol acyltransferase inhibitor, FR145237.

The adrenal toxicity of an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, FR145237, was investigated using Japanese White (normal) and low density lipoprotein (LDL) receptor deficient Watanabe heritable hyperlipidemic (WHHL) rabbits. In the normal rabbits, severe necrosis of the cells in the zona fasciculata and reticularis was observed 24 hr after intravenous injection of 3.2 mg/kg of FR145237, whereas no morphological changes could be found in the adrenal cells of the WHHL rabbits in spite of a higher plasma concentration of the drug. Since most of the FR145237 (87%) in the plasma of the WHHL rabbits was recovered in the LDL fraction 1 hr after intravenous injection of the drug (3.2 mg/kg), it was hypothesized that the delivery of the drug to the adrenal cells may be limited by the LDL receptor deficiency. However, the concentration of FR145237 in the adrenal gland of the WHHL rabbits (13.3 microg/g) was identical to that in the normal rabbits (13.6 microg/g). These results suggest that the susceptibility of the adrenal cells of the WHHL rabbits to the toxicity of FR145237 truly differs from that of normal rabbits, and that the WHHL rabbit may be a useful animal model for the investigation of the mechanisms of the adrenal toxicity of ACAT inhibitors.

Implication of sensory neurons in the diverse mechanisms of adaptive cytoprotection in the rat stomach.

Adaptive cytoprotection is mediated by diverse mediators and mechanisms. We investigated the implication of capsaicin-sensitive afferent neurons in the adaptive cytoprotection in the rat stomach, taking special notice of nitric oxide, prostaglandins and luminal dilution. Sensory deafferentation abolished the protective effect of capsaicin against 0.6 N HCl-induced gastric injury but not the indomethacin-resistant or NG-nitro-L-arginine-resistant adaptive cytoprotection conferred by 0.1 N NaOH. Nor did it attenuate the protection by 0.35 N HCl which accompanied luminal dilution. These findings suggest that certain mild irritants do not require sensory neurons to provide nitric oxide- and prostaglandins-mediated adaptive cytoprotection and, furthermore, that capsaicin-sensitive afferent neurons are not crucial, either, so long as there is a contribution of luminal dilution in the adaptive cytoprotection.

Effect of FR145237, a novel ACAT inhibitor, on atherogenesis in cholesterol-fed and WHHL rabbits. Evidence for a direct effect on the arterial wall.

The hypocholesterolemic and antiatherosclerotic activities of FR145237, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, were evaluated in cholesterol-fed and Watanabe heritable hyperlipidemic (WHHL) rabbits. In the first experiment, rabbits were fed a high cholesterol (1% cholesterol) diet for 2 weeks and further fed a high cholesterol diet containing FR145237 for 8 weeks. FR145237 (0.1, 0.32 and 1.0 mg/kg) dose-dependently lowered the plasma total cholestrol levels by 80%, 96% and 97%, respectively. and reduced aortic atherosclerosis by 44%, 90% and 90%, respectively. To clarify a direct effect of FR145237 at the aortic wall, a second experiment was performed. Rabbits were fed a high-cholesterol diet for 8 weeks to establish aortic atherosclerosis and then fed a normal diet with or without FR145237 for 8 weeks. Cholesterol content in the aorta and the liver was significantly reduced in the FR145237 group (10 mg/kg) by 50% and 43%, respectively, though plasma total cholesterol level did not differ from that in the control group. In the WHHL rabbits, FR145237 (10 mg/kg) did not affect plasma cholesterol level but significantly reduced the atherosclerotic lesion in the coronary arteries by 61%. These results suggest that FR145237 potently lowers the plasma cholesterol level in hypercholesterolemia induced by dietary cholesterol but not that by LDL receptor deficiency, and that FR145237 has a direct antiatherosclerotic activity on the arterial wall independent of its hypocholesterolemic activity.

[Characterization of prostate cancer, benign prostatic hyperplasia and normal prostates using endorectal 1H magnetic resonance spectroscopy].

BACKGROUND: We evaluate the usefulness of 1H endorectal resonance spectroscopy to characterize prostate pathology. METHODS: With an endorectal surface coil we have studied 20 individuals with normal (1), benign hyperplastic (9) and malignant (10) prostates. RESULTS: The major findings of our studies were that the patients with cancer have a significantly lower citrate-to-choline ratio (cit/cho) and creatin-to-choline ratio (cre/cho) than the patients with BPH (p < 0.05). There is well correlation between cit/cho and gland-to-stroma ratio of the BPH tissue as well as histological grade of the cancer tissue. 1H spectroscopy offers the advantages of differential diagnosis between benign and malignant prostates. We, however, failed to demonstrate cancer in 2 cases; the lesion was too small in one case, and out of the region of interest in the other. It is necessary that the foci in the prostate is at least 1.5 X 1.5 X 1.5 cm3 of the volume in order to obtain genuine spectrogram of carcinoma. CONCLUSION: Endorectal 1H magnetic resonance spectroscopy can characterize metabolic differences between the normal and malignant prostate.

Microdomain formation in phosphatidylethanolamine bilayers detected by 2H-NMR.

In deuterium NMR spectra of phosphatidylethanolamine bilayers with an extremely high content of saturated fatty acids, each C1 deuteron of the glycerol backbone gave rise to a doublet [Yoshikawa et al., (1988) Biochim. Biophys. Acta 944, 321-328]. This suggests the presence of two backbone conformations, the exchange between which is slow on an NMR time-scale. The origin of the two conformations has been investigated in this work using saturated 1,2-diacyl-sn-glycero-3-phosphoethanolamine specifically deuterated in the glycerol backbone. The results showed that the two conformations originate from different domains, which have different fatty acid compositions. The differential scanning calorimetry of the bilayers suggested that the size of the domain is not large enough to show an independent phase transition. Thus, the formation of microdomains in the phosphatidylethanolamine bilayers has been concluded. Conformational difference in different domains was shown to be restricted to the C1 position of the glycerol backbone. The microdomains of phosphatidylethanolamine were retained even in the presence of other phospholipids.

Young female patient with testosterone-producing adrenocortical adenoma also showing signs of subclinical Cushing's syndrome.

A 28-year old female patient with virilization due to left adrenocortical adenoma was studied. The patient had clinical features of hyperandrogenism such as hirsutism and a low pitched voice, but not of hypercorticoidism. Plasma testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were high. Although the basal plasma cortisol concentration and urinary excretion of 17-hydroxycorticosteroids (17-OHCS) were within the normal range, the absence of diurnal variation in plasma cortisol and loss of suppressibility by dexamethasone suggested constitutive secretion of cortisol by the tumor. Inappropriate cortisol secretion was also supported by blunted ACTH response to provocative stimuli. After successful removal of the left adrenal tumor, such endocrinological abnormalities were all normalized. Immunohistochemical analysis revealed that tumor cells were positively stained for C21 hydroxylase cytochrome P-450 (P-450C21) and P-450(11) beta which convert 17-hydroxy (OH) progesterone to cortisol as well as P-450SCC, 3 beta-hydroxysteroid dehydrogenase and P-450(17) alpha which are involved in testosterone biosynthesis. These findings suggest that adrenocortical adenoma secretes predominantly testosterone and constitutively cortisol in a young woman patient with virilization.

Luminal dilution caused by certain mild irritants and capsaicin contributes to their gastric mucosal protection.

We have recently shown that certain mild irritants caused the increase in fluid volume in the rat stomach. The present study was conducted to investigate 1) whether standing fluid in the gastric cavity can prevent gastric mucosal injury caused by 0.6 N HCl and 2) the mechanisms by which certain mild irritants increase the gastric fluid volume. One milliliter of water administered immediately before irritants greatly inhibited gastric lesion formation. Sodium chloride and capsaicin induced a profound enhancement of gastric fluid volume, as acid mild irritants did also. Sensory denervation completely abolished the volume increase caused by capsaicin but hardly influenced that caused by mild irritants. Capsaicin increased the amount of Evans blue in the gastric fluid, but mild irritants did not. On the other hand, HCl and capsaicin significantly inhibited the emptying of phenol red. From these results, we conclude that mild irritants and capsaicin can induce volume increase that by itself is enough to afford protection through luminal dilution. Capsaicin but not mild irritants requires sensory neurons to increase the gastric fluid volume. Certain mild irritants may provide a fluid pooling effect partly by inhibiting gastric emptying.