Effect of Carbenoxolone on Arrhythmogenesis in Rat Ventricular Muscle.

BACKGROUND: Connexin43 (Cx43) is a major connexin that forms gap junction (GJ) channels in the heart and is also present in the cell membrane as unopposed/non-junctional hemichannels and in the inner mitochondrial membrane. By using carbenoxolone (CBX), a blocker of Cx43, the effect of the blockade of Cx43 on Ca(2+)waves and triggered arrhythmias in the myocardium with non-uniform contraction was examined. METHODS AND RESULTS: Trabeculae were obtained from rat hearts. Force, [Ca(2+)]i, and the diffusion coefficient were measured. Non-uniform contraction was produced with a 2,3-butanedione monoxime jet. Ca(2+)waves were induced by electrical stimulation. Inducibility of arrhythmias was estimated based on the minimal [Ca(2+)]oat which arrhythmias were induced. The Ca(2+)spark rate was measured in isolated single rat ventricular myocytes. CBX reduced the GJ permeability, whereas it did not change force and [Ca(2+)]itransients. CBX increased the Ca(2+)leak from the sarcoplasmic reticulum in trabeculae and increased the Ca(2+)spark rate in isolated single myocytes. CBX increased the velocity of Ca(2+)waves and further increased the inducibility of arrhythmias. Modulation of mitochondrial KATPchannels by diazoxide, cromakalim and 5-hydroxydecanoic acid affected the inducibility of arrhythmias increased by CBX. CONCLUSIONS: These results suggest that in diseased hearts, Cx43 plays an important role in the occurrence of triggered arrhythmias, probably under the modulation of mitochondrial KATPchannels.

Blocking Pannexin-1 Channels Alleviates Thalamic Hemorrhage-Induced Pain and Inflammatory Depolarization of Microglia in Mice.

Central post-stroke pain (CPSP) is a neuropathic pain syndrome that frequently occurs following cerebral stroke. The pathogenesis of CPSP is mainly due to thalamic injury caused by ischemia and hemorrhage. However, its underlying mechanism is far from clear. In the present study, a thalamic hemorrhage (TH) model was established in young male mice by microinjection of 0.075 U of type IV collagenase into the unilateral ventral posterior lateral nucleus and ventral posterior medial nucleus of the thalamus. We found that TH led to microglial pannexin (Panx)-1, a large-pore ion channel, opening within the thalamus accompanied with thalamic tissue injury, pain sensitivities, and neurological deficit, which were significantly prevented by either intraperitoneal injection of the Panx1 blocker carbenoxolone or intracerebroventricular perfusion of the inhibitory mimetic peptide 10Panx. However, inhibition of Panx1 has no additive effect on pain sensitivities upon pharmacological depletion of microglia. Mechanistically, we found that carbenoxolone alleviated TH-induced proinflammatory factors transcription, neuronal apoptosis, and neurite disassembly within the thalamus. In summary, we conclude that blocking of microglial Panx1 channels alleviates CPSP and neurological deficit through, at least in part, reducing neural damage mediated by the inflammatory response of thalamic microglia after TH. Targeting Panx1 might be a potential strategy in the treatment of CPSP.

Topical 11ß-Hydroxysteroid Dehydrogenase Type 1 Inhibition Corrects Cutaneous Features of Systemic Glucocorticoid Excess in Female Mice.

Glucocorticoid (GC) excess drives multiple cutaneous adverse effects, including skin thinning and poor wound healing. The ubiquitously expressed enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activates mouse corticosterone from 11-dehydrocorticosterone (and human cortisol from cortisone). We previously demonstrated elevated 11ß-HSD1 activity during mouse wound healing, but the interplay between cutaneous 11ß-HSD1 and systemic GC excess is unexplored. Here, we examined effects of 11ß-HSD1 inhibition by carbenoxolone (CBX) in mice treated with corticosterone (CORT) or vehicle for 6 weeks. Mice were treated bidaily with topical CBX or vehicle (VEH) 7 days before wounding and during wound healing. CORT mice displayed skin thinning and impaired wound healing but also increased epidermal integrity. 11ß-HSD1 activity was elevated in unwounded CORT skin and was inhibited by CBX. CORT mice treated with CBX displayed 51%, 59%, and 100% normalization of wound healing, epidermal thickness, and epidermal integrity, respectively. Gene expression studies revealed normalization of interleukin 6, keratinocyte growth factor, collagen 1, collagen 3, matrix metalloproteinase 9, and tissue inhibitor of matrix metalloproteinase 4 by CBX during wound healing. Importantly, proinflammatory cytokine expression and resolution of inflammation were unaffected by 11ß-HSD1 inhibition. CBX did not regulate skin function or wound healing in the absence of CORT. Our findings demonstrate that 11ß-HSD1 inhibition can limit the cutaneous effects of GC excess, which may improve the safety profile of systemic steroids and the prognosis of chronic wounds.

Cortisol metabolism in hypertension.

Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates cortisone to cortisol to facilitate glucocorticoid receptor (GR)-mediated action. By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of cortisol to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by cortisol. Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which cortisol activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension.

Carbenoxolone exposure during late gestation in rats alters placental expressions of p53 and estrogen receptors.

Gestational carbenoxolone exposure inhibits placental 11ß-hydroxysteroid dehydrogenase (11ß-HSD), the physiological barrier for glucocorticoids, which increases fetal exposure to glucocorticoids and induces intrauterine growth restriction (IUGR). We hypothesized that carbenoxolone exposure influences the expression of placental estrogen receptors-α and ß (ERα & ERß) and p53 leading to inhibited fetal and placental growth. Pregnant Sprague-Dawley rats were injected twice daily with either carbenoxolone (10mg/kg; s.c.) or vehicle (control group) from gestational days (dg) 12 onwards. Maternal blood and placentas were collected on 16 dg, 19 dg and 21 dg. The expression of ERα, ERß and p53 were studied in placental basal and labyrinth zones by RT-PCR, Western blotting and immunohistochemistry. Carbenoxolone did not affect placental and fetal body weights, but ELISA showed decreased estradiol levels on 19 dg and 21 dg, and increased maternal luteinizing hormone levels on all dg. The follicle stimulating hormone levels decreased on 16 dg and 19 dg, and increased on 21 dg. Carbenoxolone decreased ERα mRNA levels on 16 dg in both zones and its protein level on 19 dg in the labyrinth zone. However, carbenoxolone increased ERß mRNA levels on 19 dg and 21 dg and protein levels on 16 dg and 19 dg in the labyrinth zone. The p53 mRNA levels increased on all dg, but its protein levels increased on 21 dg in both zones. In conclusion, carbenoxolone exposure changes placental p53, ERα, ERß expression in favor of cell death but these changes do not induce IUGR in rats.

High blood pressure. A side effect of drugs, poisons, and food.

Arterial hypertension, either transient or persistent, may be induced or aggravated by ingestion of various chemical agents, such as drugs, poisons, and food. Most of these agents either cause sodium retention and expand extracellular fluid volume or act as direct or indirect sympathomimetics. Others act directly on arteriolar smooth muscle. For a few agents, no precise mechanism has been ascertained. Hypertensive reactions may also occur as a result of drug interactions or food and drug interactions. In addition, paradoxical increases in pressure may be encountered during or after discontinuance of antihypertensive therapy. In general, these pressure increases are small and transient; however, a few have been associated with severe hypertension involving encephalopathy, strokes, and irreversible renal failure. Careful review of a patient's drug regimen, including over-the-counter preparations, may avoid chemically induced hypertension. Identification of any offending or incriminating agent will prevent the labeling of a chronic illness and obviate the need for lifelong antihypertensive therapy.

Carbenoxolone damages endothelium and enhances vasoconstrictor action in aortic rings.

Carbenoxolone causes hypertension indirectly by inhibition of 11beta-hydroxysteroid dehydrogenase and consequent elevation of intracellular glucocorticoid levels and enhancement of vasoconstrictor action. We performed the present study to determine whether carbenoxolone also enhances vascular tone directly by mechanisms independent of glucocorticoids and other systemic influences. Exposure of rat aortic rings to 10 to 100 micromol/L carbenoxolone in aerated Krebs-Henseleit buffer for 24 hours resulted in concentration-dependent increases in angiotensin II (Ang II) (100 nmol/L)-stimulated contractions and significant shifting of the phenylephrine cumulative contraction curve to the left but not increases in KCI (120 mmol/L)-stimulated contractions. Maximal enhancement of Ang II contraction was 39 percent. In contrast, brief (15-minute) exposure to 100 micromol/L carbenoxolone did not alter Ang II contractions. Mechanical denudation of the endothelium obviated enhancement of Ang II contractions by carbenoxolone, suggesting interaction of carbenoxolone with the endothelium. Endothelium-dependent relaxation of precontracted rings to acetylcholine or ATP was reduced by more than 90 percent by 24-hour pretreatment with 100 micromol/L carbenoxolone but not with 100 micromol/L deoxycorticosterone acetate (a mineralocorticoid) or 100 mu mol/L glycyrrhizic acid (a natural 11beta-hydroxysteroid dehydrogenase inhibitor). Vascular smooth muscle relaxation with sodium nitroprusside was not inhibited by carbenoxolone. Incubation of cultured endothelial cells with 100 mu mol/L carbenoxolone for 24 hours did not inhibit nitric oxide synthase activity, as measured by conversion of [3H]L-arginine to [3H]L-citrulline. Electron micrography demonstrated that endothelial cell ultrastructure but not vascular smooth muscle cell ultrastructure was abnormal after incubation of rings for 24 hours with 100 micromol/L carbenoxolone. These studies suggest that carbenoxolone concentrations higher than 10 micromol/L enhance vasoconstrictor action via selective toxicity to the endothelium and elimination of endothelium-dependent relaxation.

Problems associated with medical treatment of peptic ulcer disease.

In the United States, the drugs most commonly used to treat peptic ulcer disease are antacids and the H2-receptor antagonists cimetidine and ranitidine. Other available agents include anticholinergics and the coating agent sucralfate. Investigational drugs such as colloidal bismuth, carbenoxolone, prostaglandins, the tricyclic compound pirenzepine, and substituted benzimidazoles are not available for use in the United States. Most of the commercially available and investigational compounds have similar efficacy; therefore the optimal drug may be the one associated with the fewest adverse effects and the most convenient dosing regimen. Cimetidine causes a small number of adverse effects, including neuropsychiatric disorders, gynecomastia, impotence, loss of libido, elevation of serum creatinine and serum transaminases concentrations, and drug interactions. Some of these reactions have been of clinical significance. Presently, there are rare reports of gynecomastia, bradycardia, inhibition of acetylcholinesterase, headache, lethargy, diarrhea, and rash in patients receiving ranitidine. Antacids can produce either diarrhea or constipation and have been associated with low serum phosphorus concentrations, and metabolic alkalosis. Anticholinergics, especially in elderly or debilitated patients, can cause central nervous system disorders, intestinal atony, or urinary retention. Sucralfate may cause constipation, diarrhea, nausea, and headache. The investigational agents have their own side effect profiles. The adverse effects of anticholinergics make them unattractive therapeutic choices, and antacids and sucralfate have inconvenient dosing requirements compared with some equally efficacious alternatives. In addition, clinical experience with sucralfate in the United States is limited. The safety record of cimetidine is admirable. As clinical experience with ranitidine increases, currently unrecognized adverse effects may be reported. However, based on current data, ranitidine is as effective as cimetidine and is associated with a lower incidence of side effects.

Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess.

Excessive ingestion of licorice induces a syndrome of hypokalemia and hypertension that reflects increased activation of renal mineralocorticoid receptors by cortisol. A similar syndrome of cortisol-dependent mineralocorticoid excess occurs in congenital deficiency of the enzyme 11 beta-hydroxysteroid dehydrogenase, which normally inactivates cortisol to cortisone. It has been shown that licorice inhibits 11 beta-dehydrogenase, preventing local inactivation of cortisol and allowing cortisol inappropriate access to intrinsically nonspecific renal mineralocorticoid receptors. Further studies with licorice and its derivatives have revealed a widespread role for 11 beta-dehydrogenase in regulating tissue sensitivity to cortisol. Deficient 11 beta-dehydrogenase activity provides a novel pathogenetic mechanism for hypertension, and current research suggests that several common forms of hypertension can be explained by the mechanisms that operate in licorice-induced hypertension.

Carbenoxolone sodium: its role in ulcer healing.

In summary, carbenoxolone is a useful drug in accelerating short-term ulcer healing during ambulatory treatments. Provided treatment is responsibly controlled the adverse effects should not present frequent or severe problems; however, there is a clear need for an analogue which is substantially side-effect free.

Carbenoxolone: a review of its pharmacological properties and therapeutic efficacy in peptic ulcer disease.

Carbenoxolone sodium has been shown to accelerate the rate of healing of both gastric and duodenal ulcers, but its overall value in duodenal ulcer is probably less because of the high rate of natural remission of duodenal ulcers. Further studies are required to decide whether it should be used prophylactically to delay ulcer recurrence. Carbenoxolone may act by affecting both the proliferative activity of gastric epithelium and the differentiation of the epithelial cells to produce mucus (as well as favourably altering the physicochemical properties of mucus and by reducing peptic activity), factors which may be relevant ot the prevention of acute gastric ulcers. Some studies suggest that carbenoxolone adds to the effect of hospitalisation and bed rest on ulcer healing. Whether bed rest confers additional benefit to the drug's ulcer healing effect in outpatients is also uncertain. There is no evidence that accelerated healing by carbenoxolone is associated with improved overall prognosis. Carbenoxolone is of greatest benefit in accelerating the healing of gastric ulcers in patients for whom hospitalisation is not possible or desirable, but it should only be used in the ambulatory patient when careful and regular observation of serum electrolytes (particularly potassium), blood pressure and weight is possible and when it is known that the patient will attend regular follow-up. Patient must be educated in the proper use of the drug. If severe mineralocorticoid-like toxic effects such as sodium and water retention and hypokalaemia appear, as they do in a variable proportion of patients but most frequently in those receiving excessive doses, carbenoxolone should be stopped and the complication treated; they respond to thiazide diuretics and potassium supplements, and probably to amiloride given in conjunction with a low dose of a thiazide diuretic. Treatment with carbenoxolone can continue with concurrent diuretic therapy in patients with less severe side-effects. Optimum therapeutic effect in gastric ulcer with the least side-effects is achieved with a dosage of 100mg carbenoxolone tablets 3 times daily for the first week followed by 50mg 3 times daily thereafter, best taken before meals. A lower dosage is desirable in the elderly and in those with liver, cardiac or renal disease. Barium meal or preferably endoscopic examinations should be performed regularly and therapy continued until the ulcer is healed. Dosage for duodenal ulcer is 50mg 4 times daily, in special positioned-release capsules. These are best taken about 20 minutes before meals.

Drug-induced hypertension: pathogenesis and management.

PIP: Estrogenic compounds are the most important group of drugs that can induce hypertension. Studies have shown an incidence of significant hypertension amounting to less than 1% after 1 year of taking oral contraceptives and about 2% after 5 years. The ratio of the incidence of hypertension among ''takers'' to that of ''nontakers'' has been assessed at 1.8 by 1 study and 2.6 by another. Small but significant increments in systolic and diastolic pressures can be discerned during the first 2 years of treatment. Cessation of treatment has resulted in pressures returing to pretreatment levels within 3 months. In those previously normal the highest readings during oral contraceptive use were only 155/90 mm of Hg. Severe hypertension is more likely to occur in the predisposed, and malignant hypertension has been reported. Previous hypertension, toxemia of pregnancy, obesity, and nephropathy are predisposing conditions. Although progestagens, used alone, do not cause clinical hypertension the incidence of hypertension associated with an estrogen-progestogen combination was directly related to the dose of progestagen used. Weight gain is often observed in oral contraceptive users and is occasionally accompanied by edema and hypertension. There is a marked increase in the circulating level of renin substrate (angiotensinogen) which is caused by the estrogen component of the pill. The increase in renin substrate is associated with increase in plasma levels of renin activity, angiotensin 2, and aldosterone, together with a fall in plasma renin concentration. The suppression of plasma renin concentration can persist for weeks after stopping the pill. The factors responsible for hypertension are probably intrinsic and may be either neural, vascular, or renal. Patients taking oral contraceptives should have blood pressure checks at 6-month intervals, and more frequently in high risk cases. In the management of those with only mild blood pressure elevation, such patients should change to a preparation with the lowest available estrogen dosage, 30 mcg of ethinyl estradiol, or reserve the method for use during crucial periods of family planning. With moderate hypertension the oral contraceptive should be suspended for 3-6 months. If the blood pressure falls, oral contraceptives should not be resumed but another method recommended. Continuing hypertension requires further study and possibly elective sterilization. Severe hypertension requires withdrawal of the pill, urgent investigation, and treatment. Other drugs may cause hypertension. Management of these patients is outlined. Structural formulae of progesterone, norethisterone acetate, medroxyprogesterone acetate, and norgestrel are shown.^ieng

Controlled trial of a carbenoxolone/alginate antacid combination in reflux oesophagitis.

A double-blind controlled trial was carried out in 37 patients with oesophagitis, confirmed endoscopically and histologically, to compare the efficacy of treatment with a carbenoxolone/alginate antaacid combination with that of the alginate antacid compound used alone. The total daily dosage of carbenoxolone was 100 mg. During the 8-week-period of the trial patients were seen every 2 weeks and endoscoped at 4 and 8 weeks. Response to treatment was assessed symptomatically and endoscopically using 6-point grading scales, and multiple oesophageal biopsies were taken at each endoscopy. The addition of carbenoxolone to the alginate antacid compound was shown to enhance symptomatic relief and to increase healing of oesophagitis and oesophageal ulceration significantly. No serious side-effects were reported in either group. Although there were a number of biochemical or clinical abnormalities recorded, none required any alteration in treatment.

Comparison of pirenzepine and carbenoxolone in the treatment of chronic gastric ulcer. A double-blind endoscopic trial.

The purpose of the present study was to compare the effectiveness of pirenzepine and carbenoxolone in accelerating the healing of chronic gastric ulcer. Sixty-six out-patients with endoscopically proven gastric ulcer, without major systemic diseases, were admitted to the study. Patients were randomly allocated to either pirenzepine, 50 mg three times a day for 6 weeks, or carbenoxolone, 100 mg three times a day for one week followed by 50 mg three times a day for the remaining five weeks. At 6 weeks, the ulcers had healed in 20 out of 34 patients (59%) treated with pirenzepine, and in 15 out of 29 patients (52%) treated with carbenoxolone. Symptomatic improvement was similar with both drugs. Some major side effects (oedema, hypokalaemia and hypertension) occurred in approximately 30% of patients treated with carbenoxolone; of those receiving pirenzepine 25% complained of minor symptoms (e.g. dry mouth, headache, tachycardia). It is concluded that pirenzepine and carbenoxolone are of similar, but rather limited, efficacy in speeding the healing of chronic gastric ulcer, but show important differences with respect to tolerability.

Stridor due to drug-induced hypokalaemic alkalosis.

A 76-year-old on long-term Lasix and Pyrogastrone presented with stridor. This became worse with local irritation, e.g. on coughing or during indirect laryngoscopy. Indirect laryngoscopy showed a narrow glottis with an otherwise normal larynx. Blood investigation showed a low serum potassium with a raised bicarbonate level, and a serum calcium level just within the acceptable normal range. A diagnosis of laryngospasm secondary to drug-induced hypokalaemic alkalosis was made. This was treated with the withdrawal of the above drugs and supplementing potassium orally.

Carbenoxolone patients with gastric ulcers. A double-blind trial.

Carbenoxolone was compared with placebo in a randomised double-blind study involving 40 patients with gastric ulcer (20 each in the treated and placebo groups). The evaluation was based on eight variables. The endoscopic findings on completion of 4 or 6 weeks of treatment, revealed greater improvement in response to carbenoxolone than to placebo. The difference was statistically significant at the previously fixed level of significance of p less than 0.05. The plasma potassium level fell significantly in the treated group but the actual reduction of 7% was slight. No statistically significant differences were measured in any of the other variables, i.e. plasma sodium, SGOT, SGPT, systolic and diastolic blood pressure, bodyweight, or oedema formation.

Serum carbenoxolone: ulcer-healing and metabolic effects.

The relationship of serum carbenoxolone to dosage, age, sex, efficacy and side-effects were studied in 92 patients. Log serum carbenoxolone was correlated with dose and with age, and was higher in women. Serum levels were not significantly different in those patients with duodenal (or gastric) ulcer whose ulcers had or had not healed after allowance was made by analysis of variance for the effects of age and sex. However, oedema and hypokalaemia were associated with higher serum levels. These results support the concept that the ulcer-healing effect of carbenoxolone is topical rather than systemic.

Long-term therapy with carbenoxolone in the prevention of recurrence of gastric ulcer. Natural history and evolution of important side-effects and measures to avoid them.

Between 1970 and 1979, 140 patients aged between 19 and 84 years with endoscopically confirmed gastric ulcer (GU), were treated with Biogastrone in reducing doses for 6 months. They received a daily dose of 300 mg for one week, 150 mg for 5 weeks, 100 mg for 6 weeks and 50 mg for the remainder of the 6 months. All the patients were reviewed at 2, 4, 6, 8, 12, 16, 20, 32, and 38 weeks and thereafter every 3 months or earlier in the event of significant dyspepsia. The anticipated recurrence rate of GU of approximately 42% at 2 years (3) was nearly halved to 26.7% over a median follow-up of 36 months in 140 cases completing the full six months course of treatment. The incidence of side effects was as follows: (i) A weight gain of 3.5 kg or more was seen in 23% of the patients at 2 weeks; this effect was maintained through the 6 month period. (ii) Oedema was noted in 14% of the patients at 2 weeks but declined to a 2% incidence by the end of the study. (iii) Elevated diastolic blood pressure in 14--18% of patients below 60 years and 20--27% patients above 60 years of age was noted throughout the study period. A high proportion of patients (38%) receiving other therapy had hypertension prior to the trial period; Carbenoxolone treatment had little further effect on blood pressure in these patients. (iv) Hypokalaemia was noted in the early stages of treatment especially in those over 60 years (43%). The incidence declined with the reduction in dosage through the 6 month treatment period. All side effects were successfully treated by diuretics and potassium supplements.

Pyrogastrone treatment of peptic oesophagitis: analysis of 104 patients treated during a 3 1/2-year period.

A retrospective analysis was carried out in 104 patients with peptic oesophagitis treated with Pyrogastrone (carbenoxolone with alginate-antacid) during a 3 1/2-year period. There wer 3 treatment groups: one had Pyrogastrone alone, another pyrogastrone with metoclopramide and in the third, both agents were given together with cimetidine. Highly significant symptomatic improvement was achieved in 85% of 96 patients treated between 4 and 8 weeks and equally significant endoscopic healing was noted in 76% of 55 patients for the same period. Best results were seen in those given Pyrogastrone alone; the concurrent use of metoclopramide and cimetidine did not enhance healing or symptom relief. 40% of patients received multiple courses, 22% were treated for at least six months and 16% for one year or longer continuously; 3 patients for over 3 years. The only noteworthy side effects were due to the tablet flavour and chewing property. These results confirm clinical trial experience that Pyrogastrone is highly effective in healing peptic esophagitis.

Carbenoxolone treatment ameliorated metabolic syndrome in WNIN/Ob obese rats, but induced severe fat loss and glucose intolerance in lean rats.

BACKGROUND: 11beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regulates local glucocorticoid action in tissues by catalysing conversion of inactive glucocorticoids to active glucocorticoids. 11ß-HSD1 inhibition ameliorates obesity and associated co-morbidities. Here, we tested the effect of 11ß-HSD inhibitor, carbenoxolone (CBX) on obesity and associated comorbidities in obese rats of WNIN/Ob strain, a new animal model for genetic obesity. METHODOLOGY/PRINCIPAL FINDINGS: Subcutaneous injection of CBX (50 mg/kg body weight) or volume-matched vehicle was given once daily for four weeks to three month-old WNIN/Ob lean and obese rats (n = 6 for each phenotype and for each treatment). Body composition, plasma lipids and hormones were assayed. Hepatic steatosis, adipose tissue morphology, inflammation and fibrosis were also studied. Insulin resistance and glucose intolerance were determined along with tissue glycogen content. Gene expressions were determined in liver and adipose tissue. CBX significantly inhibited 11ß-HSD1 activity in liver and adipose tissue of WNIN/Ob lean and obese rats. CBX significantly decreased body fat percentage, hypertriglyceridemia, hypercholesterolemia, insulin resistance in obese rats. CBX ameliorated hepatic steatosis, adipocyte hypertrophy, adipose tissue inflammation and fibrosis in obese rats. Tissue glycogen content was significantly decreased by CBX in liver and adipose tissue of obese rats. Severe fat loss and glucose- intolerance were observed in lean rats after CBX treatment. CONCLUSIONS/SIGNIFICANCE: We conclude that 11ß-HSD1 inhibition by CBX decreases obesity and associated co-morbidities in WNIN/Ob obese rats. Our study supports the hypothesis that inhibition of 11ß-HSD1 is a key strategy to treat metabolic syndrome. Severe fat loss and glucose -intolerance by CBX treatment in lean rats suggest that chronic 11ß-HSD1 inhibition may lead to insulin resistance in normal conditions.