Allopurinol and valproic acid improve cardiac triglyceride and Na+-K+-ATPase activity independent of circulating aldosterone in female rats with glucose intolerance.

Context: Studies have shown that cardiac triglyceride accumulation and impaired Na+-K+-ATPase activity are linked to diabetes- related cardiovascular disease, particularly in women.Objectives: We hypothesised that allopurinol (ALL) and valproic acid (VPA) treatment would improve cardiac triglyceride and Na+-K+-ATPase activity independent of circulating aldosterone in Combined Oral Contraceptive (COC)-induced dysglycemiaMaterials and methods: Rats received COC (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel; po) with or without ALL (1 mg; po) and VPA (20 mg; po) for 6 weeks.Results: COC-treatment led to impaired glucose tolerance, accumulated abdominal fat, dyslipidemia, elevated plasma MDA, PAI-1 and aldosterone levels and also reduced plasma nitric oxide bioavailability and cardiac Na+-K+-ATPase activity. However, either ALL or VPA treatment ameliorated these alterations comparably independent of elevated aldosterone levelDiscussion and conclusion: Our results suggest that either ALL or VPA would improve cardiac TG and Na+-K+-ATPase activity comparably in COC-treated rats, regardless of circulating aldosterone level.

Acetate causes renoprotection like androgen and mineralocorticoid receptors blockade in testosterone-exposed pregnant rats.

The kidney plays a critical role in human health and deviation from its normal function can lead to severe morbidity and mortality. Exposure to excess testosterone in women has been linked to several disorders, including kidney disorder and acting undoubtedly through androgen receptor (AR), whereas the involvement of mineralocorticoid receptor (MR) is unclear. Likewise, the renal effect of sodium acetate (SAc) during late gestational exposure to testosterone is not well known. We hypothesized that SAc or MR blockade would protect the kidney of testosterone-exposed pregnant rats against glutathione and adenosine depletion. Twenty-five pregnant Wistar rats were treated (sc) with olive oil, testosterone propionate (0.5 mg/kg) singly or in combination with SAc (200 mg/kg; p.o.), androgen receptor (AR) blocker, flutamide (Flu; 7.5 mg/kg; p.o.) or (MR) blocker, eplerenone (Eple; 0.5 mg/kg) between gestational days 14 and 19. Glutathione, adenosine and nitric oxide were decreased while uric acid (UA), xanthine oxidase (XO), malondialdehyde (MDA), lactate dehydrogenase activity and free fatty acids were increased in the kidneys of gestational rats exposed to testosterone. Also, plasma urea and creatinine were elevated. SAc and Eple reversed tested testosterone-induced effects in gestational rats. The exposure to testosterone impairs renal antioxidant defense via AR and MR during late gestation in pregnant rats. The study also provides evidence that sodium acetate protects the kidneys of gestational testosterone-exposed rats against defective antioxidant defense in like manner as MR or AR antagonist.

Low dose spironolactone-mediated androgen-adiponectin modulation alleviates endocrine-metabolic disturbances in letrozole-induced PCOS.

Polycystic ovarian syndrome (PCOS), is a multifactorial endocrine disorder in women of reproductive age. It usually associates with metabolic disorders (MDs), which aggravates the risk of infertility, cardiometabolic events and associated comorbidities in women with PCOS. Adiponectin, a circulating protein produced by adipocytes, which has been suggested to inversely correlate with MDs. Spironolactone, a non-selective mineralocorticoid receptor (MR) antagonist, has been in wide clinical use for several decades. Herein, we investigated the effects of low dose spironolactone (LDS) and the role of adiponectin in endocrine-metabolic disturbances in experimentally-induced PCOS rats. Eighteen female Wistar rats (160-180 g) were randomly allotted into 3 groups and treated with vehicle (p.o.), letrozole (LET; 1 mg/kg) and LET + LDS (0.25 mg/kg), once daily for 21 days, respectively. The results showed that LET-treated animals had features of PCOS, characterized by elevated plasma testosterone and prolactin, increased body weight gain and ovarian weight as well as disrupted ovarian cytoarchitecture and degenerated follicles. Additionally, elevated fasting blood glucose, 1 h-postload glucose and plasma insulin, impaired glucose tolerance, insulin resistance, reduced insulin sensitivity, increased plasma and ovarian lipid profile, plasma lipid peroxidation, TNF-α, IL-6 and decreased plasma glutathione peroxidase and glutathione content were observed. These alterations were associated with decreased circulating adiponectin and were reversed when treated with LDS. The present results suggest that LDS ameliorates endocrine-metabolic disturbances and inflammation-related comorbidities associated with LET-induced PCOS by modulating circulating androgen-adiponectin status.

Sodium butyrate arrests pancreato-hepatic synchronous uric acid and lipid dysmetabolism in high fat diet fed Wistar rats.

High fat diet (HFD) is a risk factor for metabolic syndrome which is characterized by overt glucose dysmetabolism and tissue derangement. The liver and pancreas are important metabolic tissues with anatomical proximity sharing splanchnic and mesenteric circulation but it is unclear whether, there is an associated metabolic status between the two organs in health and disease. Uric acid (UA) hypersecretion and ectopic lipid accumulation are characteristic pathophysiology of an array of non-communicable diseases. Sodium butyrate (BUT) is reputed for therapeutic roles in metabolic derangement. Therefore, the present study investigated synchrony in hepatic and pancreatic UA and lipid metabolic status in HFD-induced glucose dysregulation and probed the beneficial effects of BUT. Twenty-four female Wistar rats were treated with normal rat chow and distilled water (po) or sodium butyrate (200 mg/kg; po) or high fat diet and distilled water (po) or high fat diet and sodium butyrate. Results showed that HFD increased plasma, pancreatic and hepatic triglyceride, triglyceride-glucose index, malondialdehyde, uric acid (UA), lactate dehydrogenase but reduced glucose-6-phosphate dehydrogenase. Histological analysis revealed hepatic and pancreatic architectural derangement and cellular degeneration in HFD-fed animals. However, BUT reversed the HFD-induced systemic, pancreatic and hepatic synchronous dysmetabolism with evidence of improved histology. HFD-induced lipid and UA alterations were synchronous in the pancreas and liver. BUT elicits beneficial effects on systemic and tissue HFD-induced deleterious metabolic changes which were synchronized in pancreas and liver of rats.

Spironolactone reversed hepato-ovarian triglyceride accumulation caused by letrozole-induced polycystic ovarian syndrome: tissue uric acid-a familiar foe.

Polycystic ovarian syndrome (PCOS) is a complex endocrine disease among women of reproductive age and is one of the main causes of infertility. Non-alcoholic fatty liver disease (NAFLD), the most prominent chronic liver disease in adults, is characterized by excess hepatic triglyceride (TG) accumulation. PCOS women have increased risk of NAFLD and uric acid has been documented to have a positive correlation with subclinical tissue damage and might be the link in the cystic. Spironolactone (SPL) is a mineralocorticoid receptor (MR) blocker that has been in wide clinical use for some decades. In this research, we investigated the effects of SPL on ovarian and hepatic tissue damage in experimental PCOS rats induced by letrozole (LET). A total of eighteen adult female Wistar rats were used for this study and the animals divided into 3 groups are treated with vehicle, LET (1 mg/kg), and LET+SPL (SPL; 0.25 mg/kg), p.o. once daily respectively for 21 uninterrupted days. Results showed that LET treatment induced features of PCOS characterized by increased plasma testosterone (T) and luteinizing hormone (LH) together with increased body weight. Abnormal ovarian and hepatic histomorphological changes were also observed with elevated uric acid (UA) and TG accumulation in both tissues respectively. Treatment with SPL however attenuated the elevated testosterone in the LET-induced PCOS model accompanied with a reversal in the observed ovarian and hepatic UA, TG accumulation, and altered histomorphological changes. Taken together, spironolactone reversed the PCOS-induced ovarian and hepatic tissue damage by suppressing tissue UA and TG accumulation.

Drospirenone-containing oral contraceptives do not affect glucose regulation and circulating corticosterone.

Background Combined oral contraceptive (COC) use has been associated with an increased risk of insulin resistance (IR) and other adverse cardiovascular events, despite efforts to reduce the dosage and/or progestin type. COC containing drospirenone (DRSP) is an analog of spironolactone, hence its antimineralocorticoid and antiandrogenic characteristics have been deemed beneficial, although the benefits and/or negative outcome of its usage have not been fully elucidated. We therefore hypothesized that COC with DRSP component will not affect glucose regulation and circulating corticosterone. Method Ten-week-old female Wistar rats were divided into three groups: control (CON), ethinylestradiol/drospirenone COC (EE/DRSP)-treated, and ethinylestradiol/levonorgestrel COC (EE/LN)-treated rats. The treatment lasted for 8 weeks. Results Results showed that with the exception of lipid profiles, EE/LN but not EE/DRSP COC treatment affected body weight, glucose tolerance, plasma insulin, corticosterone, (IR), and pancreatic ß-cell dysfunction. Conclusion Taken together, the findings showed that the beneficial effect of EE/DRSP could possibly be through the DRSP component. The result also implies that COCs containing DRSP may be a better and safer means of contraception than those with LN with less cardiovascular risks.

Sodium butyrate recovers high-fat diet-fed female Wistar rats from glucose dysmetabolism and uric acid-associated cardiac tissue damage.

Increased global consumption of high-fat/high-calorie diet has led to higher incidence of the multifactorial cardiometabolic syndrome especially among women. The links between glucose deregulation and eventual mortal cardiac diseases are still being investigated. However, several reports have implicated elevated uric acid (UA) in the progression of metabolic disorders especially during high-fructose diet. Also, butyrate (BUT) a short-chain fatty acid is being identified with intriguing therapeutic potentials in metabolic disorders. We therefore hypothesized that high-fat diet-induced glucose deregulation and cardiac tissue damage are associated with elevated UA and attenuated by BUT in female rats. Twenty-four 10-week-old female Wistar rats with weights ranging from 135 to 150 g were treated with normal rat chow and distilled water (po) or sodium butyrate (200 mg/kg; po) or high-fat diet and distilled water (po) or high-fat diet and sodium butyrate. Treatments lasted for 6 weeks. Results showed that high-fat diet caused glucose dysmetabolism, elevated plasma triglyceride (TG), total cholesterol (TC), corticosterone, malondialdehyde (MDA), plasma and cardiac UA, and lactate dehydrogenase (LDH). High-fat diet also led to depressed reduced glutathione (GSH). Histological analysis of cardiac tissue showed cellular infarction, infiltration, and fibrosis in high-fat diet-fed rats. However, all these effects were ameliorated by BUT treatment. The findings here showed that high-fat diet resulted in glucose dysmetabolism and cardiac tissue damage through a UA-dependent mechanism and that BUT can protect against high-fat diet-induced cardiometabolic disorders through UA suppression and augmentation of glutathione antioxidant defenses.

Very low dose spironolactone protects experimentally-induced polycystic ovarian syndrome from insulin-resistant metabolic disturbances by suppressing elevated circulating testosterone.

Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women of reproductive age and hyperandrogenism is a prominent feature of PCOS resulting in infertility and increased risk of developing metabolic disorders including insulin resistance (IR), abdominal adiposity, glucose intolerance and cardiovascular diseases. Spironolactone (SPL), a non-selective mineralocorticoid receptor (MR) antagonist, has been in wide clinical use for several decades. In this study, we investigated the effects of SPL on IR and metabolic disturbances in letrozole-induced PCOS rats. Eighteen adults female Wistar rats were randomly divided into 3 groups and treated with vehicle, letrozole (LET; 1 mg/kg) and LET + SPL (SPL; 0.25 mg/kg), p.o. once daily for 21 consecutive days. Results showed that LET treatment induced PCOS characterised by elevated plasma testosterone and luteinizing hormone (LH) accompanied with increased body weight and visceral adiposity, IR, glucose intolerance, dyslipidemia and altered histomorphological ovaries. Treatment with SPL however attenuated the elevated testosterone in LET-induced PCOS model accompanied with a reversal in all the observed alterations. Taken together, analysis of the physical, biochemical and histological evidences shows that the protective effect of this very low dose spironolactone may be through its anti-androgenic mechanism.

Drospirenone-containing contraceptive exerts positive effects on cardiac uric acid and PAI-1 but not GSK-3: Improved safety profiles in contraception?

The use of combined oral contraceptives (COC) have been associated with increased risk of adverse cardiovascular events and elevated cardiac and circulating plasminogen activator inhibitor-1 (PAI-1) and glycogen synthase kinase-3 (GSK-3) have been implicated in these events. Contraceptives containing drospirenone, a progestin with anti-androgenic actions may have a positive or neutral effect on cardiac PAI-1 and GSK-3 levels. Studies on the favorable effects of oral contraceptives containing drospirenone when compared with other androgenic contraceptives have not been fully elucidated. We therefore sought to compare the effect of a contraceptive containing ethinyl estradiol and drospirenone (DSP) with a contraceptive containing ethinyl estradiol and levonorgestrel (LVG) on cardiac uric acid (UA), PAI-1, GSK-3 and some hematological parameters. Ten weeks old female Wistar rats were divided into three groups; control (CON), LVG or DSP treated rats. The treatment lasted for 8 weeks. Results showed that LVG and not DSP treatment led to increase in plasma and cardiac tissue UA, plasma and cardiac PAI-1 as well as granulocyte-lymphocyte ratio (GLR) and platelet-lymphocyte ratio (PLR). However, the DSP treatment affected the circulating GSK-3. Taken together, the findings showed that LVG and not DSP affected cardiac UA and PAI-1. These results suggest that COC containing drospirenone appears to have positive effects on cardiac UA and PAI-1 levels but do not affect GSK-3, hence, COC containing drospirenone may be a better and safer means of contraception compared to androgenic contraceptives.

Ameliorative effect of low-dose spironolactone on obesity and insulin resistance is through replenishment of estrogen in ovariectomized rats.

Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but the reverse is the case after menopause, indicating a possible protective effect of estrogen on cardiometabolic function. Although various hormonal therapies have been formulated to combat the CVD risks in postmenopausal state, the beneficial effects have not been consistent. Obesity with insulin resistance (IR) is closely linked to CVD risks while ovariectomized rodents have been shown to mimic a state of obesity and IR. We therefore hypothesized that low-dose spironolactone would ameliorate obesity and IR in estrogen-deprived rats by replenishing estrogen and suppressing elevated glycogen synthase kinase-3 (GSK-3). Ten-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM), spironolactone (SPL; 0.25 mg/kg), and ovariectomized (OVX) rats treated with or without spironolactone daily for 8 weeks. Results showed that estrogen deprivation through ovariectomy caused increased body mass gain and visceral adiposity that are accompanied by increased HOMA-IR, HOMA-ß, 1-hour postload glucose, glucose intolerance, platelet/lymphocyte ratio, plasma insulin, atherogenic dyslipidemia, uric acid, GSK-3, corticosterone, and aldosterone and depressed 17ß-estradiol. However, treatment of OVX rats with spironolactone ameliorated all these effects. Taken together, the results demonstrate that treatment with low-dose spironolactone improves obesity and IR, which appears to involve replenishment of estrogen and suppression of GSK-3 along with circulating mineralocorticoid and glucocorticoid. The findings imply a positive cardiometabolic effect of low-dose spironolactone usage in estrogen-deprived conditions.

Oral hormonal therapy with ethinylestradiol-levonorgestrel improves insulin resistance, obesity, and glycogen synthase kinase-3 independent of circulating mineralocorticoid in estrogen-deficient rats.

Estrogen deficiency has been associated with increased incidence of cardiovascular diseases , and recent clinical trials of standard formulations of hormonal therapies have not demonstrated consistent beneficial effects. Estrogen-progestin therapy has been used as exogenous estrogen to normalize depressed estrogen level during menopause. Ovariectomized rodents mimic an estrogen-deficient state in that they develop cardiometabolic dysfunction, including insulin resistance (IR). We therefore hypothesized that hormonal therapy with combined oral contraceptive steroids, ethinylestradiol-levonorgestrel (EEL), improves IR, obesity, and glycogen synthase kinase-3 (GSK-3) through reduction of circulating mineralocorticoid in ovariectomized rats. Twelve-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM) and ovariectomized (OVX) rats were treated with or without EEL (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel) daily for 8 weeks. Results showed that OVX or SHM + EEL treated rats had increased HOMA-IR (homeostatic model assessment of IR), 1 h postload glucose, HOMA-ß, triglycerides (TG), total cholesterol (TC), TC/HDL cholesterol, TG/HDL cholesterol, plasma insulin, GSK-3, corticosterone, and aldosterone. On the other hand, OVX + EEL treatment ameliorated all these effects except that of aldosterone. Taken together, the results demonstrate that oral hormonal replacement with EEL improves IR and pancreatic ß-cell function and suppresses GSK-3 and glucocorticoid independent of circulating aldosterone, suggesting a positive cardiometabolic effect of oral EEL therapy in estrogen-deficient rats.

Low-dose spironolactone ameliorates insulin resistance and suppresses elevated plasminogen activator inhibitor-1 during gestational testosterone exposure.

CONTEXT: Elevated gestational circulating testosterone has been associated with pathological pregnancies that increase the risk of development of cardiometabolic disorder in later life. OBJECTIVE: We hypothesised that gestational testosterone exposure, in late pregnancy, causes glucose deregulation and atherogenic dyslipidaemia that would be accompanied by high plasminogen activator inhibitor-1 (PAI-1). The study also hypothesise that low-dose spironolactone treatment would ameliorate these effects. METHODS: Pregnant Wistar rats received vehicle, testosterone (0.5 mg/kg; sc), spironolactone (0.5 mg/kg, po) or testosterone and spironolactone daily between gestational days 15 and 19. RESULTS: Gestational testosterone exposure led to increased HOMA-IR, circulating insulin, testosterone, 1-h post-load glucose, atherogenic dyslipidaemia, PLR, PAI-1 and MDA. However, all these effects, except that of circulating testosterone, were ameliorated by spironolactone. CONCLUSIONS: These results demonstrate that low-dose spironolactone ameliorates glucose deregulation and atherogenic dyslipidaemia during elevated gestational testosterone exposure, at least in part, by suppressing elevated PAI-1.

High salt intake does not aggravate glucose dysregulation and dyslipidemia induced by estrogen-progestin oral contraceptive.

BACKGROUND: Estrogen-progestogen combined oral contraceptive (OC) use has been associated with increased cardiometabolic risk factors, including glucose dysregulation, dyslipidemia, hypertension, and pro-inflammatory state. However, the effect of a high-salt diet on these risk factors during OC use is not yet investigated. We therefore hypothesized that a high-salt diet would increase cardiometabolic risk factors in female rats treated with a combination of OC steroids, levonorgestrel (L) and ethinylestradiol (EE), and that elevated plasma levels of pro-inflammatory markers are associated with the cardiometabolic effects. METHODS: Female Wistar rats were given (p.o.) vehicle, high-dose (1.0µg EE plus 5.0µgL) or low-dose (0.1µg EE plus 0.5µgL) OC with or without a high-salt diet (8%) daily for 8 weeks. Insulin resistance (IR) was estimated using the homeostatic model of assessment (HOMA). RESULTS: Results showed that OC treatment or high salt diet led to significant increases in insulin resistance, plasma insulin, total cholesterol (TC), triglyceride (TG), TC/HDL-cholesterol, uric acid levels, and decreased glucose tolerance. OC treatment but not a high-salt diet resulted in increased plasma C-reactive protein and TG/HDL-cholesterol. However, a high-salt diet did not aggravate the effects of OC treatment. CONCLUSION: The results from the present study indicate that glucose dysfunction and dyslipidemia induced by OC use, but not those induced by increased dietary salt are associated with elevated plasma C-reactive protein. Besides, increased dietary salt does not worsen abnormal cardiometabolic impact of OC use.