OBJECTIVE: Despite availability of an array of antihypertensive drugs, malignant hypertension remains a life-threatening condition, and new therapeutic strategies for the treatment of malignant hypertension and malignant hypertension-associated organ damage are needed. The aim of the present study was to assess the effects of nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) stimulator on the course of malignant hypertension. The second aim was to investigate if the treatment with sodium-glucose cotransporter type 2 (SGLT2) inhibitor would augment the expected beneficial actions of the sGC stimulation on the course of malignant hypertension. METHODS: As a model of malignant hypertension, Ren-2 transgenic rats (TGR) treated with nonspecific NO synthase inhibitor (Nω-nitro- l -arginine methyl ester, l -NAME) was used. Blood pressure (BP) was monitored by radiotelemetry, and the treatment was started 3 days before administration of l -NAME. RESULTS: The treatment with sGC stimulator BAY 41-8543, alone or combined with SGLT2 inhibitor empagliflozin, abolished malignant hypertension-related mortality in TGR receiving l -NAME. These two treatment regimens also prevented BP increases after l -NAME administration in TGR, and even decreased BP below values observed in control TGR, and prevented cardiac dysfunction and malignant hypertension-related morbidity. The treatment with the SGLT2 inhibitor empagliflozin did not further augment the beneficial actions of sGC stimulator on the course of malignant hypertension-related mortality. CONCLUSION: The treatment with NO-independent sGC stimulator displayed marked protective actions on the course of malignant hypertension-related mortality and malignant hypertension-related cardiac damage. This suggests that application of sGC stimulator could be a promising therapeutic means for the treatment of malignant hypertension.

• Klíčová slova
• malignant hypertension, renin–angiotensin system, sodium-glucose cotransporter type 2 inhibitor, soluble guanylyl cyclase stimulator,
• MeSH
• benzhydrylové sloučeniny farmakologie   MeSH
• glifloziny MeSH
• glukosidy farmakologie   terapeutické užití   MeSH
• hypertenze maligní * prevence a kontrola   farmakoterapie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• morfoliny MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• potkani transgenní MeSH
• pyrazoly * farmakologie   terapeutické užití   MeSH
• pyrimidiny * terapeutické užití   farmakologie   MeSH
• rozpustná guanylátcyklasa * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BAY 41-8543 MeSH Prohlížeč
• benzhydrylové sloučeniny MeSH
• empagliflozin MeSH Prohlížeč
• glifloziny MeSH
• glukosidy MeSH
• morfoliny MeSH
• NG-nitroargininmethylester MeSH
• pyrazoly * MeSH
• pyrimidiny * MeSH
• rozpustná guanylátcyklasa * MeSH

BACKGROUND AND AIMS: Recent studies suggest that empagliflozin reduces total and cardiovascular mortality in both diabetic and nondiabetic subjects. Although the exact mechanism is unclear, it is understood to positively affect myocardial energetics, including the metabolism of ketone bodies, lipids, and fatty acids. In this study, we compared empagliflozin effects on lipid metabolism in the heart and liver in a prediabetic rat model with severe dyslipidemia. MATERIALS AND METHODS: Wistar rats served as the control group, while hereditary hypertriglyceridemic (HHTg) rats were used as a nonobese, prediabetic model. Rats were treated with or without empagliflozin at a dose of 10 mg/kg body weight (BW) for 8 weeks. RESULTS: In HHTg rats, empagliflozin decreased body weight and adiposity, improved glucose tolerance, and decreased serum triacylglycerols (TAGs) (p < 0.001). Empagliflozin decreased the activity and gene expression of the lipogenic enzyme SCD-1 (p < 0.001) in the myocardium, which may have led to a decrease in the ectopic accumulation of TAGs and lipotoxic diacylglycerols and lysophosphatidylcholines (p < 0.001). Changes in the myocardial phosphatidylcholine/phosphatidylethanolamine ratio (p < 0.01) and in the fatty acid profile of myocardial phospholipids may have contributed to the antifibrotic effects of empagliflozin. The anti-inflammatory effects of empagliflozin were evidenced by an increased IL-10/TNFα ratio (p < 0.001), a marked decrease in arachidonic acid metabolites (20-HETE, p < 0.001), and an increase in PUFA metabolites (14,15-EETs, p < 0.001) in the myocardium. However, empagliflozin did not significantly affect either the concentration or utilization of ketone bodies. In the liver, empagliflozin decreased lipogenesis and the accumulation of TAGs and lipotoxic intermediates. Its effect on arachidonic acid metabolites and alterations in n-3 PUFA metabolism was less pronounced than in the myocardium. CONCLUSION: Our findings suggest that empagliflozin treatment in the heart and liver reduced the accumulation of neutral lipids and lipotoxic intermediates and altered the metabolism of n-3 PUFA. In the heart, empagliflozin altered arachidonic acid metabolism, which is likely associated with the anti-inflammatory and antifibrotic effects of the drug. We assume that these alterations in lipid metabolism contribute to the cardioprotective effects of empagliflozin in prediabetic states with severe dyslipidemia.

• Klíčová slova
• SGLT2 inhibitors, arachidonic acid, cardiovascular disease, empagliflozin, inflammation, ketone body, lipid metabolism,
• Publikační typ
• časopisecké články MeSH

A new class of antidiabetic drugs - gliflozins (inhibitors of sodium glucose cotransporter-2; SGLT-2i) stimulate glucose and sodium excretion, thereby contributing to improved glycemic control, weight loss and blood pressure reduction in diabetic patients. Large clinical trials in patients with type 2 diabetes treated with empagliflozin, canagliflozin or dapagliflozin have demonstrated their excellent efficacy in improving many cardiovascular outcomes, including the reduction of death from cardiovascular diseases, non-fatal myocardial infarction or stroke, and hospitalization for heart failure. Moreover, the beneficial effects of SGLT-2i were also demonstrated in the decrease in proteinuria, which leads to a lower risk of progression to end-stage renal disease and thus a delay in initiation of the renal replacement therapy. Unexpectedly, their cardioprotective and renoprotective effects have been demonstrated not only in patients with diabetes but also in those without diabetes. Recently, much effort has been focused on patients with heart failure (either with reduced or preserved ejection fraction) or liver disease. Experimental studies have highlighted pleiotropic effects of SGLT-2 inhibitors beyond their natriuretic and glycosuric effects, including reduction of fibrosis, inflammation, reactive oxygen species, and others. Our results in experimental non-diabetic models of hypertension, chronic kidney disease and heart failure are partially consistent with these findings. This raises the question of whether the same mechanisms are at work in diabetic and non-diabetic conditions, and which mechanisms are responsible for the beneficial effects of gliflozins under non-diabetic conditions. Are these effects cardio-renal, metabolic, or others? This review will focus on the effects of gliflozins under different pathophysiological conditions, namely in hypertension, chronic kidney disease, and heart failure, which have been evaluated in non-diabetic rat models of these diseases. Key words: SGLT-2 inhibitor, hypertension, chronic kidney disease, heart failure, liver disease, rat.

• Klíčová slova
• SGLT-2 inhibitor, Hypertension, Chronic kidney disease, Heart failure, Liver disease, Rat,
• MeSH
• glifloziny * terapeutické užití   farmakologie   MeSH
• hypoglykemika terapeutické užití   farmakologie   MeSH
• kardiovaskulární nemoci * farmakoterapie   prevence a kontrola   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• glifloziny * MeSH
• hypoglykemika MeSH

Gliflozins (sodium-glucose transporter-2 inhibitors) exhibited renoprotective effects not only in diabetic but also in non-diabetic patients with chronic kidney disease (CKD). Controversial results were reported in experimental non-diabetic models of CKD. Therefore, we examined empagliflozin effects in three CKD models, namely, in fawn-hooded hypertensive (FHH) rats, uninephrectomized salt-loaded (UNX + HS) rats, and in rats with Goldblatt hypertension (two-kidney, one-clip 2K1C) that were either untreated or treated with empagliflozin (10 mg/kg/day) for eight weeks. Plethysmography blood pressure (BP) was recorded weekly, and renal parameters (proteinuria, plasma urea, creatinine clearance, and sodium excretion) were analyzed three times during the experiment. At the end of the study, blood pressure was also measured directly. Markers of oxidative stress (TBARS) and inflammation (MCP-1) were analyzed in kidney and plasma, respectively. Body weight and visceral adiposity were reduced by empagliflozin in FHH rats, without a significant effect on BP. Experimentally induced CKD (UNX + HS and 2K1C) was associated with a substantial increase in BP and relative heart and kidney weights. Empagliflozin influenced neither visceral adiposity nor BP in these two models. Although empagliflozin increased sodium excretion, suggesting effective SGLT-2 inhibition, it did not affect diuresis in any experimental model. Unexpectedly, empagliflozin did not provide renoprotection because proteinuria, plasma urea, and plasma creatinine were not lowered by empagliflozin treatment in all three CKD models. In line with these results, empagliflozin treatment did not decrease TBARS or MCP-1 levels in either model. In conclusion, empagliflozin did not provide the expected beneficial effects on kidney function in experimental models of CKD.

• Klíčová slova
• SGLT-2 inhibition, fawn-hooded hypertensive rat, one-clip hypertension, proteinuria, two-kidney, uninephrectomized salt-loaded,
• Publikační typ
• časopisecké články MeSH

Gliflozins (inhibitors of sodium-glucose cotransporter 2) show many beneficial actions beyond their antidiabetic effects. The underlying mechanisms of these additional protective effects are still not well understood, especially under non-diabetic conditions. Therefore, we analyzed the effects of empagliflozin in young (3-month-old) and adult (12-month-old) male spontaneously hypertensive rats (SHR) expressing human C-reactive protein (CRP) in the liver. SHR-CRP rats are a non-diabetic model of metabolic syndrome, inflammation, and organ damage. Empagliflozin was given in a daily dose of 10 mg/kg body weight for 8 weeks. Both age groups of SHR-CRP rats treated with empagliflozin had lower body weight, decreased weight of fat depots, reduced ectopic fat accumulation in the liver and kidneys, and decreased levels of plasma insulin and β-hydroxybutyrate. Empagliflozin effectively reduced ectopic renal fat accumulation, and was associated with decreased inflammation. Exclusively in young rats, decreased microalbuminuria after empagliflozin treatment was accompanied by attenuated oxidative stress. In adult animals, empagliflozin also improved left ventricle function. In conclusion, in young animals, the beneficial renoprotective effects of empagliflozin could be ascribed to reduced lipid deposition in the kidney and the attenuation of oxidative stress and inflammation. In contrast, hepatic lipid metabolism was ameliorated in adult rats.

• Klíčová slova
• SGLT-2 inhibitor, SHR-CRP, age, gene expression, lipid metabolism,
• Publikační typ
• časopisecké články MeSH

Recent studies suggest that treatment with SGLT-2 inhibitors can reduce hepatic lipid storage and ameliorate non-alcoholic fatty liver disease (NAFLD) development beyond their glycemic benefits. However, the exact mechanism involved is still unclear. We investigated the hepatic metabolic effect of empagliflozin (10 mg/kg/day for eight weeks) on the development of NAFLD and its complications using HHTg rats as a non-obese prediabetic rat model. Empagliflozin treatment reduced neutral triacylglycerols and lipotoxic diacylglycerols in the liver and was accompanied by significant changes in relative mRNA expression of lipogenic enzymes (Scd-1, Fas) and transcription factors (Srebp1, Pparγ). In addition, alterations in the gene expression of cytochrome P450 proteins, particularly Cyp2e1 and Cyp4a, together with increased Nrf2, contributed to the improvement of hepatic lipid metabolism after empagliflozin administration. Decreased circulating levels of fetuin-A improved lipid metabolism and attenuated insulin resistance in the liver and in peripheral tissues. Our results highlight the beneficial effect of empagliflozin on hepatic lipid metabolism and lipid accumulation independent of obesity, with the mechanisms understood to involve decreased lipogenesis, alterations in cytochrome P450 proteins, and decreased fetuin-A. These changes help to alleviate NAFLD symptoms in the early phase of the disease and before the onset of diabetes.

• Klíčová slova
• SGLT-2 inhibitors, cytochrome P450, empagliflozin, fatty liver, fetuin-A, lipid metabolism, oxidative stress,
• MeSH
• benzhydrylové sloučeniny farmakologie   MeSH
• glifloziny farmakologie   MeSH
• glukosidy farmakologie   MeSH
• hyperglykemie farmakoterapie   etiologie   metabolismus   MeSH
• hyperlipoproteinemie typ IV komplikace   farmakoterapie   metabolismus   MeSH
• inzulinová rezistence MeSH
• játra účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• mediátory zánětu metabolismus   MeSH
• metabolismus lipidů účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• mutantní kmeny potkanů MeSH
• nealkoholová steatóza jater etiologie   metabolismus   prevence a kontrola   MeSH
• obezita komplikace   metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• potkani Wistar MeSH
• prediabetes komplikace   farmakoterapie   metabolismus   MeSH
• progrese nemoci MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzhydrylové sloučeniny MeSH
• empagliflozin MeSH Prohlížeč
• glifloziny MeSH
• glukosidy MeSH
• mediátory zánětu MeSH
• systém (enzymů) cytochromů P-450 MeSH