Direct renin inhibitors are the newest antihypertensive therapeutic class. The review describes their antihypertensive and antiproteinuric effects and possible renoprotective capabilities. RECENT FINDINGS: Clinical trials demonstrate direct renin inhibitors reduce systolic and diastolic blood pressure comparable with other commonly used antihypertensive drugs, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. They also reduce proteinuria and are renoprotective in experimental models of kidney disease. Direct renin inhibitors, when used with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, offer incremental blood pressure reduction far greater than that observed when an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker are used together. This suggests that renin inhibitors possess a unique and distinct mechanism of action compared with the other two therapeutic classes. SUMMARY: Direct renin inhibitors, due to their antihypertensive and antiproteinuric effects, and the unique mechanism of action resulting in reduction in plasma renin activity and suppression of angiotensin II levels, may offer a unique opportunity to facilitate blood pressure reduction with both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as well as other commonly used therapeutic classes. More effective blood pressure and proteinuria reduction coupled with a unique means of suppressing the renin angiotensin system may offer improved opportunity for renoprotection.

• MeSH
• antagonisté receptorů pro angiotenzin MeSH
• antihypertenziva terapeutické užití   MeSH
• biologické modely MeSH
• časové faktory MeSH
• fixní kombinace léků MeSH
• hypertenze farmakoterapie   MeSH
• krevní tlak účinky záření   MeSH
• ledviny metabolismus   účinky léků   MeSH
• lidé MeSH
• proteinurie metabolismus   MeSH
• receptory angiotensinu metabolismus   MeSH
• renin antagonisté a inhibitory   krev   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH

1. Hypertension plays a critical role in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), but it has also been postulated that antihypertensive drugs that block the renin-angiotensin system (RAS) show class-specific renoprotective actions beyond their blood pressure (BP)-lowering effects. 2. Because this notion has recently been questioned, in the present study we compared the effects of a RAS-dependent antihypertensive therapy (a combination of trandolapril, an angiotensin-converting enzyme inhibitor (ACEI) and losartan, an angiotensin-II (AngII) receptor subtype 1A receptor antagonist) with a 'RAS-independent' antihypertensive therapy (a combination of labetalol, an alfa- and beta-adrenoreceptor antagonist with the diuretics, hydrochlorothiazide and furosemide) on the progression of CKD after 5/6 renal ablation (5/6 NX) in Ren-2 renin transgenic rats (TGR), a model of AngII-dependent hypertension. Normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats after 5/6 NX served as controls. 3. RAS-dependent and -independent antihypertensive therapies normalized BP and survival rate, and prevented the development of cardiac hypertrophy and glomerulosclerosis to the same degree in 5/6 NX HanSD rats and in 5/6 NX TGR. The present findings show that renoprotection, at least in rats after 5/6 NX, is predominantly BP-dependent. When equal lowering of BP was achieved, leading to normotension, cardio- and renoprotective effects were equivalent irrespective of the type of antihypertensive therapy. 4. These findings should be taken into consideration in attempts to develop new therapeutic approaches and strategies aimed to prevent the progression of CKD and to lower the incidence of ESRD.

• MeSH
• aldosteron moč   MeSH
• angiotensin II krev   metabolismus   MeSH
• antihypertenziva farmakologie   MeSH
• blokátory receptorů AT1 pro angiotensin II farmakologie   MeSH
• chronické selhání ledvin farmakoterapie   metabolismus   prevence a kontrola   MeSH
• chymosin metabolismus   MeSH
• diabetické nefropatie farmakoterapie   prevence a kontrola   MeSH
• diuretika farmakologie   MeSH
• furosemid farmakologie   MeSH
• hydrochlorthiazid farmakologie   MeSH
• hypertenze farmakoterapie   metabolismus   MeSH
• indoly farmakologie   MeSH
• inhibitory ACE farmakologie   MeSH
• kardiomegalie farmakoterapie   prevence a kontrola   MeSH
• kombinovaná farmakoterapie MeSH
• kreatinin krev   metabolismus   moč   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• labetalol farmakologie   MeSH
• losartan farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• proteinurie krev   metabolismus   moč   MeSH
• renin-angiotensin systém účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Association of congestive heart failure (CHF) and chronic kidney disease (CKD) worsens the patient's prognosis and results in poor survival rate. The aim of this study was to examine if addition of endothelin type A (ETA) receptor antagonist to the angiotensin-converting enzyme inhibitor (ACEi) will bring additional beneficial effects in experimental rats. METHODS: CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of aorto-caval fistula (ACF). The follow-up was 24 weeks after the first intervention (5/6 NX). The treatment regimens were initiated 6 weeks after 5/6 NX and 2 weeks after ACF creation. RESULTS: The final survival in untreated group was 15%. The treatment with ETA receptor antagonist alone or ACEi alone and the combined treatment improved the survival rate to 64%, 71% and 75%, respectively, however, the difference between the combination and either single treatment regimen was not significant. The combined treatment exerted best renoprotection, causing additional reduction in albuminuria and reducing renal glomerular and tubulointerstitial injury as compared with ACE inhibition alone. CONCLUSIONS: Our results show that treatment with ETA receptor antagonist attenuates the CKD- and CHF-related mortality, and addition of ETA receptor antagonist to the standard blockade of RAS by ACEi exhibits additional renoprotective actions.

• MeSH
• antagonisté endotelinového receptoru A * farmakologie   terapeutické užití   MeSH
• chronická renální insuficience * komplikace   farmakoterapie   metabolismus   MeSH
• endotelin-1 metabolismus   MeSH
• inhibitory ACE farmakologie   terapeutické užití   MeSH
• krysa rodu rattus MeSH
• ledviny MeSH
• píštěle * metabolismus   MeSH
• potkani transgenní MeSH
• receptor endotelinu A metabolismus   MeSH
• renin-angiotensin systém MeSH
• srdeční selhání * farmakoterapie   etiologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• antihypertenziva MeSH
• hypertenze MeSH
• kardiologie MeSH
• nemoci cév MeSH

• Konspekt
• Lékařské vědy. Lékařství
• NLK Obory
• kardiologie
• farmakoterapie
• angiologie

AIMS: There is evidence that in addition to hypertension and hyperactivity of the renin-angiotensin system (RAS), enhanced intrarenal activity of endothelin (ET) system contributes to the pathophysiology and progression of chronic kidney disease (CKD). This prompted us to examine if this progression would be alleviated by addition of type A ET receptor (ETA) blockade to the standard blockade of RAS. MAIN METHODS: Ren-2 transgenic rats (TGR) after 5/6 renal ablation (5/6 NX) served as a model of CKD. For RAS inhibition a combination of angiotensin-converting enzyme inhibitor (trandolapril, 6 mg/L drinking water) and angiotensin II type 1 receptor blocker (losartan, 100 mg/L drinking water) was used. Alternatively, ETA receptor blocker (atrasentan, 5 mg·kg(-1)·day(-1) in drinking water) was added to the combined RAS blockade. The follow-up period was 44 weeks after 5/6 NX, and the rats' survival rate, systolic blood pressure (SBP), proteinuria and indices of renal glomerular damage were evaluated. KEY FINDINGS: The survival rate was at first improved, by either therapeutic regime, however, the efficiency of RAS blockade alone considerably decreased 36 weeks after 5/6 NX: final survival rate of 65% was significantly lower than 91% achieved with combined RAS and ETA receptor blockade. SBP was not affected by the addition of ETA blockade while proteinuria and renal glomerular damage were further reduced. SIGNIFICANCE: Our data show that a combined RAS and ETA receptor blockade exhibits additional beneficial effects on survival rate and the progression of CKD in 5/6 NX TGR, as compared with RAS inhibition alone.

• MeSH
• angiotensin II krev   MeSH
• antagonisté endotelinového receptoru terapeutické užití   MeSH
• endotelin-1 metabolismus   MeSH
• kardiomegalie krev   komplikace   farmakoterapie   patologie   MeSH
• krevní tlak účinky léků   MeSH
• ledviny účinky léků   patologie   patofyziologie   MeSH
• nefrektomie * MeSH
• nemoci ledvin krev   komplikace   farmakoterapie   patologie   MeSH
• ochranné látky farmakologie   terapeutické užití   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• receptor endotelinu A metabolismus   MeSH
• renin-angiotensin systém účinky léků   MeSH
• renin genetika   MeSH
• systola účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Objective: Our previous study in heterozygous Ren-2 transgenic rats (TGR) demonstrated that long-term treatment with endothelin receptor A (ETA) blocker atrasentan added to the renin-angiotensin system (RAS) blockade had renoprotective effects in a model of chronic kidney disease (CKD) induced by partial nephrectomy. Since ETA blockade is known to cause edema, we were interested whether diuretic treatment added to this therapy would be beneficial. Design and Methods: Partial nephrectomy (NX) was performed at the age of 3 months in TGR rats which were subjected to: (i) RAS blockade alone (angiotensin receptor blocker losartan and angiotensin converting enzyme inhibitor trandolapril), (ii) combined RAS (losartan and trandolapril) and ETA receptor blockade (atrasentan), or (iii) diuretic (hydrochlorothiazide) added to the combined RAS + ETA blockade for 50 weeks following NX. Results: At the end of the study systolic blood pressure and cardiac hypertrophy were similarly decreased in all treated groups. Survival was significantly improved by ETA receptor blockade added to RAS blockade with no further effects of diuretic treatment. However, additional diuretic treatment combined with RAS + ETA blockade decreased body weight and had beneficial renoprotective effects - reductions of both kidney weight and kidney damage markers. Proteinuria gradually increased in rats treated with RAS blockade alone, while it was substantially lowered by additional ETA blockade. In rats treated with additional diuretic, proteinuria was progressively reduced throughout the experiment. Conclusion: A diuretic added to the combined RAS and ETA blockade has late renoprotective effects in CKD induced by partial nephrectomy in Ren-2 transgenic rats. The diuretic improved: renal function (evaluated as proteinuria and creatinine clearance), renal morphology (kidney mass, glomerular volume), and histological markers of kidney damage (glomerulosclerosis index, tubulointerstitial injury).

• Publikační typ
• časopisecké články MeSH

BACKGROUND/AIMS: We found recently that increasing renal epoxyeicosatrienoic acids (EETs) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, shows renoprotective actions and retards the progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX). This prompted us to examine if additional protection is provided when sEH inhibitor is added to the standard renin-angiotensin system (RAS) blockade, specifically in rats with established CKD. METHODS: For RAS blockade, an angiotensin-converting enzyme inhibitor along with an angiotensin II type receptor blocker was used. RAS blockade was compared to sEH inhibition added to the RAS blockade. Treatments were initiated 6 weeks after 5/6 NX in TGR and the follow-up period was 60 weeks. RESULTS: Combined RAS and sEH blockade exhibited additional positive impact on the rat survival rate, further reduced albuminuria, further reduced glomerular and tubulointerstitial injury, and attenuated the decline in creatinine clearance when compared to 5/6 NX TGR subjected to RAS blockade alone. These additional beneficial actions were associated with normalization of the intrarenal EETs deficient and a further reduction of urinary angiotensinogen excretion. CONCLUSION: This study provides evidence that addition of pharmacological inhibition of sEH to RAS blockade in 5/6 NX TGR enhances renoprotection and retards progression of CKD, notably, when applied at an advanced stage.

• MeSH
• albuminurie farmakoterapie   MeSH
• chronická renální insuficience farmakoterapie   mortalita   patofyziologie   chirurgie   MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• hypertenze MeSH
• inhibitory ACE terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu rattus MeSH
• míra přežití MeSH
• nefrektomie MeSH
• potkani transgenní MeSH
• renin-angiotensin systém účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články 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.

• Publikační typ
• časopisecké články MeSH

Onemocnění ledvin v důsledku diabetes mellitus (DM) je spojeno s vysokým rizikem chronického selhání ledvin. Ke zpomalení progrese renální insuficience u pacientů s diabetickým onemocněním ledvin byly dříve využívány především inhibitory systému renin-angiotenzin, nověji byl prokázán výrazný renoprotektivní účinek také u inhibitorů sodíko-glukózového kontransportéru 2 (SGLT2) – gliflozinů. Renoprotektivní účinek inhibitorů SGLT2 je převážně hemodynamický a nezávislý na jejich antidiabetickém účinku, proto mohou inhibitory SGLT2 příznivě ovlivňovat progresi renální insuficience i u pacientů bez DM. Zatím prvním lékem ze skupiny inhibitorů SGLT2, u něhož byl tento účinek prokázán, je dapagliflozin. Při jeho podávání ve studii DAPA-CKD bylo zaznamenáno snížení výskytu primárního složeného ukazatele (trvalý pokles odhadované glomerulární filtrace o 50 %, terminální chronické selhání ledvin nebo úmrtí z renálních či kardiovaskulárních příčin) o 39 % v porovnání s placebem, z toho u pacientů s DM 2. typu o 39 %, a u nediabetiků dokonce o 50 %. Inhibitory SGLT2 by se tak mohly stát standardem léčby i u nediabetických pacientů s chronickým onemocněním ledvin.

Diabetic kidney disease is associated with a high risk of chronic renal failure. To slow down the progression of renal insufficiency in patients with diabetic kidney disease, renin- -angiotensin system inhibitors have been used and more recently, a significant renoprotective effect has also been demonstrated with inhibitors of the sodium-glucose cotransporter 2 (SGLT2) – gliflozins. The renoprotective effect of SGLT2 inhibitors is predominantly hemodynamic and independent of their antidiabetic effect, SGLT2 inhibitors therefore might favorably affect the progression of renal insufficiency even in patients without DM. So far, dapagliflozin is the first drug from the group of SGLT2 in which this effect has been shown. When administered in the DAPA-CKD study, there was a 39% reduction in the incidence of the primary composite endpoint (a permanent decrease in estimated glomerular filtration rate of 50%, terminal chronic renal failure or death from renal or cardiovascular causes) compared with placebo, a 39% reduction in patients with type 2 DM and even a 50% reduction in non-diabetic patients. Thus, SGLT2 inhibitors could become the standard of treatment even in non- -diabetic patients with chronic kidney disease.

Hlavní příčinou morbidity a mortality u nemocných s DM 2. typu představují kardiovaskulární choroby. Jejich pravděpodobnost dále zvyšuje přítomnost diabetického onemocnění ledvin, které se rozvíjí až u 40 % pacientů s diabetem 2. typu. Ve velké rando‑ mizované, placebem kontrolované studii EMPA‑REG OUTCOME byl prokázán účinek inhibitoru sodíkoglukózového kotransportéru (SGLT-2) empagliflozinu na kardiovaskulární morbiditu a mortalitu a zhoršení nefropatie, přičemž šlo o nemocné s vysokým rizikem kardiovaskulárních příhod. Nedávno byly prokázány kardio- a nefroprotektivní účinky i u kanagliflozinu. Mechanismů nefroprotektivního působení je diskutováno více, např. obnova tubuloglomerulární zpětné vazby, pokles intraglomerulární tenze, snížení krevního tlaku, příznivé ovlivnění tělesné hmotnosti nebo prevence tubulárního poškození při hyperglykemii změnami v mitochondriálních procesech. V nejbližší době lze očekávat další data ze studií v podmínkách „reálného života“ a také údaje k bezpečnosti a účinnosti jednotlivých zástupců této perspektivní lékové skupiny.

Cardiovascular diseases are the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Their likelihood is further increased by the presence of diabetic kidney disease which develops in up to 40% of patients with T2DM. In the EMPA REG OUTCOME trial, which was a large randomized, placebo-controlled study, empagliflozin, an inhibitor of sodi‑ um-glucose cotransporter 2 (SGLT-2), was shown to have an effect on cardiovascular morbidity and mortality and on exacerbation of nephropathy; the study included patients with a high risk of cardiovascular events. Recently, cardio- and nephroprotective effects have also been demonstrated in canagliflozin. Several mechanisms of nephroprotective action have been suggested, e.g. restoration of tubuloglomerular feedback, decrease in intraglomerular pressure, reduction in blood pressure, positive body weight change, or prevention of hyperglycaemia-induced tubular injury by changes in mitochondrial processes. In the very near future, further data from studies in “real-life” conditions can be expected as well as data on the safety and efficacy of the individual agents in this promising drug group.

• MeSH
• diabetes mellitus farmakoterapie   MeSH
• glifloziny * farmakologie   terapeutické užití   MeSH
• kardiovaskulární nemoci prevence a kontrola   MeSH
• lidé MeSH
• nemoci ledvin prevence a kontrola   MeSH
• riziko MeSH
• Check Tag
• lidé MeSH