The effect of blocking the first and rate-limiting step in renin-angiotensin cascade on the renal function in ischemia reperfusion injury has not been previously investigated. We investigated the effect of aliskiren, the first approved direct oral renin inhibitor, on the alterations in renal functional parameters in this condition. Wistar rats underwent left renal ischemia for 40 min. Group-1 received normal saline whereas Group-2 received aliskiren (30 mg/kg/day) by gavage for 6 days commencing one day before IRI. The hemodynamic and tubular functions and gene expression of neutrophil gelatinase-associated lipocalin (NGAL) and plasminogen activating inhibitor (PAI-1) in the right and left kidneys were measured five days following the IRI. Comparing Group-1 and Group-2, the left renal blood flow was significantly higher in Group-2 (1.28+/-0.36 vs. 0.39+/-0.05, P=0.007). Left kidney glomerular filtration rate was also higher in Group-2 but did not reach statistical significance (0.18+/-0.05 vs. 0.10+/-0.02, P=0.07). The left renal FE(Na) was significantly lower in Group-2 (29.9+/-6.4 vs. 49.7+/-7.8, P=0.03). Aliskiren also caused a significant decrease in the gene expression of both NGAL and PAI-1 in the left ischemic kidney. In conclusions, the administration of aliskiren before and after IRI appears to have ameliorated the IRI effect on the total renal artery blood flow, fractional excretion of sodium and gene expression of both NGAL and PAI-1 indicating a renoprotective effects in IRI.
- MeSH
- amidy aplikace a dávkování MeSH
- fumaráty aplikace a dávkování MeSH
- hodnoty glomerulární filtrace účinky léků MeSH
- krysa rodu Rattus MeSH
- ledvinné látky aplikace a dávkování MeSH
- ledviny účinky léků patofyziologie MeSH
- nemoci ledvin farmakoterapie patofyziologie MeSH
- potkani Wistar MeSH
- renální oběh účinky léků MeSH
- renin-angiotensin systém účinky léků MeSH
- renin antagonisté a inhibitory MeSH
- reperfuzní poškození patofyziologie prevence a kontrola MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- aliskiren MeSH Prohlížeč
- amidy MeSH
- fumaráty MeSH
- ledvinné látky MeSH
- renin MeSH
The renin-angiotensin system plays an important role in various physiological and pathophysiological regulatory mechanisms. Within the past few years, the classical concept of a linear enzymatic cascade has experienced substantial changes. A parallel counterregulatory axis has been identified which involves the angiotensin converting enzyme homologue ACE2, angiotensin (1-7), and receptors Mas. The research in prorenin and its non-proteolytic activation has greatly advanced after the discovery of cellular receptors (P)RR; binding of renin or prorenin to these receptors not only facilitates angiotensin generation, but at the same time activates specific signal transduction pathways. The long-term search for clinically useful direct renin inhibitors has recently succeeded with the new antihypertensive drug aliskiren. While beneficial effects of aliskiren on some markers of cardiovascular and renal diseases have been proved in large clinical studies, important questions remain to be solved.
- MeSH
- aktivace enzymů účinky léků MeSH
- amidy farmakologie MeSH
- antihypertenziva farmakologie MeSH
- fumaráty farmakologie MeSH
- lidé MeSH
- receptory buněčného povrchu fyziologie MeSH
- renin-angiotensin systém fyziologie MeSH
- renin antagonisté a inhibitory fyziologie MeSH
- vakuolární protonové ATPasy fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- aliskiren MeSH Prohlížeč
- amidy MeSH
- antihypertenziva MeSH
- ATP6AP2 protein, human MeSH Prohlížeč
- fumaráty MeSH
- receptory buněčného povrchu MeSH
- renin MeSH
- vakuolární protonové ATPasy MeSH
The role of renin-angiotensin-aldosterone system (RAAS) in regulating the volume and composition of extracellular fluid, blood pressure (BP) as well as onset and progression of cardiovascular and renal diseases has been studied for more than 150 years. The compounds that block the vital stages of the RAAS cascade, such as ACE-inhibitors (ACEI), AT1-receptor blockers (ARB) and aldosterone receptor antagonists, importantly extended our treatment options. However, the positive therapeutic effects of these compounds also have certain negative consequences. Administration of ACEIs and ARBs interrupts physiological feedback for renal renin release and leads to reactive elevation of circulating active renin and greater production of angiotensin I and angiotensin II with subsequent return of aldosterone secretion to the pre-treatment levels ('escape' phenomenon). These possible adverse effects of the intermediary products of incomplete RAAS blockade leading to organ complications have facilitated the efforts to develop compounds blocking the initial stages of renin-angiotensin cascade--i.e. direct renin blockers. After several years of unsuccessful attempts, the recent years have seen development of the first non-peptide, orally long-term effective renin inhibitor, aliskiren fumarate. In monotherapy or in combination with other antihypertensives (hydrochlorothiazide, ARB, ACEI), aliskiren reduces BP in a dose-dependent manner (75-600 mg/den). Aliskiren reduces plasma renin activity (PRA) and neutralises hydrochlorothiazide-induced RAAS activation. Once daily administration of the drug leads to longer than 24-hour activity and its prolonged blocking effects on the kidneys are the basis for its renoprotectivity. In addition to the significant antihypertensive effect, clinical studies also showed a range of organoprotective properties in patients with left ventricle hypertrophy (ALLAY study), heart failure (ALOFT study) and diabetic nephropathy (AVOID study). Similar to other AT1-blockers, aliskiren has a minimum of adverse side effects. Aliskiren for hypertension therapy was launched in clinical practice in USA in 2007 (Tekturna and combination formulation TekturnaHCl, respectively) and shortly after that in European Union as Rasilez. In the Czech Republic, aliskiren (Rasilez) was released for clinical use by diabetologists and nephrologists in patients with hypertension and concomitant diabetes, nephropathy and proteinuria in doses of 150-300 mg per day on 1. 8. 2009. It is recommended as monotherapy or in combination with other antihypertensives to treat conditions with elevated PRA, including PRA elevation following diuretic, ACEI or ARB administration. Aliskiren might be used in patients who do not tolerate ACEIs as well as in patients in whom angiotensin II participates in the pathogenesis of their diseases. Reno-protective properties leading to a reduction in proteinuria and delaying renal failure progression were observed in patients with diabetic as well as non-diabetic nephropathy. The drug is the subject to similar precautions and contraindications as ACEIs and ARBs, i.e. pregnancy and bilateral renal artery stenosis. To make meaningful conclusions about the so far positive contribution of this new treatment class and its broad applicability for the therapy of hypertension and other cardiovascular diseases, it will be imperative to assess its long-term effects on morbidity and mortality as well as to compare these agents with other RAAS blockers in long-term clinical studies; this represents a research effort for another 7-8 years.
- MeSH
- amidy terapeutické užití MeSH
- fumaráty terapeutické užití MeSH
- kardiovaskulární nemoci farmakoterapie metabolismus MeSH
- lidé MeSH
- nemoci ledvin farmakoterapie metabolismus MeSH
- renin-angiotensin systém účinky léků MeSH
- renin antagonisté a inhibitory MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- aliskiren MeSH Prohlížeč
- amidy MeSH
- fumaráty MeSH
- renin MeSH
The renin-angiotensin-aldosterone system (RAAS) plays an important part in the pathogenesis of arterial hypertension and the complications it causes in organs (the heart, the circulatory system, the brain, the kidneys), heart failure and kidney diseases. Materials that block the most upstream point of the RAAS cascade (ACE inhibitors - ACEI, AT1,-receptor (AT1R) blockers, aldosterone receptor blockers) have greatly expanded our options in the treatment and primary and secondary prevention of cardiovascular and renal diseases. ACEI and AT1R blockers interrupt the normal feedback provided by the release of renin into the circulatory system from the kidneys. After they are applied the reactive increase in active circulating renin leads to increased creation of angiotensin I and angiotensin II and the subsequent return of aldosterone secretions to pre-treatment values ("escape" phenomenon). The possible negative effect of these intermediary products of an incomplete blockade of RAAS on organ complications lead to an effort to develop a material that could block the renin-angiotensin cascade at its first stage--i.e. a renin blocker. The first efforts with renin antibodies or peptide analogues of renin prosegments failed to satisify the basic requirements for long-term medication--effectiveness when used orally. In recent years the first non-peptidic, oral renin ihibitor providing sustained effects has been developed, aliskiren fumarate. Aliskiren reduces BP depending on the dose (50-300 mg/day) in monotherapy or in combination with hydrochlorothiazide. Aliskiren lowers plasma renin activity (PRA) and neutralises the activation of the RAAS triggered by hydrochlorothiazide. Ambulatory BP monitoring has shown that taking the medicine once a day has a 24-hour effect and its continued residence in the kidneys suggests renoprotective effects. The compound is in the third stage of clinical tests as a monotherapy or in combination for the treatment of hypertension. It has also been shown to have an influence on the regression of cardiac hypertrophy (Aliskiren in Left-Ventricular Hypertrophy trial - ALLAY), the treatment of heart failure (Aliskiren Observation of Heart Failure Treatment trial - ALOFT) and diabetic (Aliskiren in the Evaluation of Proteinuria in Diabetes trial - AVOID). In April 206, the FDA permitted the use of aliskiren in the USA for the treatment of high BP and it is currently undergoing testing in Europe. The renin inhibitor has minimal undesirable side effects, like AT1-receptor blockers. The slightly lower effectiveness ofaliskiren than AT1-receptor blockers in reducing BP is caused by the fact that it does not block bradykinins. It is recommended as a monotherapy for clinical use or in combination with other antihypertensive medicines for conditions with high levels of PRA including its rise after diuretics, ACEI and AT1-receptor blockers. Aliskiren could therefore be used primarily with young patients, Caucasians, persons with ACEI intolerance, and also in diseases where angiotensin II is involved in the pathogenesis and the secondary prevention of cardiovascular disease. It is also safe for persons with concurrent renal problems, because it is mainly removed by the liver without great interference with other materials. Like ACEI, the renin inhibitor has a vasodilatory effect which could potentially improve the elasticity of arteries. The medicine has the same limitations and contraindications as ACEI and AT1R blockers, such as pregnancy and bilateral renal artery stenosis. A definitive assessment of the benefit of this new class of medicines and its broad application in the treatment of cardiovascular and other diseases will require demonstration of its long-term effect on morbidity and mortality, as well as comparison with other RAAS blockers in long clinical studies, which represent research programmes lasting another 7 to 8 years.
- MeSH
- amidy farmakologie terapeutické užití MeSH
- antihypertenziva terapeutické užití MeSH
- fumaráty farmakologie terapeutické užití MeSH
- hypertenze farmakoterapie patofyziologie MeSH
- kardiovaskulární nemoci farmakoterapie patofyziologie MeSH
- krevní tlak účinky léků MeSH
- lidé MeSH
- renin-angiotensin systém účinky léků MeSH
- renin antagonisté a inhibitory krev MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- aliskiren MeSH Prohlížeč
- amidy MeSH
- antihypertenziva MeSH
- fumaráty MeSH
- renin MeSH
- MeSH
- angiotensinogen MeSH
- pepstatiny MeSH
- peptidové fragmenty MeSH
- protilátky MeSH
- renin antagonisté a inhibitory imunologie MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- angiotensinogen MeSH
- pepstatiny MeSH
- peptidové fragmenty MeSH
- protilátky MeSH
- renin MeSH
- MeSH
- jaterní oběh MeSH
- játra analýza metabolismus MeSH
- kočky MeSH
- králíci MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- myši MeSH
- nadledviny analýza MeSH
- nefrektomie MeSH
- pojivová tkáň metabolismus MeSH
- prasata MeSH
- psi MeSH
- renin analýza antagonisté a inhibitory krev metabolismus fyziologie MeSH
- žluč metabolismus MeSH
- zvířata MeSH
- Check Tag
- kočky MeSH
- králíci MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- myši MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- renin MeSH
