Libor Kopkan

Institute for Clinical and Experimental Medicine (IKEM) | IKEM · Center for Experimental Medicine

Heart failure (HF) is life-threatening disease due to electro-mechanical dysfunction associated with hemodynamic overload, while alterations of extracellular matrix (ECM) along with perturbed connexin-43 (Cx43) might be key factors involved. We aimed to explore a dual impact of pressure, and volume overload due to aorto-caval fistula (ACF) on Cx43...

Heart failure (HF) is life-threatening disease due to electro-mechanical dysfunction associated with hemodynamic overload, while alterations of extracellular matrix (ECM) along with perturbed connexin-43 (Cx43) might be key factors involved. We aimed to explore an impact of volume overload due to aorto-caval fistula (ACF) on Cx43 and ECM as well as...

Objective Heart failure is a clinical syndrome characterized by cardiac dysfunction due to structural abnormalities of the myocardium that results in the inability of the heart to eject sufficient volume of the blood to the circulation. HF is a major cause of morbidity and mortality in the world. The ECM is a highly dynamic structure controlling th...

Aldosterone regulates blood pressure (BP) through water and sodium balance. In our study, we studied if continuous treatment with a mineralocorticoid receptor antagonist, spironolactone (30 mg/kg/day) for 20 days can: 1) attenuate hypertension development and restore inverted 24-h BP rhythm in hypertensive transgenic (mRen-2)27 rats (TGR) measured...

The extracellular matrix (ECM) is a highly dynamic structure controlling the proper functioning of heart muscle. ECM remodeling with enhanced collagen deposition due to hemodynamic overload impairs cardiomyocyte adhesion and electrical coupling that contributes to cardiac mechanical dysfunction and arrhythmias. We aimed to explore ECM and connexin-...

Pathogenesis of heart failure (HF) and hypertension with a focus on extracellular matrix (ECM) and communication in the heart is still a current scientific topic that calls for new findings. We used as experimental model normotensive (HSD) and hypertensive (TGR) rats with aortocaval fistula (ACF) supplemented with an ACE inhibitor (ACEi)(15weeks, 6...

Objective: New findings in the pathogenesis of heart failure (HF) with a focus on extracellular matrix (ECM) and communication in the heart are still relevant for more effective treatment. We focused on signaling pathways involved in cardiac structural remodeling in HF due to pressure and volume overload, as well as on investigating the efficacy o...

To provide novel insights into the pathogenesis of heart failure-induced renal dysfunction, we compared the effects of ACE inhibitor (ACEi) and AT1 receptor blocker (ARB) on systemic and kidney hemodynamics during heart failure in normotensive HanSD and hypertensive transgenic (TGR) rats. High-output heart failure was induced by creating an aorto-c...

In 2011 Fujita and coworkers proposed that beta-adrenergic stimulation causes decreased serine/threonine-protein kinase WNK4 transcription leading to the activation of Na-Cl cotransporter (NCC) which participates in salt sensitivity and salt hypertension development in rodents. The aim of our study was to investigate whether the above hypothesis is...

Our previous studies demonstrated that chronic systemic blockade of renin-angiotensin system (RAS) lowered blood pressure (BP) of Ren-2 transgenic rats (TGR) by the attenuation of both angiotensin II-dependent and sympathetic vasoconstriction. Since systemic RAS blockade also inhibits brain RAS, we were interested which effects on these two types o...

The insertion of mouse renin gene (Ren-2) into the genome of normotensive rats causes a spontaneous rise of blood pressure (BP), leading to an angiotensin II (Ang II)-dependent form of hypertension in transgenic (mRen-2)27 rats (TGR). However, enhanced sympathetic BP component was demonstrated in heterozygous TGR aged 20 weeks. In the present study...

Patients suffering from heart failure have a poorer outcome if kidney dysfunction develops. To improve deteriorated renal functions, we first need to fully understand mechanisms that lead to their worsening. Therefore, we set up to investigate which factors contribute to changes in renal hemodynamics observed in heart failure and if manipulation wi...

An association between congestive heart failure (CHF) and chronic kidney disease (CKD) results in extremely poor patient survival rates. Previous studies have shown that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, improves the survival rate in CHF induce...

Basal calcium sensitization is decreased in spontaneously hypertensive rats, although their blood pressure (BP) response to acute Rho-kinase inhibition is enhanced. Using fasudil (Rho-kinase inhibitor) or nifedipine (L-VDCC blocker), we evaluated the contribution of calcium sensitization and calcium entry to BP maintenance in hypertensive transgeni...

Suboptimal conditions during prenatal and early postnatal development can increase risk of hypertension later in life. We studied consequences of a changed perinatal environment by initiating the cross-fostering of homozygous Ren-2 transgenic rat (TGR) offspring to normotensive, transgene-negative control mothers, and vice versa. We hypothesized th...

Background/Aims: Reduction of renal blood flow (RBF) is commonly thought to be a causative factor of renal dysfunction in congestive heart failure (CHF), but the exact mechanism of the renal hypoperfusion is not clear. Apart from the activation of neurohormonal systems controlling intrarenal vascular tone, the cause might be altered reactivity of t...

We hypothesized that vascular actions of 20-hydroxyeicosatetraenoic acid (20-HETE), the product of cytochrome P450-dependent ω-hydroxylase, potentiate prohypertensive actions of angiotensin II (ANG II) in Cyp1a1-Ren-2 transgenic rats, a model of ANG II-dependent malignant hypertension. Therefore, we evaluated the antihypertensive effectiveness of a...

The development of renal dysfunction plays an important role in the progression of congestive heart failure (CHF), but the exact underlying mechanism(s) remain unclear. We hypothesized that the mechanisms involved might be augmented renal vascular responsiveness to endogenous vasoconstrictors and/or impaired renal vascular responsiveness to endothe...

Objective: We examined the effects of treatment with soluble epoxide hydrolase inhibitor (sEHi) and epoxyeicosatrienoic acids (EETs) analogue (EET-A), given alone or combined, on blood pressure (BP) and ischemia/reperfusion myocardial injury in rats with angiotensin II (ANG II)-dependent hypertension. Methods: Ren-2 transgenic rats (TGR) were us...

Rationale and Objective: We recently showed that increasing epoxyeicosatrienoic acids (EETs) in kidney by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, markedly attenuated the development of renal dysfunction and progression of aorto-caval (ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hyper...

The cardiac effects of dual angiotensin receptor and neprilysin inhibitor (LCZ696) as a novel therapeutic approach for inhibition of renin-angiotensin system was assessed in volume overload-induced chronic heart failure (CHF) in hypertensive Ren2 transgenic rats (TGR) with aorto-caval fistula (ACF) and compared with valsartan (VAL). CHF model was i...

Rationale and Objective: Interplay of 20-HETE and ANG II might be a factor in pathophysiology of many forms of experimental hypertension. We hypothesized that intrarenal 20-HETE potentiates prohypertensive actions of ANG II in Cyp1a1-Ren-2 transgenic rats (TGR), a model of ANG II-dependent malignant hypertension. Therefore, we evaluated the antihyp...

Rationale and Objective: We showed recently that increasing kidney tissue epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH) and thereby blocking EETs degradation to inactive dihydroxyeicosatrienoic acids (DHETEs) substantially attenuated the progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats...

Background There is vast evidence that the renin-angiotensin system is not the sole determinant of blood pressure (BP) elevation in human renovascular hypertension or the relevant experimental models. This study tested the hypothesis that kidney deficiency of 20-hydroxyeicosatetraenoic acid (20-HETE), a product of cytochrome P450 (CYP)-dependent ω-...

Background: Early addition of endothelin (ET) type A (ETA) receptor blockade to complex renin-angiotensin system (RAS) blockade has previously been shown to provide better renoprotection against progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX). In this study, we examined if a...

Solid organ transplantation is an established treatment modality in patients with end-stage organ damage in cases where other therapeutic options fail. The long-term outcomes of solid organ transplant recipients have improved considerably since the introduction of the first calcineurin inhibitor (CNI) - cyclosporine. In 1984, the potent immunosuppr...

The fawn-hooded hypertensive (FHH) rat serves as a genetic model of spontaneous hypertension associated with glomerular hyperfiltration and proteinuria. However, the knowledge of the natural course of hypertension and kidney disease in FHH rats remains fragmentary and the underlying pathophysiological mechanisms are unclear. In this study, over the...

Objective: We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension. Methods: Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobioti...

The role of intrarenal renin-angiotensin system (RAS) in the pathophysiology of malignant hypertension is not fully understood. Accumulating evidence indicates that recently discovered vasodilator axis of the RAS: angiotensin-converting enzyme (ACE) type 2 (ACE2)/angiotensin 1-7 (ANG 1-7) constitutes an endogenous system counterbalancing the hypert...

We elucidated the role of collecting duct kinin B2 receptor (B2R) in the development of salt-sensitivity and angiotensin II (ANG II)-induced hypertension. To this end, we used a Cre-Lox recombination strategy to generate mice lacking Bdkrb2 gene for B2R in the collecting duct (Hoxb7-Cre(tg/+):Bdkrb2(flox/flox)). In 3 groups of control (Bdkrb2(flox/...

Study objective We tested the hypothesis where the combined renin‐angiotensin system (RAS) and endothelin 1 (ET A ) receptor blockade could be more effective in the slowing of progression of CKD with already established sings of renal injury than antihypertensive treatment based on isolated RAS inhibition in 5/6 nephrectomized (NX) Ren‐2 transgenic...

Bradykinin is an important antihypertensive peptide acting mostly via the kinin B 2 receptor (gene: Bdkrb2; protein: B 2 R). We elucidated the role of collecting duct B 2 R in the development of salt‐sensitivity and angiotensin II (ANG II)‐induced hypertension. We used a Cre‐Lox recombination strategy to generate mice lacking Bdkrb2 gene for B 2 R...

AIM: It has been demonstrated that tumor necrosis factor alpha (TNF-α) via its receptor 2 (TNFR2) plays a role in the cardioprotective effects of preconditioning. It is also well known that chronic hypoxia is associated with activation of inflammatory response. With this background, we hypothesized that TNF-α signaling may contribute to the improv...

AimIt has been demonstrated that tumor necrosis factor alpha (TNF-α) via its receptor 2 (TNFR2) plays a role in the cardioprotective effects of preconditioning. It is also well known that chronic hypoxia is associated with activation of inflammatory response. With this background, we hypothesized that TNF-α signaling may contribute to the improved...

Recent studies have shown that long-term antihypertensive action of soluble epoxide hydrolase inhibition (sEHi) in angiotensin II (ANG II)-dependent hypertension might be mediated by the suppression of intrarenal ANG II levels. To test this hypothesis, we examined the effects of acute (2 days) and chronic (14 days) sEH inhibition on blood pressure...

Chronic immunosuppressive therapy is often complicated by the development of both arterial hypertension and renal dysfunction. The principal aim of this study was to assess the effects of dual inhibition of renin-angiotensin system (RAS) and other antihypertensive treatment on blood pressure and renal function in normotensive and hypertensive Fawn-...

Objective: The present study was performed to investigate in a model of malignant hypertension if the antihypertensive actions of soluble epoxide hydrolase (sEH) inhibition are nitric oxide (NO)-dependent. Methods: ANG II-dependent malignant hypertension was induced through dietary administration for 3 days of the natural xenobiotic indole-3-car...

Objective: The present study was performed to examine whether the blood pressure (BP)-lowering effects of soluble epoxide hydrolase (sEH) inhibition in two-kidney, one-clip (2K1C) Goldblatt hypertension are nitric oxide (NO) dependent. Methods: Mice lacking the endothelial NO synthase (eNOS) gene (eNOS-/-) and their wild-type controls (eNOS+/+)...

The present study was undertaken to evaluate the effects of chronic treatment with c-AUCB {cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid}, a novel inhibitor of sEH (soluble epoxide hydrolase), which is responsible for the conversion of biologically active EETs (epoxyeicosatrienoic acids) into biologically inactive DHETEs (dihydroxyei...

There are only few studies documenting the long-term outcome of aorto-caval fistula (ACF) in rats, a model of volume overload heart failure (HF). The aim of the present study was to describe HF-related morbidity and mortality, and to examine the relation between cardiac hypertrophy and survival. Adult male Wistar rats underwent needle ACF or sham o...

Objective: In the present study, we compared the effects of treatment with the novel soluble epoxide hydrolase (sEH) inhibitor (c-AUCB) with those of the AT1 receptor antagonist losartan on blood pressure (BP), autoregulation of renal blood flow (RBF) and on glomerular filtration rate (GFR) and the pressure–natriuresis relationship in response to s...

Alterations in renal function contribute to Goldblatt two-kidney, one-clip (2K1C) hypertension. A previous study indicated that bioavailability of cytochrome P-450 metabolites epoxyeicosatrienoic acids (EETs) is decreased while that of 20-hydroxyeicosatetraenoic acids (20-HETE) is increased in this model. We utilized the inhibitor of soluble epoxid...

Hypertensive rats with multiple extra copies of the renin gene (TGR) exert an inverted circadian blood pressure (BP) profile. We investigated whether circadian oscillations in the hypothalamic suprachiasmatic nucleus (SCN), a main circadian oscillator, and the paraventricular nucleus (PVN), involved in BP control, are influenced in TGR rats. The ex...

Hypertensive rats with multiple extra copies of the renin gene (TGR) exert an inverted circadian blood pressure (BP) profile. We investigated whether circadian oscillations in the hypothalamic suprachiasmatic nucleus (SCN), a main circadian oscillator, and the paraventricular nucleus (PVN), involved in BP control, are influenced in TGR rats. The ex...

Non‐technical summary Arachidonic acid metabolites called epoxyeicosatrienoic acids (EETs) influence vascular tone and renal tubular sodium and water transport and thus have been implicated in the control of blood pressure. Inhibition of the enzyme soluble epoxide hydrolase (sEH), which reduces EET degradation to the corresponding diols, leads to s...

A deficiency in nitric oxide (NO) generation leads to salt-sensitive hypertension, but the role of increased superoxide (O(2)(-)) in such salt sensitivity has not been delineated. We examined the hypothesis that an enhancement in O(2)(-) activity induced by high-salt (HS) intake under deficient NO production contributes to the development of salt-s...

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...

1Institute for Heart Research SAS, Bratislava, Slovak Republic 2Institute of Experimental Pharmacology SAS, Bratislava, Slovak Republic 3Medical Faculty of Comenius University, Bratislava, Slovak Republic Abstract Background: Hypertension-induced myocardial remodelling contributes to both heart failure and occurrence of life-threatening arrhythmias...

Objective In the present study, we compared the effects of treatment with the novel soluble epoxide hydrolase (sEH) inhibitor (c-AUCB) with those of the AT 1 receptor antagonist losartan on blood pressure (BP), autoregulation of renal blood flow (RBF) and on glomerular filtration rate (GFR) and the pressure–natriuresis relationship in response to s...

Recent studies have shown that the renal CYP450 (cytochrome P450) metabolites of AA (arachidonic acid), the vasoconstrictor 20-HETE (20-hydroxyeicosatetraenoic acid) and the vasodilator EETs (epoxyeicosatrienoic acids), play an important role in the pathophysiology of AngII (angiotensin II)-dependent forms of hypertension and the associated target...

In the present study we tested the efficacy of N-acetylcysteine (NAC) to minimize nephrotoxic effects of iodine contrast agents in intact rats as well as in 5/6-nephrectomized (5/6-Nx) rats. Rats were allocated to a group of intact rats (n = 42) and a group of 5/6-Nx rats (n = 42). After 1 month of recovery from surgery, 5/6-Nx rats and intact (sha...

Although hypercholesterolemia is implicated in the pathophysiology of many renal disorders as well as hypertension, its direct actions in the kidney are not yet clearly understood. In the present study, we evaluated renal responses to administration of cholesterol (8 μg·min-1·100 g body wt-1; bound by polyethylene glycol) into the renal artery of a...

Results of our previous studies have suggested that enhanced generation of superoxide (O2(-)) may contribute to the pathophysiology of hypertension in Ren-2 transgenic rats (TGR). The present study was performed to evaluate in TGR the effects of chronic treatment with the O2(-) scavenger tempol and the antioxidant apocynin on the development of hyp...

We examined the hypothesis that antihypertensive responses to inhibition of soluble epoxide hydrolase (sEH) are mediated by natriuretic effects of increased epoxyeicosanoids in transgenic rats with inducible expression of the mouse renin gene [strain name Cyp1a1‐Ren‐2]. Hypertension was induced in Cyp1a1‐Ren‐2 rats through dietary administration of...

Renin-angiotensin system (RAS) plays a key role in the regulation of renal function, volume of extracellular fluid and blood pressure. The activation of RAS also induces oxidative stress, particularly superoxide anion (O(2)(-)) formation. Although the involvement of O(2)(-) production in the pathology of many diseases is known for long, recent stud...

To assess the renal function in anesthetized Hannover Sprague‐Dawley rats with induced renovascular hypertension for 27 days (2K1C) and normotensive sham operated control rats during acute inhibition of epoxyeicosatrienoic acids (EETs) generation in the kidney, epoxygenase inhibitor, methylsulfonyl‐6‐(2‐propargyloxyphenyl) hexanamide (MS‐PPOH, 12 μ...

The present study tested the hypothesis that inhibition of soluble epoxide hydrolase (sEH), that increases the level of epoxyeicosatrienoic acids, would attenuate the development of renovascular hypertension in 2K1C rats. Renovascular hypertension was induced by placing a silver clip on the left renal artery in Wistar rats for 25 days. The sEH inhi...

The present study was performed to examine the role of superoxide (O2*) and its interaction with nitric oxide (NO) in the regulation of renal function in prehypertensive heterozygous Ren-2 transgenic rats (TGR). Renal responses to the O2* scavenger, tempol (150 microg/min per 100 g), and/or the NO synthase inhibitor, nitro-L-arginine methylester (L...

Enhanced superoxide ( ) activity as a result of the inhibition of the superoxide dismutase (SOD) enzyme results in vasoconstrictor and antinatriuretic responses in the canine kidney; these responses were shown to be greatly enhanced during inhibition of nitric oxide synthase (NOS). Glomerular filtration rate remained mostly unchanged during SOD inh...

The effectiveness of antisense (AS) phosphorothioated oligodeoxynucleotides (AS-ODN) targeted to the angiotensin (ANG) type 1 (AT1) receptor, was studies in Ren-2 transgenic rats (TGR), whose ANG II-dependent hypertension can be attributed to the insertion of a single mouse renin gene. Our results show that a single intraarterial bolus injection of...

The aim of this study was first to evaluate the effects of persistent or transient blockade of the angiotensin II (ANG II) receptor AT(1) on the development of hypertension and end-organ damage in hypertensive Ren-2 transgenic rats (TGR), and second to assess the potential role of AT(2) receptors in the control of blood pressure (BP) in this monoge...

An enhancement of superoxide (O2-) activity was shown to contribute to the development of hypertension induced by NO deficiency. To better understand the mechanistic role of O2- in this NO-deficient hypertension, we evaluated the renal responses to acute intraarterial administration of an O2- scavenger, tempol (50 microg/min per 100 g of body weigh...

This study was performed to examine the role of superoxide formation in the regulation of renal hemodynamic and excretory function and to assess its contribution in the pathogenesis of ANG II-dependent hypertension. Renal responses to acute intra-arterial infusion of the O2(-) scavenger tempol (50 microg x min(-1) x 100 g body wt(-1)) with or witho...

This study was performed to examine the role of superoxide (O2-) in the development of salt sensitivity and hypertension induced by inhibition of nitric oxide (NO) generation. Male Sprague-Dawley rats were fed with diet containing either normal salt (NS) (0.4% NaCl) or high salt (HS) (4% NaCl). These rats were treated with or without an NO synthase...

We investigated the responses of mean arterial pressure and renal blood flow to intravenous and intrarenal angiotensin II, plasma and kidney angiotensin II concentrations and renal angiotensin receptor subtype 1 protein expression, and renal functional responses to intravenous and intrarenal angiotensin receptor 1 blockade with candesartan. In male...

The first aim of the present study was to assess plasma and kidney angiotensin II (ANG II) levels and renal cortical ANG II receptor subtype 1A (AT1A) mRNA expression in hypertensive Ren-2 transgenic rats (TGR) and in normotensive Hannover Sprague-Dawley (HanSD) rats. The second aim was to investigate potential differences between TGR and HanSD in...

The present study was performed to evaluate the role of an interaction between the endothelin (ET) and the renin-angiotensin systems (RAS) in the development and maintenance of hypertension and in hypertension-associated end-organ damage in heterozygous male and female transgenic rats harboring the mouse Ren-2 renin gene (TGR). Twenty-eight days ol...