Experimental Models Of Hypertension Research Articles

Angiotensin converting enzyme 2 and diminazene: role in cardiovascular and blood pressure regulation.

Angiotensin converting enzyme 2 (ACE2) is an important regulator of the renin-angiotensin system through actions to degrade angiotensin II. Loss of ACE2 can contribute to the development and progression of cardiovascular disease, and experimental studies have highlighted a beneficial role for novel therapeutic approaches that activate or replenish tissue ACE2. This review focuses on experimental studies that have used the off-target effects of the antitrypanosomal agent, diminazene aceturate (DIZE) to activate ACE2. In cardiovascular disease, activation of the classical renin-angiotensin system and depletion of ACE2 leads to pathophysiological changes. One approach to activate ACE2 involves the drug DIZE, which has been shown to have beneficial effects in experimental models of hypertension, pulmonary hypertension, myocardial infarction, stroke, atherosclerosis, type 1 diabetes, and eye disease. The precise mechanism of action of DIZE to activate ACE2 remains under scrutiny. Activation of ACE2 may represent an important therapeutic approach in cardiovascular disease. To date, most studies have focused on the off-target actions of DIZE, in experimental models of disease. More research is required to determine the exact mechanism of action of DIZE and evaluate its therapeutic potential in comparison with currently available clinical interventions. There are no clinical studies of DIZE, and its side-effects, and toxicity make such studies unlikely. Hence, new methods of selectively activating or replenishing ACE2 will be needed in the future if this approach is to be used in a clinical context.

Abstract P135: 2-methoxyestradiol Minimizes Angiotensin II-induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice

Men and post-menopausal females are more prone to develop hypertension and renal dysfunction as compared to pre-menopausal females. It is well documented that in various experimental models of hypertension, the protection against hypertension in females is lost following ovariectomy (OVX). Recently we have shown that CYP1B1 protects against angiotensin II (Ang II)-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol (2-ME). This study was conducted to determine if 2-ME reduces Ang II-induced hypertension, renal dysfunction and end organ damage in OVX female, and intact male mice. Treatment of OVX Cyp1b1 +/+ and Cyp1b1 -/- female mice with 2-ME (1.5 mg/kg/day i.p., for 2 weeks) reduced Ang II-induced increase in systolic blood pressure (SBP) (182±5.1 vs. 143± 2.4 mmHg, 179±6.4 vs. 140± 8.6 mmHg, P < 0.05, n= 5), water consumption, urine output and osmolality, and proteinuria (5.5±0.7 vs. 3.3±0.5 mg/24 hrs, 8.4±1.3 vs. 4.4 ±0.9 mg/24 hrs) respectively. 2-ME also reduced Ang II-induced increase in SBP (188±2.6 vs. 143± 2.7 mmHg, P < 0.05, n= 5) in intact male mice. 2-ME did not alter water consumption and urine osmolality, but reduced urine output and sodium excretion, and proteinuria (14.4±2.0 vs. 6.0±0.5 mg/24 hrs) in intact Cyp1b1 +/+ male mice. Treatment with 2-ME attenuated Ang II-induced end-organ damage (actin and collagen accumulation) in OVX Cyp1b1 +/+ and Cyp1b1 -/- female and Cyp1b1 +/+ male mice. 2-ME mitigated urinary excretion of angiotensinogen in OVX Cyp1b1 +/+ and Cyp1b1 -/- female mice infused with Ang II. These data suggest that 2-ME reduces Ang II- induced hypertension and associated renal dysfunction and end-organ damage in OVX Cyp1b1 +/+ and Cyp1b1 -/- female, and intact male mice. Therefore, 2-ME could serve as a therapeutic agent for treatment of hypertension and associated pathogenesis in post-menopausal females, and intact males.

OP.8C.04] THE FLOW DETECTION ROLE OF THE VASCULAR EPITHELIAL SODIUM CHANNEL (ENAC) IN AN EXPERIMENTAL MODEL OF HYPERTENSION

Objective: Hypertension (HTN) impairs the regulation of blood flow leading to cardiovascular morbidity and mortality. A “new player” in blood-flow regulation is the endothelium Epithelial Sodium Channel (vascular ENaC). We hypothesise that dysfunction in HTN is due to changes in vascular ENaC activity. Aldosterone regulates renal ENaC and has a pivotal role in HTN and recently it has been suggested that aldosterone antagonism (spironolactone therapy) is beneficial beyond that predicted by the reduction in blood pressure. We propose that these additional effects are due to re-establishment of normal vascular function through modulation of vascular ENaC activity. Design and method: An experimental model of HTN, compared to normotensive (NTN) controls, with/without spironolactone therapy (n = 3–5) was used. HTN was induced in adult male transgenic rats (TG strain: Cyp1a1-Ren2), via diet-driven (0.167% w/w indol-3-carbinol) activation of renin-angiotensin-aldosterone system. Spironolactone treatment was administered daily (orally, 8.8 mg/kg/day) starting 7 weeks following initiation of HTN. Flow-mediated changes in the internal diameter (% change from no-flow) of isolated 3rd order mesenteric arteries, in the presence/absence of 10 μM amiloride were measured to determine the role of ENaC. Flow was induced through the vessels, whilst mean intraluminal pressure was maintained at 60 mmHg. Results: Isolated NTN arteries demonstrated flow mediated-constriction (−9.9 ± 3.6%) under basal conditions which was reduced (−6.3 ± 3.1%) by amiloride. The basal response was absent in HTN (0.8 ± 1.0%) vessels, and unaffected by amiloride (0 ± 1.5%). Spironolactone treatment of NTN rats resulted in a slight augmentation (−11.8 ± 1.9 %) of flow-mediated constriction which was unaffected by amiloride (−11.6 ± 1.7%). Spironolactone treatment did not improve the lack of flow-mediated response of HTN vessels (0.5 ± 0.7%), and was unaffected by amiloride (−0.4 ± 1.3%). Conclusions: Vascular ENaC activity augments flow-mediated constriction of mesenteric arteries. The attenuation of flow-mediated responsiveness in experimental RAAS-driven HTN is linked, in part, to a reduction in vascular ENaC activity. Spironolactone augments flow-mediated responsiveness of NTN vessels, although this may not be through increased ENaC activity. Initiation of spironolactone treatment at a late stage of HTN doesn’t appear to modulate ENaC function or re-establish normal vascular function.

Sex differences in obesity-induced hypertension and vascular dysfunction: a protective role for estrogen in adipose tissue inflammation?

Obesity is a potent predictor of cardiovascular disease and associated risk factors, including hypertension. Systemic inflammation has been suggested by a number of studies to be an important link between excess adiposity and hypertension, yet the majority of the studies have been conducted exclusively in males. This is problematic since women represent ∼53% of hypertensive cases and are more likely than men to be obese. There is a growing body of literature supporting a central role for immune cell activation in numerous experimental models of hypertension, and both the sex of the subject and the sex of the T cell have been shown to impact blood pressure (BP) responses to hypertensive stimuli. Moreover, sex steroid hormones play an important role in energy homeostasis, as well as in the regulation of immune responses; estrogen, in particular, has a well-known impact on both cardiovascular and metabolic disorders. Therefore, the purpose of this review is to examine whether sex or sex hormones regulate the role of the immune system in the development of hypertension and related vascular dysfunction in response to metabolic changes and stimuli, including a high-fat diet.

Attenuation of hypertension and renal damage in renovascular hypertensive rats by iron restriction.

Iron is a catalyst in the formation of reactive oxygen species. Oxidative stress is associated with the pathogenesis of both human and experimental animal models of renovascular hypertension. We hypothesized that iron is involved in the pathogenesis of renovascular hypertension and that iron restriction may affect the pathogenesis of renovascular hypertension via the inhibition of oxidative stress. Herein, we investigated the effect of iron restriction on hypertension and renal damage in a rat model of two-kidney one-clip (2K1C) renovascular hypertension. Renovascular hypertension was induced by 2K1C in male Sprague-Dawley rats. At the day of clipping, 2K1C rats were divided into untreated (2K1C) and dietary iron-restricted groups (2K1C+IR). The 2K1C rats showed hypertension after the day of clipping, whereas dietary iron restriction attenuated the development of hypertension. Vascular hypertrophy and the increased fibrotic area were suppressed in the 2K1C+IR group. The clipped kidney developed renal atrophy in both the 2K1C and 2K1C+IR groups after clipping. However, the unclipped kidney showed renal hypertrophy in the 2K1C and 2K1C+IR groups, and the extent was less in the 2K1C+IR group. The 2K1C rats exhibited glomerulosclerosis and tubulointerstitial fibrosis in the unclipped kidney, whereas these changes were attenuated by an iron-restricted diet. Importantly, proteinuria was decreased in the 2K1C+IR group, along with decreased urinary 8-hydroxy-2'-deoxyguanosine excretion and superoxide production of the unclipped kidney. Moreover, the expression of nuclear mineralocorticoid receptor in the unclipped kidney of the 2K1C rats was attenuated by iron restriction. These data indicate a novel effect of iron restriction on hypertension and renal damage in renovascular hypertension.

The beneficial effects on blood pressure, dyslipidemia and oxidative stress of Sambucus nigra extract associated with renin inhibitors

Context: The health effects of Sambucus nigra L. (Caprifoliaceae) could be due to polyphenols whose modes of action differ from the traditional one proposed for exogenous antioxidants.Objective: The study emphasizes the effects of the association between the renin inhibitor and the polyphenolic extract on biochemical parameters and systolic (TAS) and diastolic (TAD) blood pressure within an L NAME-induced experimental model of arterial hypertension (AHT).Materials and methods: The polyphenols are extracted with ethanol from isolated and purified vegetable material represented by the mature fruit of the S. nigra with a dosage of 0.046 g/kg body weight (PS), every 2 days, for 8 weeks. The dose represents 1/20 of LD50. The Wistar white rat blood pressure values were recorded using a CODA™ system, which uses a non-invasive blood pressure measuring method.Results and discussion: The total antioxidant capacity levels were significantly decreased (p < 0.001) in AHT group as compared to the rats in the AHT + PS group. A combination of a renin inhibitor (Aliskiren) and polyphenolic extract generated a superior antioxidant effect compared to administering the two separately. Both TAS and TAD in rats with drug-induced hypertension were reduced by polyphenolic extract. The homogeneous values of TAS record a significant decrease (p < 0.001) of the average values in AHT + PS group or AHT + Aliskiren group.Conclusion: The combination of two different classes of substances, namely, renin inhibitors and natural polyphenol extracts, reduces arterial pressure and also might reduce the side effects of the major classes of antihypertensive agents and improve the quality of live.

Inflammatory bowel and oxidative stress changes in an experimental model of portal hypertension: action of N-acetylcysteine

IntroductionPortal hypertension (PH) is characterized by vasodilatation in the portal system and the bowel is one of the severely affected organs. N-acetylcysteine (NAC) is a molecule with important properties and widely used in clinical practice. ObjectiveTo evaluate NAC action in the bowel of animals submitted to the animal model of partial portal vein ligation (PPVL). Methods18 male Wistar rats were divided into three experimental groups (n=6): sham-operated (SO), PPVL, and PPVL+NAC. On the 8th day after surgery, N-acetylcysteine (10mg/kg, ip) was administered daily for 7 days. On the 15th day the animals’ bowel was collected for oxidative stress analysis, immunohistochemistry and Western blot. We evaluated the expression of NF-KB and TNF-α by immunohistochemistry and of iNOS by Western blot. Lipid peroxidation was assessed by TBARS technique, and the activities of antioxidant enzymes superoxide dismutase (SOD) and glutation peroxidase (GPx) were checked. ResultsWe observed an increased expression of NF-KB and TNF-α in PPVL group, and an increased iNOS expression assessed by Western blot. NAC reduced the expression of all proteins evaluated. We also observed an increase in oxidative stress in the bowel of mice PPVL group compared to controls (SO), and NAC was effective in reducing these values in PPVL+NAC group. Also, a reduction in the activity of SOD and GPx enzymes was observed in the diseased group, and NAC was able to restore the activity of the enzymes assessed. ConclusionWe suggest the anti-inflammatory and antioxidant action of NAC in the bowel of animals submitted to PPVL model.

Morus alba extract modulates blood pressure homeostasis through eNOS signaling.

Morus alba is a promising phytomedicine cultivated in oriental countries that is extensively used to prevent and treat various cardiovascular problems. To date, despite its beneficial effects, the molecular mechanisms involved remain unclear. Thus, we investigate the vascular and haemodynamic effects of Morus alba extract in an experimental model focusing our attention on the molecular mechanisms involved. Through vascular reactivity studies, we demonstrate that Morus alba extract evokes endothelial vasorelaxation through a nitric oxide-dependent pathway. Our molecular analysis highlights an increase in endothelial nitric oxide synthase (eNOS) phosphorylation. In vivo administration of Morus alba extract reduces blood pressure levels exclusively in wild-type mice, whereas it fails to evoke any haemodynamic effects in eNOS-deficient mice. Molecular analyses revealed that its beneficial action on vasculature is mediated by the activation of two important proteins that act as stress sensors and chaperones: PERK and heat shock protein 90. Finally, Morus alba extract exerts antihypertensive action in an experimental model of arterial hypertension. Through its action on eNOS signaling, Morus alba extract could act as a food supplement for the regulation of cardiovascular system, mainly in clinical conditions characterized by eNOS dysfunction, such as arterial hypertension.

Nebivolol and Endothelial Dysfunction in Patients With Essential Hypertension: A Reputation Saver of β‐Blockers?

We have read with great interest the recently published article by Neuman and coworkers1 in which they hypothesized that nebivolol, a selective β1-antagonist that stimulates nitric oxide (NO), improves endothelial function in African Americans with hypertension when compared with metoprolol. In that well-designed study, the authors found evidence for NO bioavailability at rest during treatment with both nebivolol and metoprolol succinate in hypertensive African American patients, with a clear trend for a greater contribution of NO during nebivolol therapy. Moreover, after combined blockade of NO and endothelium-derived hyperpolarizing factor (EDHF), there was significantly greater vasoconstriction during nebivolol compared with metoprolol therapy, suggesting a greater contribution of both NO and EDHF combined to resting vasomotor tone during nebivolol treatment. Moreover, the contribution of NO to exercise-induced vasodilation was greater during treatment with nebivolol compared with metoprolol succinate. Nebivolol is a third-generation, β1-adrenergic receptor antagonist that has vasodilatory properties both in animals and humans independent of β1-receptor antagonism and related to β3-receptor agonist effects.2-5 It is a racemic mixture of D- and L-enantiomers, of which D-nebivolol is considered to be a highly selective β-adrenergic receptor antagonist.5-8 It was demonstrated that nebivolol stimulates NO release through both β3-receptor and adenosine triphosphate–dependent, P2Y-receptor activation.3, 9-12 In a well-designed clinical study, Tzemos and coworkers13 analyzed whether nebivolol could improve endothelial dysfunction in patients with essential hypertension. They showed that nebivolol/bendrofluazide increased both stimulated and basal endothelial NO release, whereas, for the same degree of blood pressure control, atenolol/bendrofluazide had no effect on NO bioactivity; therefore, they concluded that nebivolol may offer additional vascular protection in treating hypertension.13 Moreover, Oelze and coworkers14 demonstrated that nebivolol but not metoprolol improved endothelial function and reduced vascular oxidative stress in an experimental model of AngII-induced hypertension. These effects were associated with a normalization of the expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits Nox1, Nox2, p22phox, p47phox, p67phox, and Rac1 and an inhibition of NOS III uncoupling in a rat hypertension model. More importantly, they found that nebivolol but not metoprolol inhibited activation of vascular NADPH oxidase and were able to dissociate an already assembled and active membrane-associated NADPH oxidase complex. These observations indicate that nebivolol, in addition to its β1-receptor–blocking and NO-releasing effects, possesses substantial inhibitory effects on vascular oxidative stress, all of which may beneficially influence endothelial dysfunction because of oxidative stress in the setting of arterial hypertension.14 It is well-known that essential hypertension is associated with endothelial dysfunction, and with greater oxidative stress producing free oxygen radicals that contribute to the decrease in NO bioavailibility. Elevated plasma levels of malondialdehyde, a final product of lipid peroxidation and an index of oxidative stress, have been demonstrated in patients with essential hypertension.15, 16 Concordantly, our study group previously found that nebivolol, differently from metoprolol, improved oxidative stress and insulin sensitivity, decreased plasma sP-selectin, and increased adiponectin levels in hypertensive patients.17 From that standpoint, we concluded that nebivolol may significantly improve endothelial dysfunction in hypertensive patients. However, our study population had no African American patients, unlike the patient population from the study by Neumann and coworkers. In conclusion, nebivolol has beneficial effects on endothelial function mainly by increasing NO bioavailability. We strongly believe that although standard β-blockers are falling out of favor nowadays, perhaps the new generation of β-blockers such as nebivolol may “rescue” the reputation of these agents in the near future. There are no conflicts of interest to declare.

Effects of the Water Extracts of Mantidis Ootheca, Rosa Laevigata, and Imperata Cylindrica on Blood Pressure in Renovascular Hypertension Induced by 2K 1C

The aim of the present study is to investigate the hypotensive effect of Mantidis ootheca (WMO), Rosa laevigata (WIC), and Imperata cylindrica (WRL) in renovascular hypertension rats. Experimental hypertension model is 2-kidney and 1-clip (2K1C) induced rats. 2K1C rats were treated with WMO, WIC, and WRL at dose of 100 mg/kg/day orally for 3 weeks, respectively. Treatment groups with WMO, WIC, and WRL significantly lowered blood pressure. Interestingly, WMO, WIC, and WRL ameliorated endothelium-dependent and independent vascular relaxation in the phenylephrine-precontracted thoracic aorta in hypertension models. In addition, 2K1C-induced hypertension model increased plasma renin activity, however, WMO, WIC, and WRL attenuated those activities. These results suggest that WMO, WIC, and WRL ameliorates vascular dysfunction in 2K1C-induced hypertension models via the regulation of nitric oxide and renin-angiotensin-aldosterone system.

Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats.

The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6 Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature.

G Protein‐Coupled Receptor (GPCR) Expression in Pulmonary Artery Smooth Muscle Cells of Human and Experimental Models of Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) occurs as a primary (idiopathic) disease (IPAH) and secondary to various conditions. Both types are characterized by increased pulmonary vascular resistance and remodeling of the pulmonary artery, which derives in part from the proliferation of pulmonary artery smooth muscle cells (PASMCs), and can lead to right ventricular (RV) heart failure. Current treatments for PAH are inadequate, especially in terms of impact on mortality; thus, new therapies are needed. Animal models that mimic features of human PAH have been used to assess pathophysiology and evaluate treatments for PAH and include the exposure of rodents to chronic hypoxia (in the absence or presence of the VEGFR inhibitor SU5416) or treatment of rats with monocrotaline. Our studies are testing the hypothesis that previously unrecognized G protein‐coupled receptors (GPCRs) may contribute to PAH pathophysiology and may be new therapeutic targets. To begin to test this hypothesis, we used TaqMan® GPCR arrays as an unbiased approach to identify and quantify GPCRs in PASMCs of humans, rats and mice, including from patients with PAH and experimental PAH animal models. Development of PAH and RV hypertrophy in the animal models was confirmed by immunostaining/histology and quantified using the Fulton index (the [right ventricle]/[left ventricle + septum] weight). We found that PASMCs express &gt;100 GPCRs and that the GPCR expression profiles of mouse and rat PASMCs are similar to that of human PASMCs. Moreover, we find numerous changes (of at least 2‐fold) in GPCR expression of PASMCs from PAH patients compared to control PASMCs. GPCRs with altered expression include receptors that link to G proteins whose signaling effectors (e.g., cAMP, Ca++, etc.) are predicted to regulate PASMC proliferation and tone. These results show that PASMCs express many more GPCRs than previously known and that the GPCR expression profile differs in PAH‐PASMCs. GPCRs with altered expression may contribute to altered function in PAH and thus may be novel therapeutic targets for this disease.Support or Funding InformationSupported by DOD AWARD: No. W81XWH‐14‐1‐0372

Different regulation of miR-29a-3p in glomeruli and tubules in an experimental model of angiotensin II-dependent hypertension: potential role in renal fibrosis.

The aim of this study was to evaluate the role of the angiotensin II (Ang II) induced-differential miRNA expression in renal glomerular and tubulo-interstitial fibrosis in an experimental model of Ang II-dependent hypertension. To clarify this issue, Sprague Dawley rats were treated with Ang II (200ng/kg per minute, n=15) or physiological saline (n=14) for 4weeks. Systolic blood pressure and albuminuria were measured every 2weeks. At the end of the experimental period, renal glomerular and tubulo-interstitial fibrosis was evaluated by histomorphometric analysis, after Sirius-Red and Masson's trichrome staining. Ang II increased systolic blood pressure (P<0.0001), albuminuria (P<0.01) and both glomerular and tubulo-interstitial fibrosis (P<0.01). Using laser capture microdissection and miRNA microarray analysis this study showed that miR-29a-3p was down-regulated in renal tubules and up-regulated in glomeruli. Real-time polymerase chain reaction (PCR) experiments confirmed in Ang II-treated rats a down-regulation of miR-29a-3p in tubules (P<0.01), while no significant changes were observed in glomeruli. Matrix metalloproteinase-2 (MMP-2) was identified as putative miR-29a-3p target (by TargetScan, miRanda, Tarbase software) and functionally confirmed by luciferase activity assay. These data demonstrate that the effects of Ang II on miR-29a-3p expression in renal tubules is different from the one exerted in the glomeruli and that miR-29a-3p targets MMP-2. These results suggest that the development of renal fibrosis at glomerular and tubulo-interstitial level depends on different molecular mechanisms.

Novel Therapeutic Targets for Phosphodiesterase 5 Inhibitors: current state-of-the-art on systemic arterial hypertension and atherosclerosis.

The usefulness of selective inhibitors of phosphodiesterase 5 (PDE5) is well known, first for the treatment of male erectile dysfunction and more recently for pulmonary hypertension. The discovery that PDE5 is present in the systemic artery endothelium and smooth muscle cells led investigators to test the extra sexual effects of sildenafil, the first and most investigated PDE5 inhibitor, in diseases affecting the systemic arteries. Cumulative data from experimental and clinical studies have revealed beneficial effects of sildenafil on systemic arterial hypertension and its target organs, such as the heart, kidneys and vasculature. An important effect of sildenafil is reduction of hypertension and improvement of endothelial function in experimental models of hypertension and hypertensive subjects. Interestingly, in angiotensin-dependent hypertension, its beneficial effects on endothelial and kidney dysfunctions seem to at least in part be caused by its ability to decrease the levels of angiotensin II and increase angiotensin 1-7, in addition to improving nitric oxide bioavailability and diminishing reactive oxygen species. Another remarkable finding on the effects of sildenafil comes from studies in apolipoprotein E knockout mice, a model of atherosclerosis that closely resembles human atherosclerotic disease. In this review, we focus on the promising beneficial effects of sildenafil for treating systemic high blood pressure, especially resistant hypertension, and the endothelial dysfunction that is present in hypertension and atherosclerosis.

The Potential Role of Catheter-Based Renal Sympathetic Denervation in Chronic and End-Stage Kidney Disease.

Sympathetic activation is a hallmark of chronic and end-stage renal disease and adversely affects cardiovascular prognosis. Hypertension is present in the vast majority of these patients and plays a key role in the progressive deterioration of renal function and the high rate of cardiovascular events in this patient cohort. Augmentation of renin release, tubular sodium reabsorption, and renal vascular resistance are direct consequences of efferent renal sympathetic nerve stimulation and the major components of neural regulation of renal function. Renal afferent nerve activity directly influences sympathetic outflow to the kidneys and other highly innervated organs involved in blood pressure control via hypothalamic integration. Renal denervation of the kidney has been shown to reduce blood pressure in many experimental models of hypertension. Targeting the renal nerves directly may therefore be specifically useful in patients with chronic and end-stage renal disease. In this review, we will discuss the potential role of catheter-based renal denervation in patients with impaired kidney function and also reflect on the potential impact on other cardiovascular conditions commonly associated with chronic kidney disease such as heart failure and arrhythmias.

A New Animal Model to Study Endogenous Cardiotonic Steroids and the Progression of Cardiovascular Events in Salt-Sensitive Hypertension.

The Dahl salt-sensitive rat is a well-established model to study essential hypertension. We first described a subgroup of these rats based on the unique response pattern in systolic blood pressure during the first weeks of exposure to a high salt diet that included cataract formation. We classified this group as cataract-prone Dahl salt-sensitive rat. We also were able to predict and prevent cataract formation in these rats. Further studies showed an inhibition of lens Na, K-ATPase activity which may be in part responsible for the cataract formation. Other studies in Dahl salt-sensitive rats maintained on a high salt diet have also shown decreased Na, K-ATPase activity in several tissues and increased levels of endogenous circulating Na, K pump inhibitors. For over 20 years, endogenous cardiotonic steroids have been postulated to inhibit Na, K-ATPase in both humans as well as in experimental animal models of hypertension. Recent findings have shown results suggesting that there are several forms of cardiotonic steroids with minor differences in structural functionalities, site of production, and specific pump selectivity. We present original data that supports a role for cardiotonic steroids in disease progression related to increased salt-sensitivity. We found increased levels of free endogenous cardiotonic steroids in those rats that were classified as cataract-prone according to their initial systolic blood pressure response to a high salt intake when compared to non-cataract prone Dahl salt-sensitive rats and their control Dahl salt-resistant rats. The cataract-prone Dahl salt-sensitive rat is an animal model that can help and contribute to open a new door to possibly elucidate the role of endogenous cardiotonic steroids in the pathogenesis and progression of diseases related to salt-sensitive hypertension.

Chronic Activation of Heme Free Guanylate Cyclase Leads to Renal Protection in Dahl Salt-Sensitive Rats.

The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophasphate (cGMP)-signalling pathway is impaired under oxidative stress conditions due to oxidation and subsequent loss of the prosthetic sGC heme group as observed in particular in chronic renal failure. Thus, the pool of heme free sGC is increased under pathological conditions. sGC activators such as cinaciguat selectively activate the heme free form of sGC and target the disease associated enzyme. In this study, a therapeutic effect of long-term activation of heme free sGC by the sGC activator cinaciguat was investigated in an experimental model of salt-sensitive hypertension, a condition that is associated with increased oxidative stress, heme loss from sGC and development of chronic renal failure. For that purpose Dahl/ss rats, which develop severe hypertension upon high salt intake, were fed a high salt diet (8% NaCl) containing either placebo or cinaciguat for 21 weeks. Cinaciguat markedly improved survival and ameliorated the salt-induced increase in blood pressure upon treatment with cinaciguat compared to placebo. Renal function was significantly improved in the cinaciguat group compared to the placebo group as indicated by a significantly improved glomerular filtration rate and reduced urinary protein excretion. This was due to anti-fibrotic and anti-inflammatory effects of the cinaciguat treatment. Taken together, this is the first study showing that long-term activation of heme free sGC leads to renal protection in an experimental model of hypertension and chronic kidney disease. These results underline the promising potential of cinaciguat to treat renal diseases by targeting the disease associated heme free form of sGC.

The Effect of Magnesium on Visual Evoked Potentials in L-NAME-Induced Hypertensive Rats.

In the literature, although there are many studies regarding complications of hypertension, information concerning its influence on visual evoked potentials (VEPs) is limited. This study aims to clarify the possible therapeutic effects of the preferential magnesium (Mg) treatment on VEPs in an experimental hypertension model. Rats were divided into four groups as follows: control, Mg treated (Mg), N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension, and L-NAME hypertension + Mg treated (L-NAME + Mg). Hypertension was induced by L-NAME which was given to rats orally over 6weeks (25mg/kg/day in drinking water). A magnesium-enriched diet (0.8g/kg) was given to treatment groups for 6weeks. Systolic blood pressure (SBP) was determined by using the tail-cuff method. Flash VEPs were recorded. Our results revealed that the SBP was significantly increased in the L-NAME group compared to control. Magnesium treatment significantly attenuated SBP in the hypertensive rats compared to the L-NAME group. The mean latencies of P1, N1, P2, N2, and P3 components were significantly prolonged in hypertensive rats compared to control. Treatment with Mg provided a significant decrease in the latencies of P1, N1, P2, N2, and P3 potentials in the L-NAME + Mg group compared to the L-NAME group. Plasma Mg levels were increased in the L-NAME + Mg group compared to the L-NAME group. No change was detected in the Mg levels of the brains in all experimental groups. Magnesium treatment had no effect on the brain nitrate/nitrite and thiobarbituric acid-reactive substances (TBARS) levels in hypertensive rats compared to non-treated rats. There was a positive correlation between the brain TBARS levels and SBP of the rats. The present study suggests that Mg supplementation has the potential to prevent VEP changes in the L-NAME-induced hypertension model.

Progenitor Cells, Bone Marrow–Derived Fibrocytes and Endothelial-to-Mesenchymal Transition

See related article, pp 461–468 Tissue fibrosis, defined as an excessive accumulation of extracellular matrix (ECM) components leading to the destruction of organ architecture and impaired function, affects virtually every tissue and organ in the body, including the arteries. Vascular fibrosis of small and large arteries contributes to arterial remodeling, important in the development and complications of hypertension.1 Fibrogenesis is an active process that involves accumulation of structural proteins (collagen and fibronectin) and adhesion proteins (laminin and fibronectin), expression of adhesion molecules and integrins, and remodeling of the ECM.2 Healthy arteries are surrounded by perivascular adventitial tissue comprising collagens I and III in the intima, media, and adventitia, with collagen types I, III, IV, and V in the endothelial and vascular smooth muscle cell basement membranes.3 These fibrillar proteins maintain vascular integrity and normal vascular tone and function. In hypertension, accumulation of collagen and fibronectin and ECM reorganization lead to increased stiffness of the vessel wall.4 Initially, these processes are adaptive and reversible and may compensate for higher blood pressures, but with time and progressive increases in blood pressure, this becomes maladaptive and decompensated, leading to arterial stiffness that contributes to hypertension-associated target organ damage. These events have been demonstrated in many experimental models of hypertension and in hypertensive patients and have been attributed to activation of ERK1/2, p38mitogen-activated protein kinase, transforming growth factor-β, SMAD pathways, oxidative stress, and dysregulation of matrix metalloproteinases.2 Decreased activation of matrix metalloproteinases and increased activity of tissue inhibitors of metalloproteinase leads to reduced collagen turnover and consequent accumulation, with thickening and remodeling of the vascular wall. Vascular fibrosis is a dynamic and active phenomenon, where a proinflammatory, oxidative milieu, triggered by prohypertensive stimuli, lays the foundation for fibrosis and activation of ECM-producing cells. Until recently the process seemed fairly …

The features of expression of constitutive isoforms of the nitric oxide synthase in paraventricular and supraoptic nuclei of the hypothalamus in hypertension of different origins

Aim. The purpose was to evaluate the features of the neuronal and endothelial nitric oxide synthase expression pattern in supraoptic and magnocellular part of paraventricular nuclei of the hypothalamus in different models of hypertension. Materials and methods. The study was carried out on 20 Wistar male rats and 10 SHR male rats. There were two experimental models of hypertension used: the genetically predisposed to age-related hypertension SHR and rats with endocrine-saline model of hypertension (ESM). The object was the hypothalamus of rats. The immunohystochemical assay was used to determine the expression of NOS isoforms.Results showed the imbalance of constitutive NOS isoforms in SON and PVN of hypothalamus in both of SHR and ESM. The eNOS and nNOS expression pattern is dependent on etiological factor, topographical peculiarities of the nuclei and their functions.Conclusions. We believe the imbalance of constitutive NOS isoforms take part in the hypertension development, its progression and the formation of complications.