Garcinia dulcis Flower Extract Alters Gut Microbiota and Fecal Metabolomic Profiles of 2K1C Hypertensive Rats.

Garcinia dulcis (GD) extract has been found to have anti-hypertensive properties in animal studies. GD can also alter the colonic microbiota of rats. However, the effects of GD on changes in the gut microbiota and metabolomic profiles of normotensive and hypertensive rats are currently unknown. The purpose of this study was to evaluate changes in the gut microbiota and metabolomic profiles of 2-kidneys-1 clip (2K1C) hypertensive rats after feeding with GD flower extract. Rats were randomly divided into the following 4 groups: sham operation (SO) receiving corn oil (CO) (SO + CO), SO receiving GD (SO + GD), 2K1C receiving corn oil (2K1C + CO) and 2K1C receiving GD (2K1C + GD). Body weight (BW) and systolic blood pressure (SBP) were measured weekly throughout the study. Gut microbiota and fecal metabolites were measured from fresh fecal contents. Alpha diversity results demonstrated a similar microbial richness and diversity between groups. Linear discriminant analysis (LDA) effect size (LEfSe) suggested that GD treatment affected gut microbial community structure in both hypertensive and normotensive rats. Feeding rats with GD caused metabolic alterations that rendered 2K1C + GD rats similar to SO + CO and SO + GD rats. Findings suggest that the impact of GD on gut microbiota and metabolite profiles may be related to its anti-hypertensive properties.

Borneol reduces sympathetic vasomotor hyperactivity and restores depressed baroreflex sensitivity in rats with renovascular hypertension.

Borneol is a bicyclic monoterpene that has long been used in traditional Chinese medicine to increase blood-brain barrier permeability and has shown promising cardiovascular effects. The present study aimed to evaluate the effect of borneol on vascular tone, blood pressure, autonomic function, and baroreflex sensitivity in normotensive and hypertensive rats. A combination of in vitro and in vivo assays was performed in 2-kidneys-1-clip hypertensive rats (2K1C) and their controls (sham). We assessed the in vivo effect of oral treatment with borneol on blood pressure, heart rate, autonomic function, and baroreflex sensitivity in sham and 2K1C rats. Additionally, the vasorelaxant effect of borneol in the superior mesenteric artery isolated from rats and its mechanism of action were evaluated. Oral administration of borneol (125 mg/kg/day) reduced blood pressure, sympathetic vasomotor hyperactivity, and serum oxidative stress and improved baroreflex sensitivity in 2K1C rats. In vessel preparations, borneol induced endothelium-independent vasodilatation after precontraction with phenylephrine or KCl (60 mM). There was no difference in the vascular effect induced by borneol in either the 2K1C or the sham group. In addition, borneol antagonized the contractions induced by CaCl2 and reversed (S)-(-)-Bay K 8644-induced contraction. These data suggest that borneol presents antihypertensive effects in 2K1C rats, which is associated with its ability to improve autonomic impairment and baroreflex dysfunction. The borneol-induced relaxation in the superior mesenteric artery involves L-type Ca2+ channel blockade. This vascular action associated with the antioxidant effect induced by borneol may be responsible, at least in part, for the in vivo effects induced by this monoterpene.

Açaí Reverses Adverse Cardiovascular Remodeling in Renovascular Hypertension: A Comparative Effect With Enalapril.

ABSTRACT: This study aimed to determine if açai seed extract (ASE) could reverse pre-existing cardiovascular and renal injury in an experimental model of renovascular hypertension (2 kidney, 1 clip, 2K1C). Young male rats (Wistar) were used to obtain 2K1C and sham groups. Animals received the vehicle, ASE (200 mg/kg/d), or enalapril (30 mg/kg/d) in drinking water from the third to sixth week after surgery. We evaluated systolic blood pressure by tail plethysmography, vascular reactivity in the rat isolated mesenteric arterial bed (MAB), serum and urinary parameters, plasma inflammatory cytokines by ELISA, MAB expression of endothelial nitric oxide synthase and its active form peNOS by Western blot, plasma and MAB oxidative damage and antioxidant activity by spectrophotometry, and vascular and cardiac structural changes by histological analysis. ASE and enalapril reduced the systolic blood pressure, restored the endothelial and renal functions, and decreased the inflammatory cytokines and the oxidative stress in 2K1C rats. Furthermore, both treatments reduced vascular and cardiac remodeling. ASE substantially reduced cardiovascular remodeling and recovered endothelial dysfunction in 2K1C rats probably through its antihypertensive, antioxidant, and anti-inflammatory actions, supplying a natural resource for the treatment of renovascular hypertension.

Antihypertensive Effects of Gynura divaricata (L.) DC in Rats with Renovascular Hypertension.

Gynura divaricata (L.) DC (Compositae) (GD) could be found in various parts of Asia. It has been used as a traditional medicine to treat diabetes, high blood pressure, and other diseases, but its effects have not yet been scientifically confirmed. Therefore, we aimed at determining whether GD could affect renal function regulation, blood pressure, and the renin-angiotensin-aldosterone system (RAAS). Cardio-renal syndrome (CRS) is a disease caused by the interaction between the kidney and the cardiovascular system, where the acute or chronic dysfunction in one organ might induce acute or chronic dysfunction of the other. This study investigated whether GD could improve cardio-renal mutual in CRS type 4 model animals, two-kidney one-clip (2K1C) renal hypertensive rats. The experiments were performed on the following six experimental groups: control rats (CONT); 2K1C rats (negative control); OMT (Olmetec, 10 mg/kg/day)-treated 2K1C rats (positive control); and 2K1C rats treated with GD extracts in three different doses (50, 100, and 200 mg/kg/day) for three weeks by oral intake. Each group consisted of 10 rats. We measured the systolic blood pressure weekly using the tail-cuff method. Urine was also individually collected from the metabolic cage to investigate the effect of GD on the kidney function, monitoring urine volume, electrolyte, osmotic pressure, and creatinine levels from the collected urine. We observed that kidney weight and urine volume, which would both display typically increased values in non-treated 2K1C animals, significantly decreased following the GD treatment (###p < 0.001 vs. 2K1C). Osmolality and electrolytes were measured in the urine to determine how renal excretory function, which is reduced in 2K1C rats, could be affected. We found that the GD treatment improved renal excretory function. Moreover, using periodic acid-Schiff staining, we confirmed that the GD treatment significantly reduced fibrosis, which is typically increased in 2K1C rats. Thus, we confirmed that the GD treatment improved kidney function in 2K1C rats. Meanwhile, we conducted blood pressure and vascular relaxation studies to determine if the GD treatment could improve cardiovascular function in 2K1C rats. The heart weight percentages of the left atrium and ventricle were significantly lower in GD-treated 2K1C rats than in non-treated 2K1C rats. These results showed that GD treatment reduced cardiac hypertrophy in 2K1C rats. Furthermore, the acetylcholine-, sodium nitroprusside-, and atrial natriuretic peptide-mediated reduction of vasodilation in 2K1C rat aortic rings was also ameliorated by GD treatment (GD 200 mg/kg/day; p < 0.01, p < 0.05, and p < 0.05 vs. 2K1C for vasodilation percentage in case of each compound). The mRNA expression in the 2K1C rat heart tissue showed that the GD treatment reduced brain-type natriuretic peptide and troponin T levels (p < 0.001 and p < 0.001 vs. 2K1C). In conclusion, this study showed that GD improved the cardiovascular and renal dysfunction observed in an innovative hypertension model, highlighting the potential of GD as a therapeutic agent for hypertension. These findings indicate that GD shows beneficial effects against high blood pressure by modulating the RAAS in the cardio-renal syndrome. Thus, it should be considered an effective traditional medicine in hypertension treatment.

Myrtus communis improves cognitive impairment in renovascular hypertensive rats.

Myrtus communis has anti-inflammatory, neuroprotective and anticholinesterase activities yet there have been limited studies examining effects of Myrtus communis on cognitive functions. This study investigated the possible effects of Myrtus communis on changes in the cognitive functions of experimental renovascular hypertensive rats. Fifty-six Wistar-Albino rats were equally divided into 4 groups; sham-operated control, renovascular hypertension (RVH), ramipril (RVH + Ram) and Myrtus communis extract (RVH + MC) treatment groups. Goldblatt's 2-kidney 1-clip (2K1C) method was used to induce RVH. At the end of 9 weeks of treatment, after blood pressure recording, the animals underwent new object recognition test and Morris water maze (MWM) task. Following these tests, blood brain barrier (BBB) integrity was examined in 6 animals from each group. In the others after decapitation, osteopontin and interleukin (IL)-10 levels were measured in blood samples; while matrix metalloproteinase (MMP)-13, sodium potassium adenosine triphosphatase (Na+,K+-ATPase), cluster of differentiation (CD) 36, amyloid beta (Aß), neprilysin levels, and acetylcholinesterase (AChE) activity were investigated in hippocampal tissues. In RVH group, high systolic blood pressure decreased serum IL-10 levels, increased serum osteopontin levels and also impaired BBB permeability. Hippocampal MMP-13, CD36, Aß, neprilysin levels and AChE activities were elevated, while there were decreases in Na+,K+-ATPase levels. In new objet recognition test, discrimination index (DI) was determined as lower in saline-treated RVH group compared to control animals. In MWM training trail, 4th day performance in finding platform was significantly reduced in saline-treated RVH group compared to control group. RVH also decreased the time spent in target quadrant in probe test of MWM task compared to control group. In both of the treatment groups, all biochemical parameters were restored in parallel with improvement in the behavioral test performances. The results of this study suggest that Myrtus communis extract may improve the cognitive dysfunctions in hypertension through antihypertensive, anti-inflammatory and anticholinesterase activities.

Melatonin attenuates renal sympathetic overactivity and reactive oxygen species in the brain in neurogenic hypertension.

Sympathetic overactivation contributes to the pathogenesis of both experimental and human hypertension. We have previously reported that oxidative stress in sympathetic premotor neurons leads to arterial baroreflex dysfunction and increased sympathetic drive to the kidneys in an experimental model of neurogenic hypertension. In this study, we hypothesized that melatonin, a potent antioxidant, may be protective in the brainstem regions involved in the tonic and reflex control of blood pressure (BP) in renovascular hypertensive rats. Neurogenic hypertension was induced by placing a silver clip (gap of 0.2 mm) around the left renal artery, and after 5 weeks of renal clip placement, the rats were treated orally with melatonin (30 mg/kg/day) by gavage for 15 days. At the end of melatonin treatment, we evaluated baseline mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), and the baroreflex control of heart rate (HR) and rSNA. Reactive oxygen species (ROS) were detected within the brainstem regions by dihydroethidium staining. Melatonin treatment effectively reduced baseline MAP and sympathoexcitation to the ischemic kidney in renovascular hypertensive rats. The baroreflex control of HR and rSNA were improved after melatonin treatment in the hypertensive group. Moreover, there was a preferential decrease in ROS within the rostral ventrolateral medulla (RVLM) and the nucleus of the solitary tract (NTS). Therefore, our study indicates that melatonin is effective in reducing renal sympathetic overactivity associated with decreased ROS in brainstem regions that regulate BP in an experimental model of neurogenic hypertension.

Naringenin Ameliorates Renovascular Hypertensive Renal Damage by Normalizing the Balance of Renin-Angiotensin System Components in Rats.

Background: Naringenin, a member of the dihydroflavone family, has been shown to have a protective function in multiple diseases. We previously demonstrated that naringenin played a protective role in hypertensive myocardial hypertrophy by decreasing angiotensin-converting enzyme (ACE) expression. The kidney is a primary target organ of hypertension. The present study tested the effect of naringenin on renovascular hypertensive kidney damage and explored the underlying mechanism. Methods and Results: An animal model of renovascular hypertension was established by performing 2-kidney, 1-clip (2K1C) surgery in Sprague Dawley rats. Naringenin (200 mg/kg/day) or vehicle was administered for 10 weeks. Blood pressure and urinary protein were continuously monitored. Plasma parameters, renal pathology and gene expression of nonclipped kidneys were evaluated by enzyme-linked immunosorbent assay, histology, immunohistochemistry, real-time polymerase chain reaction, and Western blot at the end of the study. Rats that underwent 2K1C surgery exhibited marked elevations of blood pressure and plasma Ang II levels and renal damage, including mesangial expansion, interstitial fibrosis, and arteriolar thickening in the nonclipped kidneys. Naringenin significantly ameliorated hypertensive nephropathy and retarded the rise of Ang II levels in peripheral blood but had no effect on blood pressure. 2K1C rats exhibited increases in the ACE/ACE2 protein ratio and AT1R/AT2R protein ratio in the nonclipped kidney compared with sham rats, and these increases were significantly suppressed by naringenin treatment. Conclusions: Naringenin attenuated renal damage in a rat model of renovascular hypertension by normalizing the imbalance of renin-angiotensin system activation. Our results suggest a potential treatment strategy for hypertensive nephropathy.

Redox regulation and NO/cGMP plus K+ channel activation contributes to cardiorenal protection induced by Cuphea carthagenensis (Jacq.) J.F. Macbr. in ovariectomized hypertensive rats.

BACKGROUND: One of the medicinal plants widely used by the population in the treatment of hypertension, atherosclerosis and circulatory disorders is Cuphea carthagenensis (Jacq.) J.F. Macbr. (Lythraceae), popularly known as 'sete sangrias', being found in Brazil, Hawaii and in South Pacific Islands. Despite the widespread use of this species by the population, its long-term antihypertensive and cardioprotective activities have not yet been scientifically evaluated. PURPOSE: To evaluate the possible cardioprotective effects of an ethanol-soluble fraction obtained from C. carthagenensis (ESCC) using ovariectomized hypertensive rats to simulate a broad part of the female population over 50 years of age affected by hypertension. In addition, the molecular mechanism that may be responsible for its cardiorenal protective effects was also explored. METHODS: Female Wistar rats were submitted to surgical procedures of bilateral ovariectomy and induction of renovascular hypertension (two-kidneys, one-clip model). The sham-operated group was used as negative control. ESCC was obtained and a detailed phytochemical investigation about its main secondary metabolites was performed. ESCC was orally administered at doses of 30, 100 and 300  mg/kg, daily, for 28 days, 5 weeks after surgery. Enalapril (15  mg/kg) was used as standard antihypertensive drug. Renal function was evaluated on days 1, 7, 14, 21 and 28. At the end of the experimental period, systolic, diastolic, mean arterial pressure and heart rate were recorded. The activity of the tissue enzymatic antioxidant system, thiobarbituric acid reactive substances, nitrotyrosine, nitrite, aldosterone and vasopressin levels, in addition to the activity of the angiotensin-converting enzyme were also evaluated. Additionally, vascular reactivity to acetylcholine, sodium nitroprusside, and phenylephrine, and the role of nitric oxide, prostaglandins, and K+ channels in the vasodilator response of ESCC on the mesenteric vascular bed were also investigated. RESULTS: ESCC-treatment induced an important cardiorenal protective response, preserving renal function and preventing elevation of blood pressure and heart rate in ovariectomized hypertensive rats. In addition, prolonged treatment with ESCC recovered mesenteric vascular reactivity at all doses used. This effect was associated with an important modulation of the antioxidant defense system with a possible increase in NO bioavailability. Additionally, NO/cGMP activation and K+ channel opening-dependent vasodilator effect was observed on the mesenteric vascular bed, indicating a potential mechanism for the cardiovascular effects of ESCC. CONCLUSION: A 28-days ESCC treatment reduces the progression of the cardiorenal disease in ovariectomized hypertensive rats. These effects seem to be involved with an attenuation of oxidative and nitrosative stress, affecting endothelial nitric oxide production and K+ channel opening in smooth muscle cells.

Unilateral renal artery stenosis presenting as acute flaccid paralysis: a rare presentation.

Renovascular hypertension is one of the common causes of secondary hypertension. Here we report a case of patient of renal artery stenosis presenting to the emergency department as a case of acute flaccid paralysis. Renal artery stenosis has been associated with hypokalaemia, but rarely reported to be symptomatic. Initial correction of hypokalaemia leads to improvement of weakness and aetiological work up for hypokalaemia with hypertension revealed hypokalaemia due to hyperaldosteronism secondary to unilateral renal artery stenosis. The patient was managed medically with aldosterone antagonist in the anti hypertensive therapy and weakness did not recur despite withdrawal of potassium supplements. On follow-up, the patient was ambulatory with no signs of weakness, controlled blood pressure and normal potassium level.

Boldine Improves Kidney Damage in the Goldblatt 2K1C Model Avoiding the Increase in TGF-ß.

Boldine, a major aporphine alkaloid found in the Chilean boldo tree, is a potent antioxidant. Oxidative stress plays a detrimental role in the pathogenesis of kidney damage in renovascular hypertension (RVH). The activation of the renin-angiotensin system (RAS) is crucial to the development and progression of hypertensive renal damage and TGF-β is closely associated with the activation of RAS. In the present study, we assessed the effect of boldine on the progression of kidney disease using the 2K1C hypertension model and identifying mediators in the RAS, such as TGF-β, that could be modulated by this alkaloid. Toward this hypothesis, rats (n = 5/group) were treated with boldine (50 mg/kg/day, gavage) for six weeks after 2K1C surgery (pressure ≥ 180 mmHg). Kidney function was evaluated by measuring of proteinuria/creatininuria ratio (U prot/U Crea), oxidative stress (OS) by measuring thiobarbituric acid reactive substances (TBARS). The evolution of systolic blood pressure (SBP) was followed weekly. Alpha-smooth muscle actin (α-SMA) and Col III were used as markers of kidney damage; ED-1 and osteopontin (OPN) were used as markers of inflammation. We also explored the effect in RAS mediators, such as ACE-1 and TGF-β. Boldine treatment reduced the UProt/UCrea ratio, plasma TBARS, and slightly reduced SBP in 2K1C hypertensive rats, producing no effect in control animals. In 2K1C rats treated with boldine the levels of α-SMA, Col III, ED-1, and OPN were lower when compared to 2K1C rats. Boldine prevented the increase in ACE-1 and TGF-β in 2K1C rats, suggesting that boldine reduces kidney damage. These results suggest that boldine could potentially be used as a nutraceutic.

Diuretic herb Gomphrena celosioides Mart. (Amaranthaceae) promotes sustained arterial pressure reduction and protection from cardiac remodeling on rats with renovascular hypertension.

ETHNOPHARMACOLOGICAL RELEVANCE: Gomphrena celosioides Mart., belonging to the Amaranthaceae family, is a weed known as "perpétua," and its ethnopharmacological use is to treat of urinary tract disorders and kidney stones. Urinary tract disorders and kidney stones could include several pathological conditions such hypertension, diuretic and lithiasic problems. In the present work a model of renovascular hypertension was developed in vivo to investigate its usefulness as an antihypertensive drug. AIM OF THE STUDY: Evaluate the effect of acute and 28 day oral administration of G. celosioides extract on systemic arterial pressure and diuresis of renovascular-hypertensive rats, as well as its effect on cardiac remodeling and vascular reactivity. MATERIALS AND METHODS: Ethanolic extract of G. celosioides (EEGC) was used. To induce renovascular hypertension, adult male Wistar rats were submitted to Goldblatt 1K1C or 2K1C surgery. The mean arterial pressure (MAP) of 1K1C animals was directly assessed by cannulation of the carotid artery before and after intraduodenal acute administration of 30, 100 or 300 mg/kg of EEGC. For the 4-week assay, 2K1C animals received daily treatments with water (control group), 100 mg/kg EEGC or 15 mg/kg enalapril for 28 days. Diuresis and caudal blood pressure were assessed weekly, and at the 28th day of treatment, the MAP was directly quantified shortly before euthanasia. Internal organs were removed, weighed and routinely processed for histology and the left ventricle wall was measured. Blood was collected for biochemical analysis and mechanism investigation by quantification of angiotensin converting enzyme (ACE) activity and aldosterone, nitrite and thiobarbituric acid reactive substances (TBARS) concentration. The rats' mesenteric beds were isolated and cannulated to have their pressure variation assessed after crescent doses of phenylephrine (Phe), acetylcholine (ACh) and sodium nitroprusside (SNP). RESULTS: EEGC acutely reduced MAP the dose of 100 mg/kg. In the 4-week assay, EEGC acted as diuretic after acute administration after 1, 2, 3 and 4 weeks of treatment. EEGC also acted as an antihypertensive and it showed significant difference already after 1 week (and after 3 and 4 weeks) compared to control, with its MAP close to pre-surgery values at the end of the experiment. It promoted ACE inhibition, which led to lower aldosterone levels. The lower TBARS and higher nitrite concentration found in the EEGC group suggest antioxidant activity and NO maintenance. Moreover, EEGC counteracted the impairment of vascular reactivity induced by renovascular hypertension. The extract group presented thinner left ventricle wall compared to the control, meaning reduced hypertension-induced cardiac remodeling. CONCLUSIONS: The G. celosioides diuretic effect is maintained on renovascular hypertensive rats and can reduce the blood pressure after the first week of treatment by inhibiting ACE and these effects are longstanding and strong enough to promote protection against cardiac remodeling. Therefore, it shows potential as an antihypertensive drug.

Carthamus tinctorius L. extract improves hemodynamic and vascular alterations in a rat model of renovascular hypertension through Ang II-AT1R-NADPH oxidase pathway.

Carthamus tinctorius L. (CT) is widely used in Asian countries as a beverage and in folk medicine. The effects of CT extract on hemodynamics, vascular remodeling, the renin-angiotensin system (RAS) and oxidative stress in the two-kidney, one clip (2K-1C) hypertensive rat model were investigated. Renovascular hypertension was induced in male Sprague-Dawley rats and were treated with CT extract (500mg/kg/day) or captopril (5mg/kg/day) or vehicle for four weeks. CT extract or captopril reduced blood pressure, hindlimb vascular resistance, and increased hindlimb blood flow in 2K-1C hypertensive rats (p<0.05). Increases in aortic wall thickness, cross-sectional area and collagen deposition in 2K-1C rats were alleviated with CT extract or captopril treatment (p<0.05). CT extract or captopril suppressed RAS activation, including elevated serum ACE activity, and plasma Ang II level and up-regulated aortic AT1R protein expression in 2K-1C rats (p<0.05). Furthermore, CT extract or captopril reduced vascular superoxide production, aortic NADPH oxidase subunit gp91phox expression and increased plasma nitric oxide metabolite levels in 2K-1C rats (p<0.05). These findings suggest that CT extract ameliorated hemodynamic alteration and vascular remodeling in 2K-1C hypertensive rats. Possible mechanisms may involve RAS inhibitor effects and potent antioxidant activity.

Effect of asiatic acid on the Ang II-AT1R-NADPH oxidase-NF-κB pathway in renovascular hypertensive rats.

Asiatic acid, a triterpenoid compound derived from Centella asiatica, has been demonstrated to have antioxidant and anti-inflammatory effects. The present study evaluated the effects of asiatic acid on hemodynamic alterations, renin-angiotensin system (RAS), oxidative stress, and inflammation in 2K-1C hypertensive rats. Renovascular hypertension was induced in male Sprague-Dawley rats and treated with vehicle, asiatic acid (30 mg/kg/day), or captopril (5 mg/kg/day) for 4 weeks. We observed that 2K-1C hypertensive rats exhibited hemodynamic alterations such as high blood pressure, heart rate, hindlimb vascular resistance, and low hindlimb blood flow. Signs of RAS activation, such as increased plasma angiotensin II and serum angiotensin-converting enzyme activity, enhanced AT1R protein expression, and suppressed AT2R expression was observed in 2K-1C hypertensive rats. Overproduction of vascular superoxide, high levels of plasma MDA, low levels of plasma nitric oxide metabolites (NOx), and upregulation of gp91phox protein expression were observed in hypertensive rats. Furthermore, inflammation was observed in hypertensive rats, as evidenced by increased plasma TNF-α, NF-κB, and phospho-NF-κB protein expression. Asiatic acid or captopril alleviated hemodynamic alterations, RAS activation, oxidative stress, and inflammation in 2K-1C hypertensive rats. These findings indicate that asiatic acid is an antihypertensive agent that ameliorates hemodynamic alterations in 2K-1C hypertensive rats. This effect may involve one or both of the following mechanisms: the direct effect of asiatic acid on RAS activation, oxidative stress and inflammation, and/or asiatic acid acting as an ACE inhibitor agent to inhibit the Ang II-AT1R-NADPH oxidase-NF-κB pathway.

Effect of Euterpe oleracea Mart. Seeds Extract on Chronic Ischemic Renal Injury in Renovascular Hypertensive Rats.

Previously, we have demonstrated that the seeds of Euterpe oleracia Mart. (açaí) are rich in polyphenols with antihypertensive and antioxidant properties. This study evaluated the renal protective effects of the hydroalcoholic extract obtained from the seeds of açaí (ASE) fruits in two-kidney, one-clip (2K1C) renovascular hypertension. Young male Wistar rats were used to obtain 2K1C and sham groups. Animals received ASE (200 mg/(kg·day) in drinking water) or vehicle for 40 days. We evaluated serum and urinary parameters, renal structural changes, and oxidative status. The increase in systolic blood pressure of the 2K1C group was accompanied by a decrease in left kidney volume and number of glomeruli, as well as an increase in glomerular volume and collagen deposition. ASE prevented the alterations of these parameters, except the reduced kidney volume. Serum levels of urea and creatinine and urinary protein excretion were increased in the 2K1C group and treatment with ASE improved all these functional parameters. The increased oxidative damage in the 2K1C group, assessed by lipid and protein oxidation, was prevented by ASE. The nitrite content and both expression and activity of antioxidant enzymes (superoxide dismutase-1, catalase, and glutathione peroxidase) were lower in the 2K1C group and restored by ASE. ASE substantially reduced renal injury and prevented renal dysfunction in 2K1C rats probably through its antihypertensive and antioxidant effects, providing a natural resource for treatment and prevention of renovascular hypertension-related abnormalities.

The Labdane Ent-3-Acetoxy-Labda-8(17), 13-Dien-15-Oic Decreases Blood Pressure In Hypertensive Rats / O Labdano Ácido Ent-3-Acetóxi-Labda-8(17), 13-Dieno-15-Óico Reduz Pressão Arterial Em Ratos Hipertensos

Abstract Background: Labdane-type diterpenes induce lower blood pressure via relaxation of vascular smooth muscle; however, there are no studies describing the effects of labdanes in hypertensive rats. Objective: The present study was designed to investigate the cardiovascular actions of the labdane-type diterpene ent-3-acetoxy-labda-8(17), 13-dien-15-oic acid (labda-15-oic acid) in two-kidney 1 clip (2K-1C) renal hypertension. Methods: Vascular reactivity experiments were performed in aortic rings isolated from 2K-1C and normotensive (2K) male Wistar rats. Nitrate/nitrite (NOx) measurement was performed in aortas by colorimetric assay. Blood pressure measurements were performed in conscious rats. Results: Labda-15-oic acid (0.1-300 µmol/l) and forskolin (0.1 nmol/l - 1 µmol/l) relaxed endothelium-intact and endothelium-denuded aortas from both 2K-1C and 2K rats. Labda-15-oic acid was more effective at inducing relaxation in endothelium-intact aortas from 2K pre-contracted with phenylephrine when compared to the endothelium-denuded ones. Forskolin was more potent than labda-15-oic acid at inducing vascular relaxation in arteries from both 2K and 2K-1C rats. Labda-15-oic acid-induced increase in NOx levels was lower in arteries from 2K-1C rats when compared to 2K rats. Intravenous administration of labda-15-oic acid (0.3-3 mg/kg) or forskolin (0.1-1 mg/kg) induced hypotension in conscious 2K-1C and 2K rats. Conclusion: The present findings show that labda-15-oic acid induces vascular relaxation and hypotension in hypertensive rats.

Resumo Fundamento: Diterpenos do tipo labdano induzem uma queda da pressão arterial por meio do relaxamento do músculo liso vascular; todavia, não há estudos que descrevam os efeitos de labdanos em ratos hipertensos. Objetivo: O presente estudo foi desenvolvido para investigar as ações cardiovasculares do labdano ácido ent-3-acetóxi-labda-8(17),13-dieno-15-óico (labda-15-óico) na hipertensão renal dois rins-1 clipe (2R-1C). Métodos: Foram feitos experimentos de reatividade vascular em anéis aórticos isolados de ratos machos 2R-1C e normotensos (2R). A medição de Nitrato/Nitrito (NOx) foi feita nas aortas por meio de ensaio colorimétrico. As medidas de pressão arterial foram feitas em ratos conscientes. Resultados: O ácido labda-15-óico (0,1 - 300 µmol/l) e a forscolina (0,1 nmol/l - 1 µmol/l) relaxaram as aortas com endotélio intacto e as aortas sem endotélio dos ratos 2R-1C e 2R. O labda-15-óico mostrou-se mais eficaz na indução do relaxamento em aortas com endotélio intacto de 2R pré-contraídas com fenilefrina em comparação àquelas sem endotélio. A forscolina mostrou-se mais potente do que o ácido labda-15-óico na indução do relaxamento vascular nas artérias tanto de ratos 2R-1C quanto de ratos 2R. O aumento dos níveis de NOx induzido pelo ácido labda-15-óico foi menor nas artérias de ratos 2R-1C em comparação a ratos 2R. A administração intravenosa de ácido labda-15-óico (0,3-3 mg/kg) ou forscolina (0,1-1 mg/kg) induziu hipertensão em ratos 2R-1C e 2R conscientes. Conclusão: Os presentes resultados mostram que o labda-15-óico induz relaxamento vascular e hipotensão em ratos hipertensos.

Antihypertensive activity of 80% methanol seed extract of Calpurnia aurea (Ait.) Benth. subsp. aurea (Fabaceae) is mediated through calcium antagonism induced vasodilation.

ETHNOPHARMACOLOGICAL RELEVANCE: Calpurnia aurea (Ait.) Benth. subsp. aurea (CASA) (Fabaceae) seeds are used to treat hypertension in Ethiopian folklore medicine, particularly by Shinasha, Agew-awi and Amhara people in northwest Ethiopia. However, the claim has so far not been substantiated scientifically. AIM OF THE STUDY: The study was conducted to evaluate the antihypertensive activity of 80% methanol extract of CASA in animal model of hypertension as well as its vasorelaxant effect and possible underlying mechanisms in isolated guinea pig aorta. MATERIAL AND METHODS: Hypotensive and antihypertensive effect of CASA extract was determined in vivo through the intravenous (iv) route in normotensive and hypertensive anesthetized rats using 2-kidney-1-clip (2K1C) rat model. Ex vivo, guinea pig thoracic aortic rings were isolated and suspended in organ bath, and the vasodepressor effects as well as the mechanism of action of the extract were studied by means of isometric tension recording experiments. RESULTS: The blood pressure fell dose-dependently and significantly in renal hypertensive and normotensive rats following i.v. administration, suggesting that the hydroalcoholic extract possesses hypotensive and antihypertensive effects. The extract also caused a dose-dependent relaxation of aorta pre-contracted with KCl at a concentration of 5-250mg/L, with a maximum relaxation of 92.1% achieved at 250mg/L. The relaxation mechanism was found to be independent of the muscarinic receptors, histamine receptors, ATP dependent K(+) channels, cyclooxygenase enzymes, cGMP/NO pathway and the endothelium system. The extract caused rightward shift of the Ca(++) dose-response curves, similar to that caused by verapamil, indicating that it produced vasorelaxation by inhibiting extracellular Ca(2+) influx. CONCLUSIONS: The findings demonstrate that the plant is endowed with antihypertensive effect, providing evidence for its traditional use. The effect may be, at least in part, due to dilation of blood vessels through blockage of Ca(2+) channels.

The Labdane Ent-3-Acetoxy-Labda-8(17), 13-Dien-15-Oic Decreases Blood Pressure In Hypertensive Rats.

BACKGROUND: Labdane-type diterpenes induce lower blood pressure via relaxation of vascular smooth muscle; however, there are no studies describing the effects of labdanes in hypertensive rats. OBJECTIVE: The present study was designed to investigate the cardiovascular actions of the labdane-type diterpene ent-3-acetoxy-labda-8(17), 13-dien-15-oic acid (labda-15-oic acid) in two-kidney 1 clip (2K-1C) renal hypertension. METHODS: Vascular reactivity experiments were performed in aortic rings isolated from 2K-1C and normotensive (2K) male Wistar rats. Nitrate/nitrite (NOx) measurement was performed in aortas by colorimetric assay. Blood pressure measurements were performed in conscious rats. RESULTS: Labda-15-oic acid (0.1-300 µmol/l) and forskolin (0.1 nmol/l - 1 µmol/l) relaxed endothelium-intact and endothelium-denuded aortas from both 2K-1C and 2K rats. Labda-15-oic acid was more effective at inducing relaxation in endothelium-intact aortas from 2K pre-contracted with phenylephrine when compared to the endothelium-denuded ones. Forskolin was more potent than labda-15-oic acid at inducing vascular relaxation in arteries from both 2K and 2K-1C rats. Labda-15-oic acid-induced increase in NOx levels was lower in arteries from 2K-1C rats when compared to 2K rats. Intravenous administration of labda-15-oic acid (0.3-3 mg/kg) or forskolin (0.1-1 mg/kg) induced hypotension in conscious 2K-1C and 2K rats. CONCLUSION: The present findings show that labda-15-oic acid induces vascular relaxation and hypotension in hypertensive rats.

Therapeutic evaluation of rutin in two-kidney one-clip model of renovascular hypertension in rat.

AIM: The current investigation, designed to investigate the role of rutin in two-kidney one-clip (2K1C) induced renovascular dysfunction associated with hypertension in rat. MAIN METHODS: The renovascular hypertension was developed by the application of vascular clip on left renal artery in rats; the right kidney was kept as such throughout the experimental protocol. The rutin (200 and 300 mg/kg; p.o.) and aliskiren (50mg/kg; p.o.) were administered for 9 consecutive days. The battery of pathophysiological tests i.e., systolic pressure, diastolic pressure and heart rate were performed to assess the anti-hypertensive effect of rutin. In addition, changes of kidney weight/body weight (KW/BW) ratio along with plasma renin content and renal tissue biomarkers i.e., thiobarbituric acid reactive substance (TBAR) and reduced glutathione (GSH) levels were estimated. KEY FINDINGS: The administration of rutin significantly (P<0.05) attenuated the 2K1C of left kidney induced elevated systolic and diastolic pressure in a dose dependent manner. In addition, it also reduces the ratio of KW/BW along with a decrease in plasma renin content, tissue TBARS and increase the GSH levels. There were no significant changes observed in heart rate. Similar results were observed in aliskiren treated group. SIGNIFICANCE: The anti-hypertensive effect of rutin may be a useful herbal medicine for the management of hypertension due to its potential free radical scavenging, inhibition of lipid peroxidation and plasma renin inhibitory action.

Combined Aliskiren and L-arginine treatment reverses renovascular hypertension in an animal model.

Renovascular hypertension is characterized by increased renal sympathetic activity, angiotensin II and by endothelial dysfunction. The purpose of this study was to determine the role of renal sympathetic nerve activity (RSNA) in mediating the anti-hypertensive effects of aliskiren (ALSK) and L-arginine (L-ARG) in a rat renovascular hypertension model. Hypertension was induced by clipping the right renal artery, and the following five groups were divided: SHAM operated; 2-kidney, 1-clip (2K1C); 2K1C plus ALSK; 2K1C plus L-ARG; and 2K1C plus ALSK+ L-ARG. The systolic blood pressure (SBP) of 2K1C rats increased from 114.4±5.2 to 204±12.7 mm Hg (P<0.05) and was only reduced by ALSK+L-ARG treatment (138.4±4.37 mm Hg). The 2K1C hypertension increased the baseline RSNA (SHAM: 62.4±6.39 vs. 2K1C: 97.4±8.43%). L-ARG or ALSK+L-ARG treatment significantly decreased baseline RSNA (2K1C L-ARG:70.7±2.39; 2K1C ALSK+L-ARG: 69.3±4.23%), but ALSK treatment alone did not (2K1C ALSK: 84.2±2.5%). Urinary water, Na(+), Cl(-) and urea excretion were similar in the 2K1C L-ARG, 2K1C ALSK+L-ARG and SHAM groups. The combination of ALSK+L-ARG restored urine flow and increased the glomerular filtration rate. The nNOS expression in the non clipped kidney was significantly increased in 2K1C ALSK+L-ARG rats. In conclusion, combined ALSK+L-ARG treatment normalizes SBP and prevents renal dysfunction in 2K1C hypertensive rats.

Venthamarai chooranam, a polyherbal Siddha medicine, alleviates hypertension via AT1R and eNOS signaling pathway in 2K1C hypertensive rats.

The present study was aimed to scientifically demonstrate the anti-hypertensive action of Venthamarai chooranam (VMC) in renal hypertensive rats. Two Kidney One Clip (2K1C) Goldblatt model was adopted to induce hypertension in rats. Male Sprague Dawley rats (270-320 g) were randomized into sham (n = 6), vehicle-treated 2K1C (n = 9) and VMC-treated 2K1C (400 mg/kg, p.o; n = 8) and monitored for nine weeks. Systolic blood pressure (SBP), plasma nitrate/nitrite, carotid endothelial nitric oxide synthetase (eNOS), renal angiotensin type 1 receptor (AT1R), angiotensin type 2 receptor (AT2R), TNFα, IL-6, thioredoxin 1 (TRX1), and thioredoxin reductase 1 (TRXR1) mRNA expressions were studied. VMC upregulated eNOS expression which in turn improved plasma nitric oxide and decreased SBP in hypertensive rats. It down-regulated AT1R and simultaneously upregulated AT2R expression in comparison to vehicle-treated 2K1C rats. Further, renal TNFα and IL-6 expressions were down-regulated while TRX1 and TRXR1 were upregulated by VMC. VMC potentially interacts with renin-angiotensin components and endothelial functions, and thereby exerts its antihypertensive action. This is the first study to demonstrate the mechanism of anti-hypertensive action of VMC in an animal model of renovascular hypertension.