Potential usefulness of methyl gallate in the treatment of experimental colitis.

Methyl gallate is a gallotannin widely distributed in nature. Previous studies have demonstrated its antioxidant, anti-inflammatory, antimicrobial and anti-tumor activities. In the present study, the activity of methyl gallate on experimental models of inflammatory bowel disease has been investigated. Experimental colitis was induced in Sprague-Dawley rats through the intracolonic instillation of an acetic acid solution (2 mL, 4% v/v). Methyl gallate (100 and 300 mg/kg, p.o.) and the reference drug mesalazine (100 mg/kg, p.o.) were tested. Methyl gallate induced a significant reduction in the colon weight/length ratio and macroscopic lesion score. Besides, the malondialdehyde content and the GSSG/GSH ratio were remarkably decreased. Furthermore, the administration of methyl gallate reduced the expression of COX2, IL-6, TNFα and the severity of microscopic tissue damage induced by acetic acid, while the mean goblet cell density was significantly higher in both the group treated with methyl gallate and the one treated with mesalazine, in comparison with untreated animals. The Na+K+ATPase pump activity was recovered in treated groups (control: 827.2 ± 59.6, colitis: 311.6 ± 54.8, methyl gallate 100 mg/kg: 642.2 ± 175.0, methyl gallate 300 mg/kg: 809.7 ± 100.6, mesalazine: 525.3 ± 81.7). Methyl gallate was also found to induce a significant reduction in the castor oil-induced intestinal motility in Swiss mice, decreasing the peristalsis by 74.5 and 58.82% at 100 and 300 mg/kg p.o., respectively. This compound also antagonized the jejunum contractions induced by Ach and CaCl2. This study demonstrates that methyl gallate exerts beneficial effects in a preclinical model of intestinal disorders.

Role of HDL in neutralizing the VLDL effect on endothelial dysfunction.

OBJECTIVE: It has been reported that LDL inhibits endothelium-dependent relaxation (EDR) and that HDL can neutralize this effect. However, the atherogenic properties of VLDL have been so far difficult to demonstrate. Studies on VLDL are controversial, and nothing is known about the role of HDL on potential VLDL vascular actions. We examined the effect of human VLDLs on EDR, and the role of HDL in this system. METHODS: VLDL (n=14) and LDL (n=6) were isolated from volunteer subjects. Normal HDL was obtained from one healthy donor. VLDL ability to inhibit ACh-induced vasorelaxation (10(-9)-10(-5)mM) on aortic rings previously precontracted by noradrenaline (10(-8)mM) was measured in the presence and absence of HDL. RESULTS: ACh-induced maximal relaxation (R%) was mildly, but not significantly attenuated in the presence of VLDL (72±7%), while LDL caused a significant inhibition (60±10%, p<0.05) when compared to incubation in the absence of lipoproteins. VLDLs were subdivided into 2 groups depending on their cholesterol/triglyceride ratio: 0.18-0.22 (n=8) was considered typical and 0.10-0.15, rich in triglycerides (VLDLRT, n=6). Typical VLDL had no effect on EDR (p=0.38), however R% from VLDLRT was lower (54±7%, p<0.01) similar to the one obtained with LDL (p=0.32). HDL showed favorable effects on EDR inhibition induced by the presence of VLDLRT (p<0.05.). CONCLUSION: Although typical VLDL did not cause endothelial dysfunction, triglyceride-enriched VLDL had inhibitory effect on EDR. It is proposed that alterations in VLDL composition would increase its atherogenic capacity. Moreover HDL appears to protect endothelium from VLDL action.

Hydroalcoholic extract of Urtica circularis: a neuropharmacological profile.

CONTEXT: The genus Urtica has been known since ancient times. It has known to be useful for the treatment of different human ailments. OBJECTIVE: The present work evaluated the neuropharmacological effects of a hydroalcoholic extract of Urtica circularis (Hicken) Sorarú (Urticaceae). materials and method: The effect on central nervous system of U. circularis hydroalcoholic extract (from leaves and stems) administered by the intraperitoneal route in mice was evaluated by several tests: Pentobarbital- and midazolam-induced hypnosis, open field, hole board, elevated plus-maze and forced swimming. Phytochemical analysis was performed by high-performance liquid chromatography. RESULTS: A total of 300 mg/kg i.p. of the extract produced a significant prolongation of pentobarbital- (40 mg/kg i.p.; 60.1 min versus 25.4 min) and midazolam- (50 mg/kg i.v.; 53.4 min versus 25.1 min) induced sleeping time. The extract's administration caused a marked reduction of the head-dipping response (DE50: 373 mg/kg i.p.) in the hole-board test. Urtica circularis extract (DE50: 46 mg/kg i.p.) reduced the spontaneous locomotor activity in the open field test. Flumazenil and atropine significantly antagonized the extract's effect on the locomotor activity. No motor coordination disturbance was observed in the rota rod test at any doses. In the forced swimming test, the extract did not produce any change in the immobility time and it had no significant effects in elevated plus maze test. The phytochemical analysis revealed the presence of chlorogenic acid, vanillic acid, caffeic acid, vicenin-2, p-cumaric acid, ferulic acid, vitexin and isovitexin. CONCLUSION: This study revealed that U. circularis hydroalcoholic extract possesses sedative activity, facilitating GABAergic and cholinergic transmission.

Vicenin-2, a potential anti-inflammatory constituent of Urtica circularis.

Vicenin-2 (1), a flavonoid glycoside, was isolated and identified from an ethanol extract of the aerial parts of Urtica circularis. This crude extract was found to possess significant anti-inflammatory activity in a carrageenan-induced rat hind paw edema model (41.5% inhibition at a dose of 300 mg/kg; ip). The effects of 1 on several inflammatory mediators were investigated. In cultured murine macrophages, this compound modified LPS-induced total nitrite and TNF-α production, in addition to the LPS-induced translocation of the nuclear factor NF-κB.

Heme oxygenase-1 overexpression fails to attenuate hypertension when the nitric oxide synthase system is not fully operative.

Heme oxygenase (HO) is an enzyme that is involved in numerous secondary actions. One of its products, CO, seems to have an important but unclear role in blood pressure regulation. CO exhibits a vasodilator action through the activation of soluble guanylate cyclase and the subsequent production of cyclic guanosine monophosphate (cGMP). The aim of the present study was to determine whether pathological and pharmacological HO-1 overexpression has any regulatory role on blood pressure in a renovascular model of hypertension. We examined the effect of zinc protoporyphyrin IX (ZnPP-IX) administration, an inhibitor of HO activity, on mean arterial pressure (MAP) and heart rate in sham-operated and aorta-coarcted (AC) rats and its interaction with the nitric oxide synthase (NOS) pathway. Inhibition of HO increased MAP in normotensive rats with and without hemin pretreatment but not in hypertensive rats. Pretreatment with NG-nitro-L-arginine methyl ester blocked the pressor response to ZnPP-IX, suggesting a key role of NOS in the cardiovascular action of HO inhibition. In the same way, AC rats, an experimental model of hypertension with impaired function and low expression of endothelial NOS (eNOS), did not show any cardiovascular response to inhibition or induction of HO. This finding suggests that eNOS was necessary for modulating the CO response in the hypertensive group. In conclusion, the present study suggests that HO regulates blood pressure through CO only when the NOS pathway is fully operative. In addition, chronic HO induction fails to attenuate the hypertensive stage induced by coarctation as a consequence of the impairment of the NOS pathway.

Strategies to apply 3Rs in preclinical testing.

Animal experimentation has been fundamental in biological and biomedical research. To guarantee the maximum quality, efficacy and/or safety of products intended for the use in humans in vivo testing is necessary; however, for over 60 years, alternative methods have been developed in response to the necessity to reduce the number of animals used in experimentation, to guarantee their welfare; resorting to animal models only when strictly necessary. The three Rs (Replacement, Reduction, and Refinement), seek to ensure the rational and respectful use of laboratory animals and maintain an adequate projection in terms of bioethical considerations. This article describes different approaches to apply 3Rs in preclinical experimentation for either research or regulatory purposes.

Genotoxic risk in humans and acute toxicity in rats of a novel oral high-dose coenzyme Q10 oleogel.

Coenzyme Q10 (CoQ10) supplementation has demonstrated to be safe and effective in primary and secondary CoQ10 deficiencies. Previously, we have designed a high-dose CoQ10 oleogel (1 g/disk) with excipients used in quantities that do not represent any toxic risk. However, it was necessary to demonstrate their safety in the final formulation. Following this purpose, an acute toxicity study of the oleogel in rats was performed. Furthermore, the genotoxic risk was evaluated in human volunteers after CoQ10 supplementation with oleogel and compared to the solid form (1 g/three 00-size-capsules). In addition, the general health status and possible biochemical changes of the participants were determined using serum parameters. Results suggested the absence of adverse effects caused by the interaction of the components in the oleogel formulation. Therefore, we conclude that the designed novel high-dose CoQ10 oleogel was safe for oral consumption.

Angiotensin II type 1 receptor is involved in hypertension and vascular alterations caused by environmental toxicant hexachlorobenzene.

Environmental hexachlorobenzene (HCB) increases blood pressure (BP) in female rats, causing alterations in arterial structure and function. Here we study the role of Angiotensin II receptor type 1 (AT1) in HCB-induced hypertension through the use of AT1 antagonist losartan. HCB-treated male rats showed a 22.7% increase in BP which was prevented by losartan. Losartan blocked HCB-induced changes in arterial morphology (decreased aorta cell number and increased wall thickness). Losartan also prevented HCB-induced alterations in artery relaxation by acetylcholine and nitroprusside but not the reduction in the maximum contraction by phenylephrine. Losartan rescued arterial molecular alterations caused by HCB (i.e. an increase in TGF-ß1 and AT1 expression and a decrease in eNOS expression and nitrite levels) and reduced hydrogen sulfide plasma concentration. In conclusion: in this work we demonstrate that AT1 activity is involved in HCB effects on the vascular system leading to hypertension.

Acute infusion of angiotensin II regulates organic cation transporters function in the kidney: its impact on the renal dopaminergic system and sodium excretion.

A close relationship between angiotensin II (ANG II) and the renal dopaminergic system (RDS) has been reported. Our aim was to study whether renal dopamine and ANG II can interact to modify renal sodium handling and then to elucidate the related mechanism. Anesthetized male Sprague-Dawley rats were used in experiments. ANG II, exogenous dopamine, and decynium-22 (or D-22, an isocyanine that specifically blocks electrogenic organic cation transporters, OCTs), were infused in vivo for 120 min. We analyzed renal and hemodynamic parameters, renal Na+, K+-ATPase levels, OCT activity, and urinary dopamine concentrations. We also evaluated the expression of D1 receptor, electroneutral organic cation transporters (OCTNs), and OCTs. ANG II decreased renal excretion of sodium in the presence of exogenous dopamine, increased Na+, K+-ATPase activity, and decreased the urinary dopamine concentration. D-22 treatment exacerbated the ANG II-mediated decrease in renal excretion of sodium and dopamine urine excretion but did not modify ANG II stimulation of Na+, K+-ATPase activity. The infusion of ANG II did not affect the expression of D1 receptor, OCTs, or OCTNs. However, the activity of OCTs was diminished by the presence of ANG II. Although ANG II did not alter the expression of D1 receptor, OCTs, and OCTNs in renal tissues, it modified the activity of OCTs and thereby decreased the urinary dopamine concentration, showing a novel mechanism by which ANG II decreases dopamine transport and its availability in the tubular lumen to stimulate D1 receptor. This study demonstrates a relationship between ANG II and dopamine, where both agents counteract their effects on sodium excretion.

Different protective actions of losartan and tempol on the renal inflammatory response to acute sodium overload.

The aim of this work was to study the role of local intrarenal angiotensin II (Ang II) and the oxidative stress in the up-regulation of pro-inflammatory cytokines expression observed in rats submitted to an acute sodium overload. Sprague-Dawley rats were infused for 2 h with isotonic saline solution (Control group) and with hypertonic saline solution alone (Na group), plus the AT1 receptor antagonist losartan (10 mg kg(-1) in bolus) (Na-Los group), or plus the superoxide dismutase mimetic tempol (0.5 mg min(-1) kg(-1)) (Na-Temp group). Mean arterial pressure, glomerular filtration rate, and fractional sodium excretion (FE(Na)) were measured. Ang II, NF-kappaB, hypoxia inducible factor-1 alpha (HIF-1 alpha), transforming growth factor beta1 (TGF-beta1), smooth muscle actin (alpha-SMA), endothelial nitric oxide synthase (eNOS), and RANTES renal expression was evaluated by immunohistochemistry. Ang II, NF-kappaB, and TGF-beta1 and RANTES early inflammatory markers were overexpressed in Na group, accompanied by enhanced HIF-1 alpha immunostaining, lower eNOS expression, and unmodified alpha-SMA. Losartan and tempol increased FE(Na) in sodium overload group. Although losartan reduced Ang II and NF-kappaB staining and increased eNOS expression, it did not restore HIF-1 alpha expression and did not prevent inflammation. Conversely, tempol increased eNOS and natriuresis, restored HIF-1 alpha expression, and prevented inflammation. Early inflammatory markers observed in rats with acute sodium overload is associated with the imbalance between HIF-1 alpha and eNOS expression. While both losartan and tempol increased natriuresis and eNOS expression, only tempol was effective in restoring HIF-1 alpha expression and down-regulating TGF-beta1 and RANTES expression. The protective role of tempol, but not of losartan, in the inflammatory response may be associated with its greater antioxidant effects.

Evaluation of antinociceptive, antinflammatory activities and phytochemical analysis of aerial parts of Urtica urens L.

The antinociceptive and antiinflammatory activities of the ethanol extract of the aerial part of Urtica urens were determined by experimental animal models. U. urens extract was found to possess significant antinociceptive activity in chemically induced mouse pain models (ED50 39.3 mg/kg: 17.2-74.5 mg/kg) in the writhing test and 62.8% inhibition of the licking time in the late phase of the formalin test at a dose of 500 mg/kg p.o. and antiinflammatory activity on carrageenan-induced rat hind paw edema (41.5% inhibition at a dose of 300 mg/kg i.p.). The extract displayed activity neither in the thermal model of pain nor in the topical inflammation model. The major component of the extract was determined as chlorogenic acid (670 mg/1000 g dry weight) and could be partly responsible for this activity.

Effects of third-generation ß-blockers, atenolol or amlodipine on blood pressure variability and target organ damage in spontaneously hypertensive rats.

BACKGROUND: ß-blockers are no longer considered as first-line antihypertensive drugs due to their lower cardioprotection. METHOD: Considering the differences in the pharmacological properties of ß-blockers, the present work compared the effects of third-generation ß-blockers - carvedilol and nebivolol - with a first-line agent - amlodipine - on hemodynamic parameters, including short-term blood pressure variability (BPV), and their ability to prevent target organ damage in spontaneously hypertensive rats (SHR). SHR rats were orally treated with carvedilol, nebivolol, atenolol, amlodipine or vehicle for 8 weeks. Wistar Kyoto rats treated with vehicle were used as normotensive group. Echocardiographic evaluation, BP, and short-term BPV measurements were performed. Left ventricle and thoracic aorta were removed for histological evaluations and to assess the expression of transforming growth factor ß (TGF-ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). RESULTS: Carvedilol, nebivolol or amlodipine induced a greater reduction of carotid BP, short-term BPV and echocardiography parameters than atenolol in SHR rats. Carvedilol, nebivolol and amlodipine were more effective than atenolol in the prevention of cardiac hypertrophy, and cardiac and aortic collagen deposit. Carvedilol and nebivolol, but not atenolol, reduced the expressions of fibrotic and inflammatory biomarkers - TGF-ß, TNF-α and IL-6 - in SHR rats to a similar extent to that of amlodipine. CONCLUSION: Chronic treatment with carvedilol or nebivolol attenuates carotid BP and short-term BPV, and reduces target organ damage in SHR to a greater extent than atenolol. Our findings suggest that the lower cardiovascular protection of nonvasodilating ß-blockers, as atenolol, in hypertension must not be translated to third-generation ß-blockers.

Lowering arterial pressure delays the oxidative stress generation in a renal experimental model of hypertension.

Oxidative stress produced through reactive oxygen species (ROS) enhancement is considered to play a key role in the development and maintenance of hypertension. In the vasculature, the most important source of ROS is the reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase enzyme. The principal stimulus of this enzyme is angiotensin II (Ang II). However, oxidative stress seems to be present in virtually all forms of hypertension including low-renin hypertension, where the levels of Ang II are reduced. For this reason, the question is if ROS generation is induced by Ang II or it is a consequence of hypertension. We used as hypertensive model the aortic coarctated rats, which were treated with losartan or minoxidil for 7 days. Thoracic aortic segments were excised, and the NAD(P)H oxidase subunits expression, oxidative stress parameters, and heme oxygenase-1 abundance were evaluated. Hypertensive animals had an increase in the activity and expression of NAD(P)H oxidase and, as a consequence, in the oxidative stress parameters. Interestingly, either losartan or minoxidil administration blunted those parameters, indicating that arterial pressure is the key factor in the development of oxidative stress in the hypertensive aorta. We suggest that antihypertensive drug administration at the beginning of this pathology delays the oxidative stress generation, thus preventing the aggravation of this disease.

Sodium load combined with low doses of exogenous angiotensin II upregulate intrarenal angiotensin II.

BACKGROUND/AIMS: The present study was designed to evaluate the effects of a salt load combined with exogenous low nonhypertensive angiotensin II (Ang II) doses on Ang II intrarenal regulation. METHODS: Sprague-Dawley rats were infused with Ang II nonhypertensive doses (0.1 microg.kg(-1).h(-1) and 5 microg.kg(-1).h(-1)) and saline overload (Na 0.5 M, Na 1.0 M and Na 1.5 M) for 2 h (0.04 ml.min(-1)). Sodium tubular reabsorption, sodium urinary excretion and mean arterial pressure (MAP) were measured. Ang II was evaluated in the kidneys by immunohistochemistry. RESULTS: Ang II levels in glomeruli and vessels were exacerbated when sodium load and Ang II were given simultaneously, independently of MAP elevation. In tubules, Ang II staining in the presence of sodium overload was greater in the Ang 0.1 groups than in the Ang 5 groups. Compared with the controls, sodium tubular reabsorption rose in the Ang 0.1-Na 0.5 and Ang 0.1-Na 1 groups and sodium urinary excretion decreased in the Ang 5-Na 0.5 and Ang 5-Na 1 groups. MAP increased in the Ang 5-Na 1 and Ang 5-Na 1.5 groups. CONCLUSION: We conclude that local renal Ang II levels were upregulated when acute sodium overload and nonhypertensive Ang II doses were administered simultaneously in normal rats, independently from blood pressure and glomerular function changes.

Angiotensin II increases intrarenal transforming growth factor-beta1 in rats submitted to sodium overload independently of blood pressure.

Angiotensin II (Ang II) promotes sodium-retention, cell growth and fibrosis in addition to its classical effects on blood pressure and fluid homeostasis. In this study we examined whether low and non-hypertensive doses of exogenous Ang II could enhance the intrarenal expression of transforming growth factor-beta1 (TGF-beta1) observed in rats submitted to sodium overload. Sprague-Dawley-rats were infused for 2 h with 0.1 and 5 microg kg(-1) h(-1) Ang II (Ang 0.1 and Ang 5, respectively) together with saline solution at four different concentrations (isotonic and Na 0.5 mol L(-1), Na 1.0 mol L(-1) and Na 1.5 mol L(-1)). Renal function and mean arterial blood pressure (BP) were measured. The renal distributions of TGF-beta1, alpha-smooth-muscle-actin (alpha-SMA) and nuclear factor-kappaB (NF-kappaB) were evaluated by immunohistochemistry. While the Ang 0.1 groups were normotensive, the Ang 5 groups developed arterial hypertension progressively, and the highest blood pressure values were observed when rats were simultaneously infused with Na 1.5 mol L(-1). Glomerular function was not altered in any group. In cortical tubules, all groups infused with Ang II (0.1 and 5) and hypertonic saline solution (HSS) showed an increase in TGF-beta1 immunostaining compared to those infused with HSS alone. In medullary tubules, only the Ang 5-Na 0.5 group showed a significant increase in TGF-beta 1 immunostaining compared to the Na 0.5 group. Peritubular positive staining for alpha-SMA was present in groups receiving Ang alone or Ang-Na, in a sodium concentration-dependent manner. In cortical-tubules, NF-kappaB immunostaining was significantly increased in the Ang groups in comparison with the control and in Ang-Na 0.5 and Ang-Na 1.0 groups in comparison with the Na 0.5 mol L(-1) and Na 1.5 mol L(-1) groups, respectively, except in the case of the Ang 0.1-Na 1.5 mol L(-1) and Ang 5-Na 1.5 mol L(-1) groups. Moreover, Ang II and sodium overload induced additional changes in TGF-beta1, alpha-SMA and NF-kappaB immunostanding in glomeruli, medullary tubules and renal vessels. In conclusion, the interaction of Ang II with acute-sodium overload exacerbated intrarenal TGF-beta1, alpha-SMA and NF-kappaB expression, independently from changes in blood pressure levels, in normal rats.

Angiotensin II regulates cardiac hypertrophy via oxidative stress but not antioxidant enzyme activities in experimental renovascular hypertension.

The aim of this study was to provide new insights into the role of angiotensin II and arterial pressure in the regulation of antioxidant enzyme activities in a renovascular model of cardiac hypertrophy. For this purpose, aortic coarcted rats were treated with losartan or minoxidil for 7 days. Angiotensin II induced cardiac hypertrophy and oxidative stress via Nox4, p22(phox) and p47(phox), which are components of the NAD(P)H oxidase. Antioxidant enzymes were regulated by arterial pressure and were not implicated in cardiac hypertrophy. Heme oxygenase-1, the rate-limiting enzyme in heme catabolism, behaved as a catalase and glutathione peroxidase, and is regulated by arterial pressure. In summary, the present report indicates that cardiac hypertrophy, induced by renovascular hypertension, depends on angiotensin II through reactive oxygen species and is not prevented by the action of antioxidant enzymes.

Increased hypothalamic angiotensin-(1-7) levels in rats with aortic coarctation-induced hypertension.

Since angiotensin (Ang) (1-7) injected into the brain blocked Ang II pressor actions in rats made hypertensive by aortic coarctation (CH), we examined systemic and tissue angiotensin peptide levels, specifically concentrating on the hypothalamic Ang-(1-7) levels. Plasma, heart and kidney isolated from CH rats showed increased levels of Ang I, Ang II and Ang-(1-7) compared with the normotensive group, with Ang II being the predominant peptide in heart and kidney. In the hypothalamus, equimolar amounts of Ang II and Ang-(1-7) were found in the sham group, whereas only Ang-(1-7) levels increased in CH rats. We conclude that aortic coarctation activates systemic and tissue renin-angiotensin system. The increased central levels of Ang-(1-7) in the CH rats suggest a potential mitigating role of this peptide in central control of the hypertensive process.

Immunohistochemical expression of intrarenal renin angiotensin system components in response to tempol in rats fed a high salt diet.

AIM: To determine the effect of tempol in normal rats fed high salt on arterial pressure and the balance between antagonist components of the renal renin-angiotensin system. METHODS: Sprague-Dawley rats were fed with 8% NaCl high-salt (HS) or 0.4% NaCl (normal-salt, NS) diet for 3 wk, with or without tempol (T) (1 mmol/L, administered in drinking water). Mean arterial pressure (MAP), glomerular filtration rate (GFR), and urinary sodium excretion (UVNa) were measured. We evaluated angiotensin II (Ang II), angiotensin 1-7 (Ang 1-7), angiotensin converting enzyme 2 (ACE2), mas receptor (MasR), angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R) in renal tissues by immunohistochemistry. RESULTS: The intake of high sodium produced a slight but significant increase in MAP and differentially regulated components of the renal renin-angiotensin system (RAS). This included an increase in Ang II and AT1R, and decrease in ACE-2 staining intensity using immunohistochemistry. Antioxidant supplementation with tempol increased natriuresis and GFR, prevented changes in blood pressure and reversed the imbalance of renal RAS components. This includes a decrease in Ang II and AT1R, as increase in AT2, ACE2, Ang (1-7) and MasR staining intensity using immunohistochemistry. In addition, the natriuretic effects of tempol were observed in NS-T group, which showed an increased staining intensity of AT2, ACE2, Ang (1-7) and MasR. CONCLUSION: These findings suggest that a high salt diet leads to changes in the homeostasis and balance between opposing components of the renal RAS in hypertension to favour an increase in Ang II. Chronic antioxidant supplementation can modulate the balance between the natriuretic and antinatriuretic components of the renal RAS.

Effects of carvedilol or amlodipine on target organ damage in L-NAME hypertensive rats: their relationship with blood pressure variability.

The aim of the study was to compare the effects of chronic oral treatment with carvedilol or amlodipine on blood pressure, blood pressure variability and target organ damage in N-nitro-l-arginine methyl ester (L-NAME) hypertensive rats. Wistar rats were treated with L-NAME administered in the drinking water for 8 weeks together with oral administration of carvedilol 30 mg/kg (n = 6), amlodipine 10 mg/kg (n = 6), or vehicle (n = 6). At the end of the treatment, echocardiographic evaluation, blood pressure, and short-term variability measurements were performed. Left ventricular and thoracic aortas were removed to assess activity of metalloproteinase 2 and 9 and expression levels of transforming growth factor ß, tumor necrosis factor α, and interleukin 6. Histological samples were prepared from both tissues. Carvedilol and amlodipine induced a comparable reduction of systolic and mean arterial pressure and its short-term variability in L-NAME rats. The expression of transforming growth factor ß, tumor necrosis factor α, and interleukin 6 decreased in both organs after carvedilol or amlodipine treatment and the activity of metalloproteinase was reduced in aortic tissue. Treatment with carvedilol or amlodipine completely prevented left ventricular collagen deposition and morphometric alterations in aorta. Oral chronic treatment with carvedilol or amlodipine significantly attenuates blood pressure variability and reduces target organ damage and biomarkers of tissue fibrosis and inflammation in L-NAME hypertensive rats.

Renal protective role of atrial natriuretic peptide in acute sodium overload-induced inflammatory response.

BACKGROUND: The present study was performed to explore the effect of exogenous infusions of atrial natriuretic peptide (ANP) on the early inflammatory response during acute sodium overload in normal rats. METHODS: Sprague Dawley rats were exposed to acute sodium overload (Na 1.5 M). Nonhypotensive doses of ANP (1 and 5 microg x kg(-1) x h(-1)) were infused simultaneously with sodium or after sodium infusion in order to evaluate prevention or reversion of the inflammatory response, respectively. We determined inflammation markers in renal tissue by immunohistochemistry. RESULTS: Creatinine clearance was not reduced in any case. Sodium tubular reabsorption increased after sodium overload (334.3 +/- 18.7 vs. control 209.6 +/- 27.0 mEq x min(-1), p < 0.05) without changes in mean arterial pressure. This increase was prevented (228.9 +/- 26.4; p < 0.05) and reversed (231.5 +/- 13.9; p < 0.05) by ANP-5 microg x kg(-1) x h(-1). Sodium overload increased the expression of: RANTES (38.4.3 +/- 0.8 vs. 2.9 +/- 0.6%, p < 0.001), transforming-growth-factor-beta(1) (35.3 +/- 1.0 vs. 5.0 +/- 0.7%, p < 0.001), alpha-smooth muscle actin (15.6 +/- 0.7 vs. 3.1 +/- 0.3%, p < 0.001), NF-kappaB (9.4 +/- 1.3 to 2.2 +/- 0.5 cells/mm(2), p < 0.001), HIF-1alpha (38.2 +/- 1.7 to 8.4 +/- 0.8 cells/mm(2), p < 0.001) and angiotensin II (35.9 +/- 1.3 to 8.2 +/- 0.5%, p < 0.001). ANP-5 microg x kg(-1) x h(-1) prevented and reversed inflammation: RANTES (9.2 +/- 0.5 and 6.9 +/- 0.7, p < 0.001); transforming growth factor-beta(1) (13.2 +/- 0.7 and 10.2 +/- 0.5, p < 0.001) and alpha-smooth muscle actin (4.1 +/- 0.4 and 5.2 +/- 0.4, p < 0.001). Both prevention and reversion by ANP were associated with downregulation of NF-kappaB (3.2 +/- 0.4 and 2.8 +/- 0.5, p < 0.001) and angiotensin II (8.2 +/- 0.5 and 9.1 +/- 0.7, p < 0.001) and diminished hypoxia evaluated through HIF-1alpha expression (8.4 +/- 0.8 and 8.8 +/- 0.7, p < 0.001). CONCLUSION: Our study provides evidence supporting a protective role of ANP in both prevention and reversion of renal inflammation in rats with acute sodium overload.