Oral Administration Of L-NAME Research Articles

#4544 THE ASSOCIATION OF TAMOXIFEN TO THE CONSERVATIVE CKD TREATMENT PROMOTED ADDITIONAL ANTIFIBROTIC EFFECTS IN A MODEL OF HYPERTENSIVE NEPHROSCLEROSIS

Abstract Background and Aims Chronic kidney disease (CKD) is an insidious, progressive and highly debilitating condition, which leads to the loss of renal function and to the need of life-sustaining renal replacement therapy. The conservative treatment of CKD is mainly based in the blockade of the renin-angiotensin-aldosterone system (RAAS), which can be associated to immunosuppressant drugs, according to the etiology of the renal injury. However, this pharmacological approach is not able to prevent CKD progression completely. Until the present moment, medical community still lack of a specific drug to effectively stop the progression of renal fibrosis associated to CKD, which once triggered became irreversible. Tamoxifen (TAM) is an estrogen receptor antagonist, widely employed for the clinical treatment of breast cancer, and responsible for saving a number of lives worldwide, in the past decades. This well-tolerated and cost-effective drug have been reported to exert antifibrotic effects in both experimental and human peritoneal fibrosis. Moreover, our research group already demonstrated that TAM efficiently prevented albuminuria, glomerulosclerosis, and interstitial fibrosis in a model of CKD. In the present study, we investigated if the association of TAM to the classic conservative treatment of CKD, here obtained by the association of Losartan (LOS) and Micofenolate Mofetil (MMF), could promote further renoprotection in an experimental model of hypertensive nephrosclerosis, induced by the chronic nitric oxide synthase blockade, obtained by the oral administration of L-NAME (NAME), associated to a high sodium (HS) diet, in rats. Method The experimental protocol was approved by the local Research Ethics Committee (CAPPesq) and was developed in strict conformity with the international standards for care and manipulation of laboratory animals. Thirty male Wistar rats were kept with a 3.2% HS diet for 15 days of adaptation, before the protocol start. After this period, the animals continued to receive the HS diet and were divided among 5 groups. CONT: receiving no further drugs or treatments, NAME: treated with 70 mg/kg/d of L-NAME, diluted in drinking water, LOS: NAME rats treated with 50mg/Kg/d of LOS, also diluted in drinking water, MMF: NAME rats treated with 10 mg/Kg/d of MMF given by gavage, TAM: NAME rats treated with 10 mg/Kg/d also by gavage, and LOS+MMF+TAM: NAME rats treated with all the drugs simultaneously. Systolic blood pressure (SBP), urinary albumin excretion (24 h uAE), glomerulosclerosis (GS), glomerular ischemia (GI), interstitial fibrosis (INT), tubulointerstitial infiltration of macrophages (CD68) and T-cells (CD3), as well as renal cortical interstitial collagen I (COLL1) and fibronectin (FIBRO) accumulation were evaluated after 30 days of treatment. Results The association of TAM to the classic treatment of CKD improved the renoprotection obtained by LOS+MMF. The triple combined treatment significantly reduced hypertension, albuminuria, glomerular structural damage, renal macrophage and T-cell infiltration in NAME rats, compared to the animals treated with the respective monotherapies. Moreover, both TAM alone or the association, were equally effective in reducing interstitial collagen and fibronectin accumulation, in NAME rats. Data are presented as Mean ± SE. For One-way ANOVA statistical analysis, we considered: p<0.05 vs.*CONT, #NAME, †LOS, §MMF, &TAM. Conclusion Our preliminary results shown TAM to be effective in reducing renal inflammation and fibrosis in the chronic nitric oxide synthase blockade model and to exert additional renoprotective effects when associated to LOS and MMF in all the analyzed parameters. Although further studies with different nephropathy models are still required in order to confirm our findings, here we suggest TAM to be a potential adjuvant in the conservative management of CKD.

Preeclamptic programming unevenly perturbs inflammatory and renal vasodilatory outcomes of endotoxemia in rat offspring: modulation by losartan and pioglitazone.

Introduction: Preeclampsia (PE) enhances the vulnerability of adult offspring to serious illnesses. The current study investigated whether preeclamptic fetal programming impacts hemodynamic and renal vasodilatory disturbances in endotoxic adult offspring and whether these interactions are influenced by antenatal therapy with pioglitazone and/or losartan. Methods: PE was induced by oral administration of L-NAME (50mg/kg/day) for the last 7 days of pregnancy. Adult offspring was treated with lipopolysaccharides (LPS, 5mg/kg) followed 4-h later by hemodynamic and renovascular studies. Results: Tail-cuff measurements showed that LPS decreased systolic blood pressure (SBP) in male, but not female, offspring of PE dams. Moreover, PE or LPS reduced vasodilations elicited by acetylcholine (ACh, 0.01-7.29nmol) or N-ethylcarboxamidoadenosine (NECA, 1.6-100nmol) in perfused kidneys of male rats only. The latter effects disappeared in LPS/PE preparations, suggesting a postconditioning action for LPS against renal manifestation of PE. Likewise, elevations caused by LPS in serum creatinine and inflammatory cytokines (TNFα and IL-1β) as well as in renal protein expression of monocyte chemoattractant protein-1 (MCP-1) and AT1 receptors were attenuated by the dual PE/LPS challenge. Gestational pioglitazone or losartan reversed the attenuated ACh/NECA vasodilations in male rats but failed to modify LPS hypotension or inflammation. The combined gestational pioglitazone/losartan therapy improved ACh/NECA vasodilations and eliminated the rises in serum IL-1β and renal MCP-1 and AT1 receptor expressions. Conclusion: Preeclamptic fetal programming of endotoxic hemodynamic and renal manifestations in adult offspring depends on animal sex and specific biological activity and are reprogrammed by antenatal pioglitazone/losartan therapy.

Changes in Pharmacokinetics and Pharmacodynamics of Losartan in Experimental Diseased Rats Treated with Curcuma longa and Lepidium sativum.

The current study investigated "pharmacodynamics and pharmacokinetics interactions" of losartan with Curcuma longa (CUR) and Lepidium sativum (LS) in hypertensive rats. Hypertension was induced by oral administration of L-NAME (40 mg/kg) for two weeks. Oral administration of CUR or LS shows some substantial antihypertensive activity. The systolic blood pressure (SBP) of hypertensive rats was decreased by 7.04% and 8.78% 12 h after treatment with CUR and LS, respectively, as compared to rats treated with L-NAME alone. LS and CUR display the ability to potentiate the blood pressure-lowering effects of losartan in hypertensive rats. A greater decrease in SBP, by 11.66% and 13.74%, was observed in hypertensive rats treated with CUR + losartan and LS + losartan, respectively. Further, both the investigated herbs, CUR and LS, caused an increase in plasma concentrations of losartan in hypertensive rats. The AUC0-t, AUC0-inf and AUMC0-inf of losartan were increased by 1.25-fold, 1.28-fold and 1.09-fold in hypertensive rats treated with CUR + losartan. A significant (p < 0.05) increase in AUC0-t (2.41-fold), AUC0-inf (3.86-fold) and AUMC0-inf (8.35-fold) of losartan was observed in hypertensive rats treated with LS + losartan. The present study affirms that interactions between CUR or LS with losartan alter both "pharmacokinetics and pharmacodynamics" of the drug. Concurrent administration of losartan with either CUR or LS would require dose adjustment and intermittent blood pressure monitoring for clinical use in hypertensive patients. Additional investigation is necessary to determine the importance of these interactions in humans and to elucidate the mechanisms of action behind these interactions.

Molecular Metabolic Fingerprinting Approach to Investigate the Metabolic Alterations in Heart, Aorta and Renal Tissues of Nitric Oxide Deficient Hypertensive Rats

Hypertension is the leading cause of cardiovascular diseases (CVD) globally. It is well known that the incidence of several CVDs, including stroke, coronary heart disease, and peripheral artery disease, is closely linking to hypertension. Nitric oxide is the imperative regulator of the vascular system and its deficiency leads to elevated blood pressure and metabolic alterations in the tissues such as liver, kidney heart and aorta. Fourier transform infrared spectroscopy (FTIR) is a vibrational spectroscopic technique that uses infrared radiation to vibrate molecular bonds with in the sample that absorbs it and different vibrational spectra can be used to explore the qualitative and quantitative constituent of macromolecules. The aim of this study was to compare molecular changes in the tissues of normal control rats with nitric oxide deficient hypertensive rats. Hypertension was induced in male albino Wistar rats by oral administration of L-NAME (40mg/kg body weight) dissolved in drinking water daily for four weeks. Results indicate that FTIR can successfully identify the molecular changes in hypertensive groups. Overall, the findings demonstrate that in International Journal of Scientific Research in Engineering and Management (IJSREM) Volume: 06 Issue: 12 | December - 2022 Impact Factor: 7.185 ISSN: 2582-3930 © 2022, IJSREM | www.ijsrem.com DOI: 10.55041/IJSREM17171 | Page 2 nitric oxide-deficient animals, the heart, kidney and aortic tissues metabolic programs were altered through an increase in structural modifications in proteins and triglycerides and a quantitative alteration in proteins lipids and transcription factors. Key words: Hypertension; metabolites; FTIR spectroscopy; nitric oxide

Prophylactic Treatment with Hydrogen Sulphide Can Prevent Renal Ischemia-Reperfusion Injury in L-NAME Induced Hypertensive Rats with Cisplatin-Induced Acute Renal Failure.

(Background and Objectives): Renal ischemia perfusion injury is one of the major issues in kidney transplant. The aim of the study was to investigate the hypothesis that prophylactic treatment-with a hydrogen sulphide donor to an acute renal failure case of hypertensive rats-can minimize the ischemia reperfusion injury of the kidney which is beneficial for kidney transplant. To check this hypothesis, the present study was designed to investigate the effect of chronic administration of a hydrogen sulphide (H2S) donor and sodium hydrosulfide (NaHS) on nuclear factor kappa B (NF-kB) and inter cellular adhesion molecule-1 (ICAM-1) concentration in non-renal failure (NRF) and acute renal failure (ARF) rats in the ischemia-reperfusion injury (IRI) model of the kidney in both normotensive WKY and hypertensive rats (L-nitro arginine methyl ester (L-NAME-induced); (Materials and Methods): A total number of 48 Sprague-Dawley rats were recruited into eight groups each consisting of six animals. Each of these eight groups was used to measure systemic and renal parameters, H2S, antioxidant parameters in plasma, plasma concentration of NF-kB and ICAM-1 and renal cortical blood pressure. ARF was induced by single intraperitoneal (i.p.) cisplatin injection (5 mg/kg). Hypertension was induced by oral administration of L-NAME in drinking water for four weeks at 40 mg/kg/day. NaHS was administered (i.p) at 56 µmol/kg for five weeks while dL-propargylglycine (PAG), a H2S generation inhibitor, was administered as a single intra-peritoneal injection (50 mg/kg). An acute surgical experiment was performed for the induction of renal ischemia for 30 min by renal artery clamping followed by reperfusion for three hours; (Results): Chronic administration of NaHS attenuated the severity of ARF in both normotensive and hypertensive animals (L-NAME) along with lowering the blood pressure in hypertensive groups. NaHS improved the oxidative stress parameters such as total superoxide dismutase (T-SOD), glutathione (GSH) and reduced the malondialdehyde (MDA) concentration along with reduction of NF-kB and ICAM-1 following renal IRI; Conclusions: These findings demonstrate that H2S not only reduced the severity of cisplatin induced ARF but also reduced the severity of renal IRI by upregulating antioxidants along with decreased concentrations of NF-kB and ICAM-1 in normotensive and L-NAME induced hypertensive rats.

Short-lived sensitization of cardiovascular outcomes of postpartum endotoxemia in preeclamptic rats: Role of medullary solitary tract neuroinflammation

Preeclampsia (PE) is a pregnancy-related disorder with serious maternal complications. Considering the increased importance of postpartum infection in maternal morbidity and mortality, we investigated whether preeclamptic maternal programming alters cardiovascular consequences of endotoxemia in rats and the role of cardiac and brainstem neuroinflammation in this interaction. Preeclampsia was induced by oral administration of L-NAME (50 mg/kg/day) for 7 days starting from day 14 of conception. Changes in blood pressure, heart rate, and cardiac autonomic function caused by lipopolysaccharide (LPS, 5 mg/kg i.v.) were assessed in mothers at 3 weeks (weaning time) and 9 weeks postnatally. Compared with respective non-PE counterparts, LPS treatment of weaning PE mothers caused significantly greater (i) falls in blood pressure, (ii) rises in heart rate and left ventricular contractility (dP/dtmax), (iii) reductions in time and frequency domain indices of heart rate variability and shifts in cardiac sympathovagal balance (low-frequency/high-frequency ratio, LF/HF) towards parasympathetic dominance, and (iv) attenuation of reflex bradycardic responses measured by the vasoactive method. The intensified LPS effects in weaning PE rats subsided after 9 weeks of delivery. Immunohistochemical studies showed increased protein expression of nuclear factor kappa B (NF-κB) in brainstem neuronal pools of the nucleus of the solitary tract (NTS), but not rostral ventrolateral medulla (RVLM), in endotoxic PE weaning rats compared with non-PE rats. Cardiac NF-κB expression was increased by LPS but this was similarly noted in PE and non-PE rats. Together, preeclamptic maternal programming elicits short-term exacerbation of endotoxic cardiovascular and autonomic derangements due possibly to exaggerated NTS neuroinflammatory insult.

Antihypertensive Effects of the Methanol Extract and the Ethyl Acetate Fraction from Crinum zeylanicum (Amaryllidaceae) Leaves in L-NAME-Treated Rat.

Arterial hypertension (AHT) is a leading cardiovascular disease, with a high negative impact on the quality of life. Crinum zeylanicum (C. zeylanicum) leaves extract is used in the West region of Cameroon to treat AHT and heart problems. This study aimed to investigate the antihypertensive effect of C. zeylanicum extract in Nω-nitro-L‐arginine methyl ester- (L‐NAME-) induced hypertensive rats. The aqueous extract of C. zeylanicum (LAE) was obtained by lyophilizing the juice of triturated fresh leaves. The methanol extract (LME) prepared by maceration of the dried leaves was further partitioned to chloroform (LCF), ethyl acetate (LEAF), and residual (LRF) fractions. The total polyphenol, flavonoid content, and antiradical potentials of these extracts were determined. The curative antihypertensive and renal function protective effects of LME and LEAF were evaluated in vivo on L-NAME-induced hypertensive rats. Hypertension was induced in rats by oral administration of L-NAME (30 mg/kg/day) for 3 consecutive weeks. Thereafter, plant extracts were administered orally at the doses of 30, 60, and 120 mg/kg/day, concomitantly with L-NAME for three other weeks. Body weight, heart rate, and arterial blood pressure were measured at the end of each week throughout the experimental period. At the end of the treatment, 24-hour urine and plasma were collected to assay nitric oxide (NO), creatinine, and protein. The results revealed that LEAF has the higher content of total polyphenol and flavonoid and exhibited the best antiradical potential. Moreover, treatment of hypertensive rats with LME and LEAF significantly (p < 0.001) reduced AHT and heart rate. LME and LEAF significantly increased rat's body mass, plasmatic NO, and urinary creatinine and reduced urine NO and protein contents as compared to the L-NAME group. LME and its LEAF possess potent antihypertensive effects and further protect the renal function in L-NAME-induced hypertensive rats, thus supporting the use of C. zeylanicum in the management of AHT.

Preeclamptic Programming Unevenly Modifies Hemodynamic and Renovascular Outcomes of Endotoxemia in Rat Offspring: Modulation by Sex and Antenatal Therapies

Preeclampsia (PE) enhances the vulnerability of adult offspring to serious illnesses. The current study investigated whether preeclamptic fetal programming impacts hemodynamic and renovascular responsiveness to endotoxemia in adult male and female offspring and whether antenatal reprogramming therapy with pioglitazone and/or losartan favorably modulates these interactions. PE was induced by oral administration of L-NAME (50 mg/kg/day) to pregnant dams for seven days starting from gestational day 14. Adult offspring of either sex was treated with lipopolysaccharides (LPS, 5 mg/kg) followed 4 hr later by hemodynamic and renovascular studies. Tail-cuff measurements showed that while LPS produced no hemodynamic changes in female offspring, it significantly decreased blood pressure and increased heart rate in age-matched male counterparts. In isolated perfused kidneys of male offspring, PE or LPS reduced renal vasodilations elicited by acetylcholine (0.01-7.29 nmol) or N-ethylcarboxamidoadenosine (NECA, 1.6-100 nmol), effects that disappeared in PE/LPS kidney preparations. Likewise, elevations caused by LPS in serum inflammatory cytokines (TNFα and IL-1β) and renal biomarkers (BUN and creatinine) were attenuated in PE/LPS males. Contrary to males, NECA, but not acetylcholine, vasodilation was facilitated by LPS in female preparations, an effect that was comprised in PE/LPS kidneys. Gestational administration of pioglitazone or losartan reversed the attenuated acetylcholine/NECA vasodilations but failed to modify LPS hypotension or inflammation. Gestational treatment with combined pioglitazone/losartan therapy improved acetylcholine renal vasodilations and partly attenuated the inflammatory response. Our data suggest that preeclamptic fetal programming of endotoxic manifestations in adult offspring depends on animal sex and targeted biological activity and are partly improved by pharmacologic antenatal reprogramming with pioglitazone or losartan.

Antihypertensive Effects of the Vitex cienkowskii (Verbenaceae) Stem-Bark Extract on L-NAME-Induced Hypertensive Rats.

Vitex cienkowskii stem-bark is used in Cameroonian traditional medicine to treat cardiovascular diseases including hypertension. In previous studies, the methanol/methylene chloride stem-bark extract of Vitex cienkowskii (MMVC) showed a preventive activity in L-NAME-induced hypertension and improved blood pressure of spontaneously hypertensive rats. The present study investigated the curative effects in L-NAME-induced hypertensive rats (LNHR). Hypertension was induced in rats by oral administration of L-NAME (40 mg/kg/day) for 28 days. The animals were divided into 2 groups: one group of 5 rats receiving distilled water (10 ml/kg) and another 20 rats receiving L-NAME. At the end of 4 weeks of administration of L-NAME, the animals were divided into 4 groups of 5 rats each: one group of hypertensive rats receiving distilled water, another one receiving captopril (25 mg/kg), and two groups of hypertensive rats receiving MMVC at doses of 200 and 400 mg/kg, respectively. Body weight, food, and water intake were measured weekly. At the end of the treatment, blood pressure and heart rate were recorded by invasive method. Whole heart, left ventricle, kidneys, and liver were weighed. The effects of plant extract on lipid profile and oxidative stress markers, as well as markers of hepatic and renal functions were assessed spectrophotometrically according to well described protocols. Results show that L-NAME significantly increases the mean arterial blood pressure (MABP), atherogenic index, lipid profile, and creatinine and transaminase activities of normotensive rats. MMVC significantly reduced the blood pressure in LNHR. Body weight, food and water intake, left ventricular hypertrophy, antioxidant level, renal and hepatic markers, and lipid profile were improved by the treatment with MMVC. The curative effect of MMVC on L-NAME-induced hypertension is probably related to its antihypertensive, hypolipidemic, and antioxidant properties. These results confirmed the use of Vitex cienkowskii for the treatment of hypertension in traditional medicine.

Glycyrrhizin potentially suppresses the inflammatory response in preeclampsia rat model.

The expression of high-mobility group box 1 (HMGB1) in trophoblasts is elevated, which contributes to the development of preeclampsia. Thus, this study aimed to investigate the effect of glycyrrhizin, a natural HMGB1 inhibitor, on the development of preeclampsia. Preeclampsia was induced in pregnant Lewis rats through oral administration of L-NAME (50mg/kg/day) on gestational day (GD) 13-19. Glycyrrhizin (10, 30, or 60mg/kg/day) was given by oral gavage on GD 10-19. Systolic blood pressure (SBP), diastolic blood pressure (DBP), 24-hour proteinuria, live pup birth ratio, pup weight, pup body length, and placental weight were measured. Also, the expression levels of inflammatory factors (TNF-α, iNOS, IL-1, and IL-6), HMGB1, and TLR4 in the placenta or in the serum were analyzed by enzyme-linked immunosorbent assay, RT-PCR, and Western blot analysis. Glycyrrhizin significantly reduced the SBP, DBP, and 24-hour proteinuria on GD 16 and 20 in a dose-dependent manner and ameliorated the pregnancy outcomes in preeclampsia rats. The elevated inflammatory molecule levels were markedly decreased by glycyrrhizin not only in the serum but also in the placenta. Moreover, the upregulated HMGB1 and TLR4 expression levels were diminished by glycyrrhizin administration. This study shows that glycyrrhizin could alleviate preeclampsia and the preeclampsia-associated inflammatory reaction, and this effect could be attributed to HMGB1 inhibition.

The effect of swimming training on adrenomedullin levels, oxidative stress variables, and gastrocnemius muscle contractile properties in hypertensive rats

ABSTRACT Introduction/Aim: Regular exercise may have beneficial effects on high blood-pressure, as shown in different types of experimental hypertension models in rats. The present study aims to investigate the effects of 6-week swimming training on blood pressure, oxidative stress variables of selected tissues, serum adrenomedullin (ADM) levels, and in situ muscle contraction in rats with hypertension induced by Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), an inhibitor of endothelial nitric oxide synthases (eNOs). Materials and Methods: Twenty-six male Sprague Dawley, 8 weeks of age, rats were randomly divided into four groups: (I) normotensive (C), (II) normotensive + exercise (E), (III) hypertensive (L), and (IV) hypertensive + exercise (LE). Hypertension was induced by the oral administration of L-NAME (60 mg/kg) for 6 weeks. Exercise was performed 5 times (1-h each) per week for 6 weeks. At the end of the experiment, blood and tissue samples (the gastrocnemius muscle, heart, kidney, and thoracic aorta) were collected following contractile properties of the gastrocnemius muscle in situ weredetermined. In the collected tissues, oxidative stress (e.g., lipid oxidation and antioxidant enzyme activity) and serum ADM levels were measured. 6-week L-NAME administration per se (Group L) led to a significant increase in systolic and diastolic blood pressure compared to other groups. Results: Importantly, 6-week exercise caused a protective effect of high blood pressure in the rats received L-NAME (Group LE). The level of ADM was lower in the rats received L-NAME than that of the control group. L-NAME increased lipid peroxidation in the thoracic aorta and decreased superoxide dismutase in the heart, kidney and muscle, and decreased catalase and glutathione in the heart. However, the exercise intervention did not have protective effect on the L-NAME-mediated oxidative damage in the collected tissues. Conclusion: In conclusion, 6-week exercise intervention rescued rats from high blood pressure, but did not have ameliorative effect on the decreased ADM levels.

Antihypertensive effect of Phragmanthera incana (Schum) Balle on NG-nitro-L-Arginine methyl ester (L-NAME) induced hypertensive rats

Ethnopharmacological relevancePhragmanthera incana (Schum) Balle is a member of the African mistletoes that has been reported to be used in ethnomedicine for the treatment of hypertension. AimThe aim of this study was to investigate the antihypertensive effect of Phragmanthera incana leaf ethanol extract (PILEE) in NG-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. Materials and methodsPhytochemical analysis of PILEE was determined using the Gas chromatography – Mass spectrophotometry (GC-MS) method. Antihypertensive activity was investigated in rats that received PILEE (50, 100 and 200 mg/kg) or captopril (40 mg/kg) daily for 28 days together with oral administration of L-NAME (40 mg/kg). Blood pressure parameters were measured on day 7, 14, 21 and 28. Blood was obtained for determination of serum nitrite, interleukin-6 (IL-6) and tumor necrosis factor, TNF-α. The heart, liver and kidneys were used to determine oxidative stress indices (malondialdehyde, reduced glutathione and catalase). The cardiac tissue was processed for histopathological changes. ResultsThe GC-MS profiling of PILEE identified 20 compounds namely fatty acid esters. Administration of PILEE (50, 100 and 200 mg/kg) dose dependently and significantly reduced systolic blood pressure and mean arterial pressure in hypertensive rats. PILEE administration significantly (p < 0.05) reversed elevated IL-6 and TNF-α in hypertensive rats. PILEE demonstrated antioxidant activity by attenuating L-NAME-induced elevated malondialdehyde and depletion of reduced glutathione and catalase activity in rat tissues. PILEE treatment demonstrated cardioprotective effect in L-NAME-induced cardiac hyperplasia and necrosis in rats. ConclusionIt can be concluded that Phragmanthera incana leaf ethanol extract possess antihypertensive, antioxidant and anti-inflammatory properties, suggesting a protective role in cardiovascular diseases.

Effect of Hibiscus sabdariffa and Zingiber officinale on the antihypertensive activity and pharmacokinetic of losartan in hypertensive rats

The present study aimed to determine the effect of Hibiscus sabdariffa and Zingiber officinale on antihypertensive activity and pharmacokinetic of losartan in hypertensive rats.Hypertension was induced in rats by oral administration of L-NAME (40 mg/kg per day). Pharmacodynamics and pharmacokinetics of losartan were evaluated without and with herbal treatment in hypertensive rats.Treatment of hypertensive rats with investigated herbs substantially reduced systolic blood pressure (SBP), and diastolic blood pressure (DBP) of rats. Treatment of rats (n = 5) with L-NAME plus H. sabdariffa plus losartan and L-NAME plus Z. officinale plus losartan reduced SBP by 16.20% and 14.88% and DBP by 14.82% and 17.52% respectively after 12 h, as compared to L-NAME alone treated rats. In a pharmacokinetic study, the Cmax and AUC0-t of losartan in L-NAME plus H. sabdariffa plus losartan and L-NAME plus Z. officinale plus losartan treated rats was increased by 0.7, 1.99 and 1.51, 3.00 fold respectively in comparison to the Cmax and AUC0-t obtained for L-NAME plus losartan treated group. In conclusion, both the investigated herbs significantly increased the antihypertensive effect and plasma concentration of losartan in L-NAME induced hypertensive rats. The current study predicted that the herb-drug interaction between H. sabdariffa-losartan and Z. officinale-losartan could occur; hence these results in rats may warrant further studies in humans, either in humans or in in vitro human liver microsomes.

Pre-eclamptic Fetal Programming Alters Neuroinflammatory and Cardiovascular Consequences of Endotoxemia in Sex-Specific Manners.

Pre-eclampsia (PE)-induced fetal programming predisposes offspring to health hazards in adult life. Here, we tested the hypothesis that pre-eclamptic fetal programming elicits sexually dimorphic inflammatory and cardiovascular complications to endotoxemia in adult rat offspring. PE was induced by oral administration of L-NAME (50 mg/kg per day for seven consecutive days) starting from day 14 of conception. Cardiovascular studies were performed in conscious adult male and female offspring preinstrumented with femoral indwelling catheters. Compared with non-PE male counterparts, intravenous administration of lipopolysaccharide (LPS, 5 mg/kg) to PE male offspring caused significantly greater 1) falls in blood pressure, 2) increases in heart rate, 3) rises in arterial dP/dtmax, a correlate of left ventricular contractility, and 4) decreases in time- and frequency-domain indices of heart rate variability (HRV). By contrast, the hypotensive and tachycardic actions of LPS in female offspring were independent of the pre-eclamptic state and no clear changes in HRV or dP/dtmax were noted. Measurement of arterial baroreflex activity by vasoactive method revealed no sex specificity in baroreflex dysfunction induced by LPS. Immunohistochemical studies showed increased protein expression of toll-like receptor 4 in heart as well as in brainstem neuronal pools of the nucleus of solitary tract and rostral ventrolateral medulla in endotoxic PE male, but not female, offspring. Enhanced myocardial, but not neuronal, expression of monocyte chemoattractant protein-1 was also demonstrated in LPS-treated male offspring. Together, pre-eclamptic fetal programming aggravates endotoxic manifestations of hypotension and autonomic dysfunction in male offspring via exacerbating myocardial and neuromedullary inflammatory pathways. SIGNIFICANCE STATEMENT: Current molecular and neuroanatomical evidence highlights a key role for pre-eclamptic fetal programming in offspring predisposition to health hazards induced by endotoxemia in adult life. Pre-eclampsia accentuates endotoxic manifestations of hypotension, tachycardia, and cardiac autonomic dysfunction in male offspring via exacerbating myocardial and central inflammatory pathways. The absence of such detrimental effects in female littermates suggests sexual dimorphism in the interaction of pre-eclamptic fetal programming with endotoxemia.

Antihypertensive Effect of Piper sarmentosum in L-NAME-Induced Hypertensive Rats

Hypertension is one of the risk factors for cardiovascular diseases and has been associated with about 13% of global deaths worldwide. Oxidative stress and reduced nitric oxide (NO) bioavailability contribute to the development of endothelial dysfunction and subsequently hypertension. Nɷ-nitro-L-arginine methyl ester hydrochloride (L-NAME) inhibits NO synthesis; leading to hypertension. Piper sarmentosum (PS) is an herb with antioxidant, antiatherosclerosis and antiinflammation properties. PS also stimulated NO production by endothelial cells. The aim of this study was to determine the effects of aqueous extract of Piper sarmentosum (AEPS) on blood pressure, oxidative stress and the level of nitric oxide in L-NAME-induced hypertensive rats. Hypertension was induced by oral administration of L-NAME (100 mg/L) in drinking water for four weeks. The rats were concurrently treated with AEPS by oral gavage in serial doses (125, 250 and 500 mg/kg/day). Blood pressure was measured using non-invasive tail-cuff method at baseline and fortnightly thereafter. Serum level of NO and an oxidative stress marker, malondialdehyde (MDA) were measured at baseline and at the end of treatment. The results showed that treatment with three different doses of AEPS successfully reduced systolic blood pressure (p<0.001), diastolic blood pressure (p<0.05) and mean arterial pressure (p<0.05) in L-NAME-induced hypertensive rats. Treatment with AEPS also reduced MDA level (p<0.001) and increased serum NO (p<0.001) in L-NAME-induced hypertensive rats. The findings showed that AEPS decreased blood pressure by protecting against oxidative stress and increasing NO in L-NAME-induced hypertensive rats.

O8 Study on antihypertensive activity of an aqueous extract of Anogeissus leiocarpus (AEAL) DC Guill et Perr bark of trunk in L-NAME-induced hypertensive rats

Background The present study investigates the effect of AEAL on normotensive Wistar rats and its chronic antihypertensive effects in L-NAME-induced hypertensive rats by using a non-invasive tail-cuff model. Methods The effects of AEAL (50 mg/kg) and NaCl 0.9% on blood pressure were investigated by daily oral administration in normotensive Wistar rats over four weeks. L-NAME-induced hypertensive rats were produced by L-NAME (40 mg/kg) daily oral administration for two weeks. For chronic antihypertensive effects, animals were treated with L-NAME for two weeks and then, L-NAME was administrated in combination with AEAL (10 or 50 mg/kg/day) and compared with a control group receiving only NaCl 0.9% for two following weeks. The blood pressure was measured daily by a Blood Pressure Recorder system. Results In normotensive rats, daily administration of AEAL (50 mg/kg) had no significant effect on their blood pressure, which was similar to that of the control group. Daily oral administration of L-NAME induced a progressive increase in systolic blood pressure (SBP) from 115.8 ± 7.9 mmHg to 153.5 ± 4.6 mmHg after two weeks of treatment, which was maintained to the end of the treatment. In L-NAME-induced hypertensive rats, AEAL (50 mg/kg) significantly decreased SPB from 160.0 ± 5.8 mmHg to 108.8 ± 2.7 mmHg after only four days of administration. In addition, the lower dose of AEAL (10 mg/kg) also normalized the SBP of L-NAME-induced hypertensive rats, however this was only evident after eight days of administration. Conclusion These findings suggest that AEAL affords significant antihypertensive effects against L-NAME-induced hypertensive rats.

The effects of sildenafil citrate on urinary podocin and nephrin mRNA expression in an L-NAME model of pre-eclampsia.

We investigated the effects of sildenafil citrate (SC) on podocyturia in N ω-nitro-L-arginine methyl ester hydrochloride (L-NAME) model of pre-eclampsia (PE). One hundred and twenty Sprague-Dawley rats (SDR) were divided into five groups like pregnant control (PC), early-onset PE (EOPE), late-onset PE(LOPE), early and late-onset PE with SC-treated groups [EOPE (SC); LOPE (SC)]. PE was induced in SDR by oral administration of L-NAME in drinking water for 4-8days for EOPE and 8-14day for LOPE. The blood pressure, urine volume and total urine protein were increased in EOPE and LOPE groups when compared to PC, and all the above parameters decreased in EOPE (SC) and LOPE (SC) groups when compared to EOPE and LOPE groups, respectively. The EOPE and LOPE groups showed an increase in urinary nephrin mRNA and podocin mRNA levels compared to PC group. Increases in serum and renal soluble fms-like tyrosine kinase-1 (sFlt-1) expression levels and decreases in renal vascular endothelial growth factor (VEGF) expression and serum placenta growth factor (PlGF) levels were observed in EOPE and LOPE groups when compared to PC group. In addition, decreases in serum and renal sFlt-1 expression levels and increases in renal VEGF expression and serum PlGF levels were observed in EOPE (SC) and LOPE (SC) groups when compared to EOPE and LOPE groups, respectively. The light microscopy showed that the renal tissue of L-NAME-treated rats had extensive glomerular damage, tubular damage and infiltration by mononuclear cells when compared to PC group. Therefore, SC ameliorated podocyturia through its effects on the antiangiogenic/angiogenic status in this animal model.

Dietary Supplementation of Ginger and Turmeric Rhizomes Modulates Platelets Ectonucleotidase and Adenosine Deaminase Activities in Normotensive and Hypertensive Rats.

Hypertension is associated with platelet alterations that could contribute to the development of cardiovascular complications. Several studies have reported antiplatelet aggregation properties of ginger (Zingiber officinale) and turmeric (Curcuma longa) with limited scientific basis. Hence, this study assessed the effect of dietary supplementation of these rhizomes on platelet ectonucleotidase and adenosine deaminase (ADA) activities in Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME) induced hypertensive rats. Animals were divided into seven groups (n = 10): normotensive control rats; induced (l-NAME hypertensive) rats; hypertensive rats treated with atenolol (10 mg/kg/day); normotensive and hypertensive rats treated with 4% supplementation of turmeric or ginger, respectively. After 14 days of pre-treatment, the animals were induced with hypertension by oral administration of l-NAME (40 mg/kg/day). The results revealed a significant (p < 0.05) increase in platelet ADA activity and ATP hydrolysis with a concomitant decrease in ADP and AMP hydrolysis of l-NAME hypertensive rats when compared with the control. However, dietary supplementation with turmeric or ginger efficiently prevented these alterations by modulating the hydrolysis of ATP, ADP and AMP with a concomitant decrease in ADA activity. Thus, these activities could suggest some possible mechanism of the rhizomes against hypertension-derived complications associated to platelet hyperactivity. Copyright © 2016 John Wiley & Sons, Ltd.

Effect of dietary supplementation of ginger and turmeric rhizomes on ectonucleotidases, adenosine deaminase and acetylcholinesterase activities in synaptosomes from the cerebral cortex of hypertensive rats

Ginger and turmeric rhizomes are used in folk medicine for the treatment of several cerebrovascular diseases with limited scientific basis for their action. Hence, in this study, we investigate the effects of two Zingiberaceae varieties (ginger and turmeric) on ectonucleotidases (NTPDase and 5′-nucleotidase), adenosine deaminase (ADA) and acetylcholinesterase (AChE) activities in synaptosomes of cerebral cortex from l-NAME induced hypertensive rats. The animals were divided into seven groups (n=10): normotensive control rats; hypertensive rats; hypertensive rats treated with atenolol; normotensive and hypertensive rats treated with 4% supplementation of turmeric and ginger rhizomes, respectively. After 14 days of pre-treatment with both rhizomes the animals were induced with hypertension by oral administration of l-NAME. The results revealed an increase of ATP and AMP hydrolysis as well as ADA and AChE activities of cerebral cortex synaptosomes in induced rats when compared with the control. The supplementation of both rhizomes prevented these alterations by decreasing ATP and AMP hydrolysis and ADA and AChE activities in cerebral cortex. In conclusion, this study demonstrated that both rhizomes interfere with the purinergic and cholinergic neurotransmission in cerebral cortex of hypertensive rats. Therefore, we can suggest that both rhizomes exert neuroprotective potential under hypertensive state.

Dietary supplementation of ginger and turmeric improves reproductive function in hypertensive male rats.

Ginger [Zingiber officinale Roscoe (Zingiberaceae)] and turmeric [Curcuma longa Linn (Zingiberaceae)] rhizomes have been reportedly used in folk medicine for the treatment of hypertension. However, the prevention of its complication such as male infertility remains unexplored. Hence, the aim of the present study was to investigate the preventive effects of ginger and turmeric rhizomes on some biomarkers of male reproductive function in L-NAME-induced hypertensive rats. Male Wistar rats were divided into seven groups (n = 10): normotensive control rats; induced (L-NAME hypertensive) rats; hypertensive rats treated with atenolol (10 mg/kg/day); normotensive and hypertensive rats treated with 4% supplementation of turmeric or ginger, respectively. After 14 days of pre-treatment, the animals were induced with hypertension by oral administration of L-NAME (40 mg/kg/day). The results revealed significant decrease in serum total testosterone and epididymal sperm progressive motility without affecting sperm viability in hypertensive rats. Moreover, increased oxidative stress in the testes and epididymides of hypertensive rats was evidenced by significant decrease in total and non-protein thiol levels, glutathione S-transferase (GST) activity with concomitant increase in 2′,7′-dichlorofluorescein (DFCH) oxidation and thiobarbituric acid reactive substances (TBARS) production. Similarly, decreased testicular and epididymal NO level with concomitant elevation in arginase activity was observed in hypertensive rats. However, dietary supplementation with turmeric or ginger efficiently prevented these alterations in biomarkers of reproductive function in hypertensive rats. The inhibition of arginase activity and increase in NO and testosterone levels by both rhizomes could suggest possible mechanism of action for the prevention of male infertility in hypertension. Therefore, both rhizomes could be harnessed as functional foods to prevent hypertension-mediated male reproductive dysfunction.