Fructose-induced Hypertensive Rats Research Articles

Effect of Nyctanthes arbor-tristis on cardiovascular parameters and metabolic syndrome in fructose-induced hypertensive rats

Objectives: We investigated the effects of methanolic extract of Nyctanthes arbor-tristis (MNAT) 100, 200 and 400 mg/kg/day post-operative for 6 weeks on ECG, basal mean arterial blood pressure (MABP), heart rate, respiratory rate, vascular reactivity, antioxidant activities of enzyme superoxide dismutase (SOD) and catalase (CAT), levels of thiobarbituric acid reactive substances (TBARS), serum levels of leptin, adiponectin, glucose, triglycerides, cholesterol, uric acid, insulin, sodium and potassium in fructose-fed rats. Materials and Methods: A high-fructose-diet (fructose 10%, w/v) ad libitum for 6 weeks was used to induce hypertension in male Wistar rats (150–200 g). Sixty albino Wistar rats were randomly divided into a group of six, each group containing 10 animals. Group I was considered as normal control which received chow pellets and normal drinking water ad libitum for 6 weeks. Group II received fructose (10%) solution instead of normal drinking water for 6 weeks. Group III received fructose (10%) solution instead of drinking water ad libitum and MNAT at a dose of 100 mg/kg post-operative for 6 weeks. Group IV received fructose (10%) solution instead of drinking water ad libitum and MNAT at a dose of 200 mg/kg post-operative for 6 weeks. Group V received fructose (10%) solution instead of drinking water ad libitum and MNAT at a dose of 400 mg/kg post-operative for 6 weeks. Group VI received fructose (10%) solution instead of drinking water ad libitum and enalapril at a dose of 10 mg/kg post-operative for 6 weeks. Physiological parameters, ECG, heart rate, respiratory rate and blood pressure vascular reactivity to various drugs were measured and recorded by the invasive method. The antioxidant activities of enzyme SOD and CAT, levels of TBARS, along with serum levels of leptin, adiponectin, glucose, triglycerides, cholesterol, uric acid, insulin, sodium and potassium were measured. Cumulative concentration-response curve (CCRC) of Ang II and acetylcholine (Ach) was recorded. Results: MNAT treatment decreased MABP and altered vascular reactivity to various catecholamines. The activities of SOD and CAT enzymes exhibited a considerable increase and the levels of TBARS in the liver were reduced by MNAT treatment. MNAT has shown decrease in the plasma level of triglycerides, cholesterol, insulin and sodium while increase in plasma adiponectin and potassium levels. The CCRC of Ang II was shifted towards the right by MNAT treatment using an isolated strip of rat ascending colon. MNAT treatment increased the contractile characteristics of the rat ascending colon in the CCRC of ACh as compared to the fructose-treated group. MNAT treatment reduced fructose-induced tissue damage due to the consequence of metabolic syndrome (MetS). MNAT is rich in flavonoids and, therefore, has powerful antioxidant properties. The findings show that by battling oxidative stress caused by fructose (10%) and reducing Ang II activity, MNAT may be able to prevent the development of high blood pressure caused by fructose. Conclusion: MNAT has antihypertensive action and reverses MetS in the fructose-induced hypertensive rat model.

Effects of camel milk hydrolysate on blood pressure and biochemical parameters in fructose-induced hypertensive rats

PurposeThis study aims to investigate the antihypertensive effect of camel milk hydrolysate in rats with fructose-induced hypertension.Design/methodology/approachThe antihypertensive effect of fermented camel milk was determined using 6 groups comprising 36 Wistar male rats. Blood pressure of rats was altered via exposure to a 10% fructose (w/v) diet in drinking water for 3 weeks before conducting 21 days of treatment. The authors conducted the experiment for short and long term using different doses of 800 and 1,200 mg/kg body weight. Serum was used to assay total cholesterol (TC), triglyceride (TG), glucose and insulin levels using standard biochemical kits.FindingsThe group that received 1,200 mg hydrolysate camel milk (HM) has significantly (p = 0.003) reduced systolic and diastolic blood pressure after a short exposure time (4–8 h). These effects were significantly (p = 0.005) comparable to the nifedipine (NIF) drug group. Similar long-term (21 days) effects on blood pressure were observed in 1,200 mg HM and NIF groups. Angiotensin-converting enzyme (ACE) activity and levels were also reduced in a correlation with blood pressure reduction only in HM1200 and HM800 treated groups. The authors observed no significant effect on blood pressure in groups receiving the 800 mg HM or 1,200 mg unhydrolyzed camel milk (UM). Rats receiving the 10% fructose diet showed significant differences from control rats regarding their blood biochemistry, including TG, TC, blood glucose and insulin levels. Rats in groups NIF, HM1200 and HM800 showed a significant (p < 0.05) reduction in serum glucose, insulin, TG and TC levels toward the baseline level.Research limitations/implicationsFurther mechanistic investigation on the HM antihypertensive activity is highly recommended before suggesting HM as a product to reduce blood pressure. While drug–food interaction between HM and antihypertensive drugs, especially ACE inhibitors, is probable, UM seems not to affect blood pressure or ACE activity and therefore is expected to have no or minimal effects on the activity of other antihypertensive drugs. Investigation of ACE expression from various organs including lungs and leukocytes is highly recommended in future works using sodium dodecyl-sulfate polyacrylamide gel electrophoresis and western blot analysis or reverse transcription polymerase chain reaction.Originality/valueNo previous studies have measured the antihypertensive activity of milk hydrolysate mediated by the reduction of ACE activity and levels in plasma. Mechanisms involved in attenuating the levels of ACE warrant further investigation.

The potential protective effect of the Polygonum hydropiper L against the development of fructose-induced oxidative stress and metabolic disorders in male Sprague-Dawely rats.

Polygnum hydropiper L (Polygonaceae) is commonly known as smart weed. This study was designed to assess the effect of aqueous methanolic extract of P. hydropiper on oxidative stress and metabolic changes in fructose-induced hypertensive rats. Male Sprague-Dawely rats were divided into six groups of five animals each (n = 5) and designated as normotensive group with distilled water, fructose-fed group with 10% fructose, standard control group with 10% fructose plus amlodipine (10 mg/kg) and treated groups with different doses of the aqueous methanolic extract of P. hydropiper (100, 200 and 400 mg/kg) plus 10% fructose daily for 6 weeks. Body weight gain was checked every week. Blood pressure parameters [systolic (SBP), diastolic (DBP), mean arterial pressure (MAP) and heart rate (HR)] and reactivity of extract with phenylephrine and adrenaline were measured by invasive method. Metabolic changes and oxidative stress parameters were measured from blood samples. Phytochemical analysis was also performed. Aqueous methanolic extract of P. hydropiper at 400 mg/kg decreased the blood pressure, heart rate, body weight and produced significant effect on metabolic and oxidative stress changes as compared to fructose-fed group. Phytochemical analysis revealed the presence of polyphenols and flavonoids in it. The present results showed that aqueous methanolic extract of P. hydropiper possesses effect on oxidative stress and metabolic changes due to polyphenols and flavonoids.

Methanol (80%) leaf extract of Otostegia integrifolia Benth (Lamiaceae) lowers blood pressure in rats through interference with calcium conductance

BackgroundOtostegia integrifolia Benth. (Lamiaceae) leaves are used to treat hypertension in Ethiopian folk medicine. However, the claim has so far not been investigated scientifically. Thus, the objective of this study was to evaluate the antihypertensive activity of 80% methanol leaf extract of O. integrifolia in animal model of hypertension and possible underlying mechanisms in isolated rat aorta.MethodsAntihypertensive effect of various oral doses of the extract (250, 500 and 1000 mg/kg) was determined in fructose-induced hypertensive rats using the non-invasive tail-cuff method. Thoracic aortic strips of rats were isolated and suspended in organ bath, and the vasodepressor effect as well as the possible mechanism (s) of action were studied by means of isometric tension recording experiments ex vivo. Phytochemical analysis was also performed to suggest possible constituents related to the activity.ResultsBlood pressure was significantly lowered in a dose-dependent manner following extract administration, suggesting that the extract possesses antihypertensive activity. The extract also caused a dose-dependent relaxation of aortic strip precontracted with KCl at a concentration of 6.25–125 μg/L, with a maximum relaxation (100%) achieved at a cumulative concentration of 318.75 μg/ml. The relaxation mechanism was found to be independent of muscarinic receptors, prostanoids, histamine receptors, ATP dependent K+ channels, sarcoplasmic reticulum stored Ca2+ and the endothelium system. The extract shifted the Ca2+ concentration-response curve to the right similar to that caused by nifedipine, suggesting that vasorelaxation could possibly be mediated via calcium channel blockade. The extract was found to contain phenolic compounds (164.3 mg/g, expressed as gallic acid equivalents) and flavonoids (125.7 mg/g, expressed as quercetin equivalents).ConclusionThe findings revealed that the plant is endowed with antihypertensive activity, providing evidence for its traditional use. The effect maybe, at least in part, due to dilation of blood vessels through blockade of Ca+ 2 channels mediated by phenolic and flavonoid constituents.

CX3CR1-microglia mediates neuroinflammation and blood pressure regulation in the nucleus tractus solitarii of fructose-induced hypertensive rats

BackgroundInflammation is a common pathophysiological trait found in both hypertension and cardiac vascular disease. Recent evidence indicates that fractalkine (FKN) and its receptor CX3CR1 have been linked to inflammatory response in the brain of hypertensive animal models. Here, we investigated the role of CX3CR1-microglia in nitric oxide (NO) generation during chronic inflammation and systemic blood pressure recovery in the nucleus tractus solitarii (NTS).MethodsThe hypertensive rat model was used to study the role of CX3CR1-microglia in NTS inflammation following hypertension induction by oral administration of 10% fructose water. The systolic blood pressure was measured by tail-cuff method of non-invasive blood pressure. The CX3CR1 inhibitor AZD8797 was administered intracerebroventricularly (ICV) in the fructose-induced hypertensive rat. Using immunoblotting, we studied the nitric oxide synthase signaling pathway, NO concentration, and the levels of FKN and CX3CR1, and pro-inflammatory cytokines were analyzed by immunohistochemistry staining.ResultsThe level of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, FKN, and CX3CR1 were elevated two weeks after fructose feeding. AZD8797 inhibited CX3CR1-microglia, which improved the regulation of systemic blood pressure and NO generation in the NTS. We also found that IL-1β, IL-6, and TNF-α levels were recovered by AZD8797 addition.ConclusionWe conclude that CX3CR1-microglia represses the nNOS signaling pathway and promotes chronic inflammation in fructose-induced hypertension. Collectively, our results reveal the role of chemokines such as IL-1β, IL-6, and TNF-α in NTS neuroinflammation with the involvement of FKN and CX3CR1.

Glut5‐KD reduces blood pressure via increases phosphorylation of nNOS and decreases NADPH oxidase by AMPK activation in the NTS of fructose‐induced hypertensive rats

Glucose transporter5 (GLUT5) is a fructose transporter in enterocytes. Many studies indicated that the mechanisms by which excessive fructose increases blood pressure. GLUT5 immunoreactivity is located in the epithelial cells of the choroid plexus and the ependymal cells, suggesting the possibility of the direct transportation of intravascular fructose into the nucleus tractus solitarii (NTS). The aim of this study was to investigate whether knock‐down GLUT5 in the NTS can improve hypertension in fructose‐fed rats with 10% fructose water. Our in vivo study showed that GLUT1/5 mRNA levels increased in the NTS of fructose‐fed rats at the early stage of 7 days. Our in vitro immunoblotting study found that fructose‐induced GLUT5 up‐regulated lead to AKT‐nNOS signaling pathway significantly decreased in PC12 neuronal cells after fructose treatment. In addition, we injected lentivirus‐delivered GLUT5 shRNA into the NTS of fructose‐induced hypertensive rats for 6 weeks. Two weeks after injection of lentivirus‐delivered GLUT5 shRNA, we fed with 10% fructose water for 4 weeks. Glut5‐knockdown (KD) down‐regulates blood pressure through improved sympathetic hyperactivity and central insulin signaling in the fructose‐induced hypertensive rats. Our data showed that Glut5‐KD restores AMPK‐dependent mechanism, decreases fructose‐induced oxidative stress, which attenuated NADPH oxidase in the NTS of fructose‐induced hypertensive rats. This study suggests that fructose through GLUT5‐RAGE overexpression induces ROS generation in the NTS, which lead to impairment of AKT‐nNOS‐NO signaling pathway and cause hypertension.Support or Funding InformationMOST104‐2320‐B‐075B‐003‐MY3, 107‐2320‐B‐075B‐002‐MY2This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Antihypertensive Potential of Coenzyme Q10 via Free Radical Scavenging and Enhanced Akt-nNOS Signaling in the Nucleus Tractus Solitarii in Rats.

In the Natural Medicines database, coenzyme Q10 (CoQ10) is classified as possibly effective for the treatment of hypertension. Patients with hypertension frequently have a significant deficiency of the antioxidant CoQ10. Furthermore, reactive oxygen species are overproduced in the nucleus tractus solitarii (NTS) during the cardiovascular regulation of hypertension in vivo. However, the molecular mechanisms by which CoQ10 modulates cardiovascular functions in the NTS are unclear. In this study, the effects of CoQ10 on superoxide generation, downstream NO signaling in the NTS, and blood pressure were evaluated in rats with fructose-induced hypertension. Treatment with oral CoQ10 for 4 weeks abolished nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activation, decreased p38 phosphorylation, and increased superoxide dismutase 2 production in the NTS of fructose-fed rats. The serum levels of uric acid decrease in response to CoQ10 treatment in fructose-fed rats. Oral CoQ10 reduced blood pressure by inducing Akt and nNOS phosphorylation in NTS of fructose-induced hypertensive rats. Oral CoQ10 decreases blood pressure by negatively regulating fructose-induced NADPH oxidase levels, abolishing ROS generation, reducing p38 phosphorylation, and enhancing the Akt-nNOS pathway in the NTS. These results support the beneficial effects of CoQ10 in oxidative stressassociated hypertension.

Effect of A-HRS on blood pressure and metabolic alterations in fructose-induced hypertensive rats

Fructose feeding induces a rise in blood pressure in normal rats that is associated with insulin resistance, hyperinsulinemia, hyperglycaemia, hypercholesterolaemia and hypertriglyceridaemia. We have examined the effect of chronic administration of A-HRS (100 and 300 mg kg−1; p.o.) isolated from Hibiscus rosa sinensis (Malvaceae) on systolic blood pressure (SBP), vascular reactivity, serum glucose, triglycerides, cholesterol, uric acid and insulin in fructose-induced hypertension model. A-HRS treatment (100 and 300 mg kg−1, p.o. for 6 weeks) reduced SBP, vascular reactivity changes to catecholamines and reversed the metabolic alterations induced by fructose (10%) treatment for 6 weeks. The cumulative concentration response curve (CCRC) of angiotensin II (Ang II) was shifted towards the right in rats treated with A-HRS using an isolated strip of ascending colon. The results suggest that A-HRS could prevent the development of high-blood pressure induced by a diet rich in fructose, probably by reversing the metabolic alterations induced by fructose. In conclusion, A-HRS has an antihypertensive action in a fructose model.

Role of methylglyoxal in essential hypertension

Altered glucose metabolism due to insulin resistance is a common feature of essential hypertension in humans and in animal models. Elevated endogenous aldehydes in genetic (spontaneously hypertensive rats) and acquired (fructose-induced hypertensive rats) models of essential hypertension may be due to increased production of the reactive aldehyde methylglyoxal, resulting from altered glucose metabolism. Excess methylglyoxal binds sulfhydryl groups of membrane proteins, altering calcium channels and increasing cytosolic free Ca(2+) and blood pressure. It has been demonstrated that methylglyoxal, when given in drinking water to Wistar-Kyoto rats, leads to an increase in kidney aldehyde conjugates, cytosolic free Ca(2+) concentration, decreased serum nitric oxide, renal vascular hyperplasia and hypertension. N-acetylcysteine (NAC) in the diet of these animals prevented hypertension and associated biochemical and morphological changes. NAC normalizes blood pressure by directly binding to excess methylglyoxal, thus normalizing Ca(2+) channels, cytosolic Ca(2+) and nitric oxide. NAC also leads to increased levels of tissue glutathione, a storage form of cysteine. Glutathione acts as a cofactor in the enzymatic catabolism of methylglyoxal. Cysteine and other antioxidants, such as vitamins B(6), C and E, and lipoic acid, prevented hypertension and associated biochemical and morphological changes in both genetic and acquired rat models of hypertension. The antihypertensive effect of dietary antioxidants may be due to an increase in tissue cysteine and glutathione, which improves glucose metabolism and decreases tissue methylglyoxal. A diet rich in these antioxidants may be effective in preventing and controlling hypertension in humans.

S-allyl-mercapto-captopril: a novel compound in the treatment of Cohen-Rosenthal diabetic hypertensive rats.

S-allyl-mercapto-captopril (CPSSA) is a conjugate of captopril with allicin, an active principle in garlic with multiple beneficial actions on metabolic syndrome abnormalities, including weight preservation, observed by the authors in fructose-induced hypertensive hyperinsulinemic rats and in Koletsky rats. The aim of the study was to examine blood pressure (BP) and glucose levels in the Cohen-Rosenthal Diabetic Hypertensive (CRDH) model as well as to follow their weight preservation. CRDH rats (n=14) were fed the sugar-rich copper-free diet essential for the development of diabetes mellitus. Two months later BP and blood glucose levels were measured. CPSSA was diluted in drinking water and administered at a final dose of 53.5 mg/kg/d (n=8). Control rats (n=6) received no drug (vehicle group). In contrast to control group, CPSSA prevented progressive weight gain, without a detectable effect on food and water intake. CPSSA was effective in attenuating systolic and diastolic BP (P<0.01) as well as significantly reducing glucose levels (P<0.01). Control rats continued to gain weight, whereas the groups fed CPSSA did not. CPSSA was shown to have additional beneficial effects on improving BP and glucose level, as well as preserving weight gain. The authors conclude that the combined molecule CPSSA integrates the antihypertensive feature of both allicin and captopril, making it a potential antidiabetic and cardiovascular protective agent.

Celastrol Attenuates Hypertension-Induced Inflammation and Oxidative Stress in Vascular Smooth Muscle Cells via Induction of Heme Oxygenase-1

The aim of this study was to investigate the potential beneficial effects of celastrol, a compound with anti-inflammatory and antioxidant properties, on vascular smooth muscle cells (VSMCs) under hypertensive conditions. Hypertension was induced in rats by fructose feeding. Hypertensive rats were injected with celastrol, and systolic blood pressure (SBP) and diastolic BP (DBP) were monitored by the tail-cuff method. Insulin sensitivity in animals was measured by glucose tolerance test (GTT). Serum levels of inflammatory cytokines were determined by enzyme-linked immunosorbent assay. Real-time reverse transcription-PCR and western blot were applied to quantify mRNA and protein levels in tissues and primary cultured VSMCs. Generation of reactive oxygen species (ROS) was measured using lucigenin chemiluminescence for tissue homogenates and dichlorodihydrofluorescein diacetate staining for VSMC cells. Celastrol decreased both SBP and DBP while improving insulin sensitivity in fructose-induced hypertensive rats. Celastrol also inhibited vascular and cardiac hypertrophy. Hypertension augmented circulating and mRNA levels of inflammatory cytokines, and celastrol treatment suppressed their induction. Celastrol also blocked activation of extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and Akt signaling both in vivo and in vitro. More importantly, celastrol increased heme oxygenase-1 (HO-1) expression and activity, whereas zinc protoporphyrin 9 (ZnPP9), a HO-1 inhibitor, partially abolished the beneficial effects of celastrol on hypertensive rats and VSMCs. Finally, ROS generation in tissue homogenates and in VSMCs was reduced by celastrol. These findings suggest that celastrol attenuates hypertension-induced inflammation and oxidative stress in VSMCs via HO-1 induction, and this compound may therefore serve as a novel drug to treat hypertension.

Effect of Losartan on Vascular Function in Fructose-Fed Rats: The Role of Perivascular Adipose Tissue

Recent studies have shown the effect of perivascular adipose tissue (PVAT) on the regulation of vascular function; however, its role in the model of metabolic syndrome remains unclear. The aim of this study was to examine the effect of losartan on PVAT-derived vascular dysfunction in fructose-induced hypertensive rats. Rats were fed with either water, 10% fructose, or 10% fructose with 10mg/kg losartan for 8 weeks. In the isolated aorta with PVAT and endothelium, contraction induced by norepinephrine (NE) was more potent in fructose-fed rats compared to control rats. Losartan normalized blood pressure, insulin resistance, and NE-induced vasoconstriction in fructose-fed rats. In the aortic rings with/without endothelium and with/without PVAT, losartan could not improve the acetylcholine-induced relaxation in fructose-fed rats. The observation suggested that losartan partly improved the PVAT-associated vascular regulation in fructose-induced hypertensive rats.

Changes of endothelin-1 and endothelin-A receptor and endothelial nitric oxide synthase in fructose-induced hypertensive rat model

Changes of endothelin-1 and endothelin-A receptor and endothelial nitric oxide synthase in fructose-induced hypertensive rat model

Dehydroepiandrosterone (DHEA) prevents the prostanoid imbalance in mesenteric bed of fructose-induced hypertensive rats

In previous studies we reported an altered prostanoid (PR) release-pattern in mesenteric vessels in fructose (F)-overloaded rats, an experimental model of insulin resistance and hypertension. Dehydroepiandrosterone (DHEA) and its precursor Dehydroepiandrosterone sulfate (DHEA-S) are the most abundant circulating steroid hormones produced by the adrenal and recent studies in both cells and animals suggest that DHEA may have acute non-genomic actions that mimic both metabolic and vascular actions of insulin. This study was to analyze in F-overloaded rats, the effects of DHEA treatment on arterial blood pressure and the PR production in mesenteric vessels and aorta. Male 6 week-old Sprague-Dawley rats were randomly divided in four groups: a control group (C), a DHEA (30 mg/kg/sc/48 h)-treated group (D), a fructose (10% w/v in drinking water)-fed group (F), and both treatments simultaneously group (FD). The systolic blood pressure (SBP) was measured by tail cuff method and glycemia and triglyderidemia were measured by enzymatic assays. The mesenteric beds of all groups were dissected, and incubated in Krebs solution. The PR released were measured by HPLC. F overload increased SBP and triglyceridemia and decreased the mesenteric vasodilatory PR release. DHEA treatment prevented the increment in SBP and triglyceridemia and decreased vasoconstrictor PR in F-treated rats. DHEA normalize the PGI(2)/TX ratio, diminished in F-overloaded rats, through the decrease in thromboxane (TX) production and this could be one of the mechanisms by which DHEA prevented the slight hypertension in F-animals.

Tissue kallikrein reverses insulin resistance and attenuates nephropathy in diabetic rats by activation of phosphatidylinositol 3-kinase/protein kinase B and adenosine 5'-monophosphate-activated protein kinase signaling pathways.

We previously reported that iv delivery of the human tissue kallikrein (HK) gene reduced blood pressure and plasma insulin levels in fructose-induced hypertensive rats with insulin resistance. In the current study, we evaluated the potential of a recombinant adeno-associated viral vector expressing the HK cDNA (rAAV-HK) as a sole, long-term therapy to correct insulin resistance and prevent renal damage in streptozotocin-induced type-2 diabetic rats. Administration of streptozotocin in conjunction with a high-fat diet induced systemic hypertension, diabetes, and renal damage in rats. Delivery of rAAV-HK resulted in a long-term reduction in blood pressure, and fasting plasma insulin was significantly lower in the rAAV-HK group than in the control group. The expression of phosphatidylinositol 3-kinase p110 catalytic subunit and the levels of phosphorylation at residue Thr-308 of Akt, insulin receptor B, and AMP-activated protein kinases were significantly decreased in organs from diabetic animals. These changes were significantly attenuated after rAAV-mediated HK gene therapy. Moreover, rAAV-HK significantly decreased urinary microalbumin excretion, improved creatinine clearance, and increased urinary osmolarity. HK gene therapy also attenuated diabetic renal damage as assessed by histology. Together, these findings demonstrate that rAAV-HK delivery can efficiently attenuate hypertension, insulin resistance, and diabetic nephropathy in streptozotocin-induced diabetic rats.

Antihypertensive Effect of Trigonella foenum-greacum. Seeds in Experimentally Induced Hypertension in Rats

We investigated the antihypertensive effect of a methanol extract (ME) of fenugreek seeds and its methanol fraction (MF) in deoxycorticosterone acetate (DOCA)-salt-induced and fructose-induced hypertensive rats. In the DOCA model, DOCA (15 mg/kg, twice a week; s.c.) was administered in uni-nephrectomized animals for 4 weeks. Methanol extract of fenugreek seeds (30 mg kg−1 day−1; p.o.) and its methanol fraction (15 mg kg−1 day−1; p.o.) were evaluated for their antihypertensive effect. In the fructose model, drinking water was replaced with a 10% fructose solution for 6 weeks to induce hypertension. ME (100 mg kg−1 day−1; p.o.) was assessed for its antihypertensive effect in the fructose model. After completion of the treatment schedule, blood pressure and vascular reactivity to various agonists like serotonin (5-hydroxytryptamine; 5-HT), noradrenaline (NA), and adrenaline (Adr) were recorded in rats of both models. A dose-response curve (DRC) of 5-HT was carried out in isolated rat fundus strip of the fructose-induced hypertensive rats. Chronic administration of ME (30 mg kg−1 day−1; p.o.) and MF (15 mg kg−1 day−1; p.o.) of fenugreek seeds significantly reduced blood pressure in DOCA salt and ME (100 mg kg−1 day−1; p.o.) reduced blood pressure in fructose-induced hypertensive rats. Treatment with ME (100 mg kg−1 day−1; p.o.) in fructose model for 6 weeks shifted the DRC toward the right on rat fundus. Thus, fenugreek seeds exhibit a significant antihypertensive effect. The mechanism of action may partly involve the serotonergic antagonistic property involving the 5-HT2 receptor subtype.

Potential of Gene Therapy Strategy for the Treatment of Hypertension

Hypertension is one of the most important risk factors for cardiovascular diseases (CVDs). CVD extends across all populations and represents the leading cause of morbidity and mortality in industrialized countries. Hypertension increases the risk of peripheral arterial disease, cardiomyopathy, stroke, and renal failure. The disease affects &50 million Americans and goes undetected in at least one third of the population. In spite of the tremendous progress made by pharmacotherapy in the management and control of hypertension, there has been a steady escalation in its prevalence during the last decade. This has led many to conclude that traditional pharmacotherapy has reached an intellectual plateau and that novel and innovative approaches must be sought for the treatment, control, and possible cure of hypertension. As a result, efforts of our group and those of many others have been diverted to explore the use of gene transfer and gene therapy strategies for a long-term control of hypertension. We have argued that gene therapy offers potentially significant improvements and benefits over the use of traditional pharmacotherapy: (1) noncompliance by patients can be significantly reduced or even eliminated because of the fact that a single treatment involving gene transfer could remain effective for months or even years; (2) side effects associated with pharmacotherapy can be minimized as a result of specific targeting of a therapeutic gene in a given tissue and optimally influencing cardiovascular pathophysiology on an individual patient basis; and (3) with its potential to produce long-term beneficial outcomes in end-organ damage, the gene therapy strategy could lead to a cure of hypertension and its related pathophysiology. It is noteworthy to mention that current pharmacotherapies are often unable to reverse end-organ damage associated with hypertension. In order for the gene therapy for hypertension to be successful, one must provide conceptual support of its efficacy in …

Superoxide dismustase mimetic tempol decreases blood pressure by increasing renal medullary blood flow in hyperinsulinemic-hypertensive rats

Insulin resistance and compensatory hyperinsulinemia often coexist in hypertensive patients, which may play a role in the development of hypertension. Because medullary blood flow (MBF), which is strongly influenced by the nitric oxide (NO) system, is thought to be an important component of blood pressure and sodium balance, we focused particularly on MBF in fructose-induced hypertensive rats. Moreover, it has been reported that the increased reactive oxygen species (ROS) in the kidney may contribute to the development of hypertension. Our study was thus designed to test the hypotheses that MBF is diminished in fructose-hypertensive rats (FFR) and that administration of tempol, a membrane-permeable mimetic of superoxide dismutase (SOD), decreases mean arterial pressure (MAP) by increasing MBF. Male Sprague-Dawley rats (180 to 200 g) were divided into 6 groups: control untreated (C, n = 5), control tempol-treated (in drinking water) (CT, n = 4), control l-arginine-treated (in drinking water) (CA, n = 6), fructose-fed untreated (F, n = 7), fructose-fed tempol-treated (FT, n = 7), and fructose-fed l-arginine-treated rats (in drinking water) (FA, n = 6). MAP and 24-hour urine samples were measured weekly over a 4-week test period. Changes in MBF, cortical blood flow (CBF), and renal blood flow (RBF) were determined by implanted optical fiber-, laser- and pulse-Doppler flow measurement techniques 4 weeks after starting the diet. Fructose feeding resulted in hyperinsulinemia, significantly elevated MAP, decreased MBF without changes in RBF or CBF, and decreased sodium excretion in the F group compared to the C group. Administration of tempol significantly decreased MAP and plasma insulin in contrast to increased MBF and sodium excretion in the FT group compared to those in the F group. Results indicated that MBF played an important role in the development of hypertension in the F group. Impairment of renal medullary NO systems may induce sustained elevation of blood pressure and retention of sodium in fructose-fed rats. The decrease in MAP with an increase of MBF in the FT group is consistent with the hypothesis that tempol increases the level of NO available to influence mechanisms involved in the control of MBF.

Effects of Morin on Blood Pressure and Metabolic Changes in Fructose-Induced Hypertensive Rats

High fructose (HF) feeding induces a moderate increase in blood pressure in rats, which is associated with insulin resistance, hyperinsulinemia, and hypertriglyceridemia. In the present study, we examined the chronic effect of morin, a flavonoid isolated from medicinal plants, on blood pressure, lipid profiles, and serum insulin and glucose in HF-induced hypertensive rats. Rats were divided into control group and HF-fed group during the first three weeks of experiments. Then, rats were further divided into four groups and treated for 4 more weeks as follows: 1) control group; 2) morin-treated (intraperitoneal 5 mg/kg/d) control group; 3) HF-fed group; 4) morin-treated, HF-fed group (n=8, each group). Morin-treated HF-fed group showed lower systolic blood pressure (SBP) (132.0+/-2.5 mmHg vs. 142.8+/-2.2 mmHg, p<0.05), lower serum insulin level (1.21+/-0.27 vs. 2.73+/-0.30 microIU/dl, p<0.05), and lower plasma triglycerides (47.8+/-5.0 vs. 65.5+/-5.0 mg/dl, p<0.05) than those of HF-fed group. Morin treatment also suppressed mRNA expression of endothelin-1 (ET-1) in the thoracic aorta from HF-induced hypertensive rats. Moreover, decreased renal sodium excretion in HF-induced hypertensive rats was ameliorated by morin treatment. In conclusion, the results of this study demonstrate that morin has an anti-hypertensive effect in HF-induced hypertensive rats. This effect of morin may be associated with the suppression of serum insulin and plasma triglyceride level, with the down-regulation of ET-1 in the thoracic aorta, and with the partial amelioration of renal dysfunctions in HF-induced hypertensive rats.

Gene therapy with human tissue kallikrein reduces hypertension and hyperinsulinemia in fructose-induced hypertensive rats.

This study investigates gene therapy with human tissue kallikrein as a treatment for fructose-induced hypertension in rats. Hypertension was induced by addition of 10% fructose to drinking water. Fructose-fed rats also had increased serum insulin and triglycerides, decreased urine osmolarity, increased urine volume and endothelin-1, and increased aortic endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 mRNA levels. Fructose-induced hypertensive and control rats were injected intravenously with a construct containing the human tissue kallikrein cDNA. Two weeks after injection of hypertensive rats, systolic blood pressure and serum insulin levels normalized, urine osmolarity increased, urine endothelin-1 levels decreased, and aortic endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 mRNA levels decreased. In contrast, injection of the human tissue kallikrein cDNA had minimal effect on blood pressure or insulin levels in control rats. These results suggest that gene therapy with human tissue kallikrein may have potential as a treatment for hypertension and associated insulin resistance. Moreover, our data suggest that the beneficial effects of human tissue kallikrein on these parameters are associated with changes in endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 expression.