Hypertension In Fructose-fed Rats Research Articles

The KCa3.1 channel blocker TRAM-34 and minocycline prevent fructose-induced hypertension in rats.

High fructose consumption increases blood pressure through microglia-related neuroinflammation in rats. Since intermediate-conductance calcium-activated potassium channels (KCa3.1) potentiates microglial reactivity, we examined whether the pretreatment with the KCa3.1 channel blocker TRAM-34 or minocycline prevents hypertension development in fructose-fed rats. The study involved male Wistar rats that were given either a high fructose (10% in drinking water) or a tap water for 21 days. Fructose groups also received minocycline or TRAM-34 systemically for 21 days. We measured systolic and diastolic blood pressure (SBP and DBP), heart rate (HR) periodically with tail-cuff; proinflammatory cytokines and insulin levels in plasma via ELISA, and neuroinflammatory markers in the nucleus tractus solitarii (NTS) by qPCR at the end of 21 days. We also examined endothelium-dependent hyperpolarization (EDH)-type vasorelaxations in isolated mesenteric arteries of the rats ex vivo. SBP, DBP, and HR increased in the fructose group. Both minocycline and TRAM-34 significantly prevented these increases. Fructose intake also increased plasma IL-6, IL-1β, TNF-α, and insulin levels, whereas pretreatment with TRAM-34 prevented these increases as well. Iba-1, but not CD86 levels were significantly higher in the NTS samples of fructose-fed hypertensive rats which implied microglial proliferation. EDH-type vasorelaxations mediated by endothelial KCa3.1 attenuated in the fructose group; however, TRAM-34 did not cause further deterioration in the relaxations. TRAM-34 is as effective as minocycline in preventing fructose-induced hypertension without interfering with the EDH-type vasodilation. Furthermore, TRAM-34 relieves high fructose-associated systemic inflammation.

Aqueous extract of large cardamom inhibits vascular damage, oxidative stress, and metabolic changes in fructose-fed hypertensive rats

ABSTRACT Purpose Since metabolic abnormalities such as elevated glucose level and imbalanced lipid profiles increase the risk for hypertension and cause endothelial dysfunction, we evaluated the effect of aqueous extract of large cardamom (AELC) on fructose-induced metabolic hypertension and oxidative stress Methods The male Sprague-Dawley rats were divided into 6 groups with 5 rats in each group, and each group was fed with 10% fructose in drinking water for 8 weeks. Starting from week 5, animals were treated with 50, 100, and 200 mg/kg/day AELC or Losartan (10 mg/kg/day). Systolic, diastolic, and mean arterial blood pressure was measured once in every seven days using the tail-cuff method. Vascular function, plasma nitric oxide (NO), glucose, lipid profiles, serum biochemical, and anti-oxidant parameters were also evaluated. Results Rats fed with fructose showed higher blood pressure, serum cholesterol, and triglyceride levels, but decreased in the AELC or Losartan treatment group. Treatments with AELC prevented exaggerated plasma glucose and oxidative stress and restored the nitric oxide level in fructose-fed rats. Besides, it also reduced vascular proliferation and improved the relaxation response of acetylcholine in the aorta pre-contracted with phenylephrine. Conclusion In summary, the obtained results suggest that AELC can prevent and reverse the high blood pressure induced by fructose, probably by restoring nitric oxide level and by improving altered metabolic parameters.

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.

Renin inhibition improves metabolic syndrome, and reduces angiotensin II levels and oxidative stress in visceral fat tissues in fructose-fed rats.

Renin–angiotensin system in visceral fat plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats. However, the effects of renin inhibition on visceral adiposity in metabolic syndrome are not fully investigated. We investigated the effects of renin inhibition on visceral adiposity in fructose-fed rats. Male Wistar–Kyoto rats were divided into 4 groups for 8-week experiments: Group Con (standard chow diet), Group Fru (high-fructose diet; 60% fructose), Group FruA (high-fructose diet and concurrent aliskiren treatment; 100 mg/kg body weight [BW] per day), and Group FruB (high-fructose diet and subsequent, i.e. 4 weeks after initiating high-fructose feeding, aliskiren treatment; 100 mg/kg BW per day). The high-fructose diet induced metabolic syndrome, increased visceral fat weights and adipocyte sizes, and augmented angiotensin II (Ang II), NADPH oxidase (NOX) isoforms expressions, oxidative stress, and dysregulated production of adipocytokines from visceral adipose tissues. Concurrent and subsequent aliskiren administration ameliorated metabolic syndrome, dysregulated adipocytokines, and visceral adiposity in high fructose-fed hypertensive rats, and was associated with reducing Ang II levels, NOX isoforms expressions and oxidative stress in visceral fat tissues. Therefore, this study demonstrates renin inhibition could improve metabolic syndrome, and reduce Ang II levels and oxidative stress in visceral fat tissue in fructose-fed rats, and suggests that visceral adipose Ang II plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats.

Beneficial effects of calcitriol on hypertension, glucose intolerance, impairment of endothelium-dependent vascular relaxation, and visceral adiposity in fructose-fed hypertensive rats.

Besides regulating calcium homeostasis, the effects of vitamin D on vascular tone and metabolic disturbances remain scarce in the literature despite an increase intake with high-fructose corn syrup worldwide. We investigated the effects of calcitriol, an active form of vitamin D, on vascular relaxation, glucose tolerance, and visceral fat pads in fructose-fed rats. Male Wistar-Kyoto rats were divided into 4 groups (n = 6 per group). Group Con: standard chow diet for 8 weeks; Group Fru: high-fructose diet (60% fructose) for 8 weeks; Group Fru-HVD: high-fructose diet as Group Fru, high-dose calcitriol treatment (20 ng / 100 g body weight per day) 4 weeks after the beginning of fructose feeding; and Group Fru-LVD: high-fructose diet as Group Fru, low-dose calcitriol treatment (10 ng / 100 g body weight per day) 4 weeks after the beginning of fructose feeding. Systolic blood pressure was measured twice a week by the tail-cuff method. Blood was examined for serum ionized calcium, phosphate, creatinine, glucose, triglycerides, and total cholesterol. Intra-peritoneal glucose intolerance test, aortic vascular reactivity, the weight of visceral fat pads, adipose size, and adipose angiotensin II levels were analyzed at the end of the study. The results showed that the fructose-fed rats significantly developed hypertension, impaired glucose tolerance, heavier weight and larger adipose size of visceral fat pads, and raised adipose angiotensin II expressions compared with the control rats. High- and low-dose calcitriol reduced modestly systolic blood pressure, increased endothelium-dependent aortic relaxation, ameliorated glucose intolerance, reduced the weight and adipose size of visceral fat pads, and lowered adipose angiotensin II expressions in the fructose-fed rats. However, high-dose calcitriol treatment mildly increased serum ionized calcium levels (1.44 ± 0.05 mmol/L). These results suggest a protective role of calcitriol treatment on endothelial function, glucose tolerance, and visceral adiposity in fructose-fed rats.

Selective alpha1-adrenoceptor blockade prevents fructose-induced hypertension

The purpose of this study was to investigate the effect of chronic treatment with prazosin, a selective α1-adrenoceptor antagonist, on the development of hypertension in fructose-fed rats (FFR). High-fructose feeding and treatment with prazosin (1mg/kg/day via drinking water) were initiated simultaneously in male Wistar rats. Systolic blood pressure, fasted plasma parameters, insulin sensitivity, plasma norepinephrine (NE), uric acid, and angiotensin II (Ang II) were determined following 9weeks of treatment. FFR exhibited insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension, as well as elevations in plasma NE and Ang II levels. Treatment with prazosin prevented the rise in blood pressure without affecting insulin levels, insulin sensitivity, uric acid, or Ang II levels, while normalizing plasma NE levels in FFR. These data suggest that over-activation of the sympathetic nervous system, specifically α1-adrenoceptors, contributes to the development of fructose-induced hypertension, however, this over-activation does not appear to an initial, precipitating event in FFR.

Role of Cox-2 in Vascular Inflammation: An Experimental Model of Metabolic Syndrome

The objective of this work was to demonstrate the role of COX-2 enzyme at the vascular in experimental model of metabolic syndrome. SHR male WKY rats were employed; they were distributed in 8 groups (n = 8 each): control (W); W + L: WKY rats receiving 20 mg/kg of lumiracoxib by intraesophageal administration; SHR; SHR + L: SHR + 20 mg/kg of lumiracoxib by intraesophageal administration; Fructose-Fed Rats (FFR): WKY rats receiving 10% (w/v) fructose solution in drinking water during all 12 weeks; FFR + L: FFR + 20 mg/kg of lumiracoxib by intraesophageal administration; Fructose-Fed Hypertensive Rats (FFHR): SHR receiving 10% (w/v) fructose solution in drinking water during all 12 weeks; and FFHR + L: FFHR + 20 mg/kg of lumiracoxib by intraesophageal administration. Metabolic variables, blood pressure, morphometric variables, and oxidative stress variables were evaluated; also MMP-2 and MMP-9 (collagenases), VCAM-1, and NF-κB by Westernblot or IFI were evaluated. FFHR presented all variables of metabolic syndrome; there was also an increase in oxidative stress variables; vascular remodeling and left ventricular hypertrophy were evidenced along with a significant increase in the expression of the mentioned proinflammatory molecules and increased activity and expression of collagenase. Lumiracoxib was able to reverse vascular remodeling changes and inflammation, demonstrating the involvement of COX-2 in the pathophysiology of vascular remodeling in this experimental model.

Beneficial effect of genistein on lowering blood pressure and kidney toxicity in fructose-fed hypertensive rats

The study evaluates the effects of genistein on blood pressure (BP) and ultrastructural changes in kidney of fructose-fed hypertensive rats. Male Wistar rats were fed a diet containing 60 % starch or 60 % fructose as the source of carbohydrate. After 15 d, rats in each dietary group were divided into two groups and were treated with either genistein (1 mg/kg per d) in dimethylsulfoxide (DMSO) or 30 % DMSO alone. BP, pressor mechanisms, protein kinase C-βII (PKC-βII) expression, endothelial NO synthase (eNOS) expression and renal ultrastructural changes were evaluated after 60 d. Fructose-fed rats displayed significant elevation in BP and heart rate. Significant increase in plasma angiotensin-converting enzyme (ACE) activity, alterations in renal lipid profile, nitrite and kallikrein activity, enhanced expression of membrane-associated PKC-βII and decreased expression of eNOS were observed in them. Histology and electron microscopic studies showed structural changes in the kidney. Genistein administration lowered BP, restored ACE, PKC-βII and eNOS expression and preserved renal ultrastructural integrity. These findings demonstrate that genistein has effects on eNOS activity in renal cells, leading to eNOS activation and NO synthesis. These effects could have been mediated by activation of PKC-βII. The observed benefits of genistein make it a promising candidate for therapy of diabetic kidney disease.

Direct renin inhibitor prevents and ameliorates insulin resistance, aortic endothelial dysfunction and vascular remodeling in fructose-fed hypertensive rats

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers can improve insulin resistance and vascular dysfunction in insulin-resistant rats; however, there are few reports on the effects of direct renin inhibitors on these conditions. We investigated the effects of a direct renin inhibitor, aliskiren, on insulin resistance, aortic endothelial dysfunction and vascular remodeling in fructose-fed hypertensive rats. Male Wistar-Kyoto rats were divided into four groups (n=6 per group) and studied for 8 weeks: Group Con: standard chow diet; group Fru: high-fructose diet (60% fructose); Group FruA: high-fructose diet with concurrent aliskiren treatment (100 mg kg(-1) per day); and Group FruB: high-fructose diet with subsequent aliskiren treatment 4 weeks later. Blood was collected for biochemical assays, and isolated rings of the thoracic aorta were obtained for analysis of vascular reactivity, vascular structure and lipid peroxide. Rats fed with high-fructose diets developed significant systolic hypertension, decreased plasma nitrite (NO(2); nitric oxide metabolite) levels and increased plasma glucose, insulin, triglyceride, total cholesterol and aortic lipid peroxide levels, and aortic wall thickness compared with control rats. Aliskiren treatment, either concurrent or subsequent, elevated plasma NO(2) levels and reduced systolic hypertension, insulin resistance, dyslipidemia, aortic lipid peroxide levels and aortic wall hypertrophy in FHR. The peak endothelium-dependent aortic relaxations were significantly higher in rats that received aliskiren treatment than in those that did not. In conclusion, our findings suggest that aliskiren prevents and ameliorates insulin resistance, aortic endothelial dysfunction and oxidative vascular remodeling in fructose-fed hypertensive rats.

Inhibition of matrix metalloproteinase‐2 improves endothelial function and prevents hypertension in insulin‐resistant rats

Insulin resistance is often found to be associated with high blood pressure. We propose that in insulin-resistant hypertension, endothelial dysfunction is the consequence of increased activity of vascular MMP-2. As MMP-2 proteolytically cleaves a number of extracellular matrix proteins, we hypothesized that MMP-2 impairs endothelial function by proteolytic degradation of endothelial NOS (eNOS) or its cofactor, heat shock protein 90 (HSP90). We tested our hypothesis in bovine coronary artery endothelial cells and fructose-fed hypertensive rats (FHR), a model of acquired systolic hypertension and insulin resistance. Treatment of FHRs with the MMP inhibitor doxycycline, preserved endothelial function as well as prevented the development of hypertension, suggesting that MMPs impair endothelial function. Furthermore, incubating endothelial cells in vitro with a recombinant MMP-2 decreased NO production in a dose-dependent manner. Using substrate cleavage assays and immunofluorescence microscopy studies, we found that MMP-2 not only cleaves and degrades HSP90, an eNOS cofactor but also co-localizes with both eNOS and HSP90 in endothelial cells, suggesting that MMPs functionally interact with the eNOS system. Treatment of FHRs with doxycycline attenuated the decrease in eNOS and HSP90 expression but did not improve insulin sensitivity. Our data suggest that increased activity of MMP-2 in FHRs impairs endothelial function and promotes hypertension. Inhibition of MMP-2 could be a potential therapeutic strategy for the management of hypertension.

Effect of bromocriptine on cardiovascular complications associated with metabolic syndrome in fructose fed rats

Objective:The objective of the present study was to evaluate the effect of bromocriptine on cardiovascular complications associated with type-2 diabetes mellitus (DM).Materials and Methods:Metabolic syndrome or type 2 DM was induced by administration of fructose (66% solution, p.o.) in rats. Bromocriptine mesylate (10 mg/kg, i.p.) was given in fructose-treated rats for a period of 6 weeks after induction of diabetes. After drug treatment, the parameters such as body weight, food and water intake, serum glucose, triglycerides, cholesterol, insulin, and blood pressure (BP) were measured weekly and at the end of study. At the end of treatment, BP was determined by invasive method and vascular reactivity was tested with adrenaline (Adr), noradrenaline (NA), and phenylephrine (PE). Acetylcholine-induced vasorelaxation was tested on isolated rat aorta and histopathology of hearts was also done.Results:Fructose-fed rats showed significant weight gain, hyperglycemia, hyperlipidemia, hyperinsulinemia, and rise of BP. Administration of bromocriptine at a dose 10 mg/kg, i.p. significantly decreased weight gain, serum glucose, triglyceride, cholesterol and insulin levels in rats fed on fructose. Bromocriptine also significantly reduced elevated BP in fructose-fed hypertensive rats. Chronic treatment with bromocriptine significantly improved the relaxant response to acetylcholine on fructose-fed hyperinsulinemic rat aorta and also reduced the pressor response to Adr, NA, and PE. Bromocriptine also showed a protection from hypertrophy and degenerative changes in myocardium.Conclusion:Bromocriptine has beneficial effect in reduction of cardiovascular complications associated with metabolic syndrome.

The novel ATP-sensitive potassium channel opener iptakalim prevents insulin resistance associated with hypertension via restoring endothelial function.

To investigate the effects of iptakalim on endothelial dysfunction induced by insulin resistance (IR) and to determine whether iptakalim improved IR associated with hypertension in fructose-fed rats (FFRs) and spontaneously hypertensive rats (SHRs). Human umbilical vein endothelial cells (HUVECs) were used for in vitro study. The levels of endothelial vasoactive mediators and eNOS protein expression were determined using radioimmunoassays, ELISAs, colorimetric assays or Western blotting. Sprague-Dawley rats were fed with a high-fructose diet. In both FFRs and SHRs, tail-cuff method was used to measure systolic blood pressure (SBP), and hyperinsulinemic- euglycemic clamp was used to evaluate IR states. (1) Cultured HUVECs incubated with the PI3-kinase inhibitor wortmannin (50 nmol/L) and insulin (100 nmol/L) induced endothelial dysfunction characterized by significantly reduced release of NO and expression of eNOS protein, and significantly increased production of ET-1. Pretreatment with iptakalim (0.1-10 μmol/L) could prevent the endothelial dysfunction. (2) In FFRs, the levels of SBP, fasting plasma glucose and insulin were significantly elevated, whereas the glucose infusion rate (GIR) and insulin sensitive index (ISI) were significantly decreased, and the endothelium-dependent vascular relaxation response to ACh was impaired. These changes could be prevented by oral administration of iptakalim (1, 3, or 9 mg·kg(-1)·d(-1), for 4 weeks). The imbalance between serum NO and ET-1 was also ameliorated by iptakalim. (3) In 2-4 month-old SHRs (IR was established at the age of 4 months), oral administration of iptakalim (1, 3, or 9 mg·kg(-1)·d(-1), for 8 weeks) significantly ameliorated hypertension and increased the GIR to the normal level. These results demonstrate that iptakalim could protect against IR-induced endothelial dysfunction, and ameliorate IR associated with hypertension, possibly via restoring the balance between NO and ET-1 signaling.

Administration of Rosmarinic Acid Reduces Cardiopathology and Blood Pressure Through Inhibition of p22phox NADPH Oxidase in Fructose-Fed Hypertensive Rats

Rosmarinic acid (RA), a caffeic acid ester, has insulin-sensitizing and antioxidant effects in high fructose-fed model of insulin resistance (IR). This study investigated whether RA supplementation prevents cardiac abnormalities and hypertension in fructose-fed rats (FFR). Rats fed with fructose diet (60 g/100 g) for 60 days exhibited metabolic abnormalities and rise in plasma and cardiac lipids and whole body IR. The levels of cardiac antioxidants and plasma ferric reducing antioxidant power were significantly reduced in FFR concomitant with increased levels of lipid peroxidation and protein oxidation products. A significant rise in troponin T, creatine kinase-MB, aspartate transaminase, and lactate dehydrogenase in plasma of FFR was noted. RA supplementation to FFR (10 mg/kg from the 16th day) significantly improved insulin sensitivity, reduced lipid levels, oxidative damage, and the expression of p22phox subunit of nicotinamide adenine dinucleotide phosphate reduced oxidase, and prevented cardiac hypertrophy. Fructose-induced rise in blood pressure was also lowered by RA through decrease in endothelin-1 and angiotensin-converting enzyme activity and increase in nitric oxide levels. Histology revealed a reduction in myocardial damage in RA-supplemented FFR. These findings suggest that RA acts as a vasoactive substance and a cardioprotector through its antioxidant property. Thus, RA may be useful in reducing the cardiovascular risk associated with IR.

The fructose-fed rat: a review on the mechanisms of fructose-induced insulin resistance and hypertension

The metabolic syndrome is an important public health concern that predisposes individuals to the development of cardiovascular disease and/or Type 2 diabetes. The fructose-fed rat is an animal model of acquired systolic hypertension that displays numerous features of the metabolic syndrome. This animal model is used to study the relationship between insulin resistance/compensatory hyperinsulinemia and the development of hypertension. Several mechanisms have been proposed to mediate the link between insulin resistance and hypertension. In this review, we have addressed the role of sympathetic nervous system overactivation, increased production of vasoconstrictors, such as endothelin-1 and angiotensin II, and prostanoids in the development of hypertension in fructose-fed rats. The roles of nitric oxide, impaired endothelium-dependent relaxation and sex hormones in the pathogenesis of the fructose-fed induced hypertensive rats have also been highlighted. More recently, increased formation of reactive oxygen species and elevated levels of uric acid have been reported to contribute to fructose-induced hypertension.

Chronic etanercept treatment prevents the development of hypertension in fructose-fed rats

The purpose of this study was to investigate the effect of chronic treatment with etanercept (a soluble recombinant fusion protein consisting of the extracellular ligand-binding domain of tumor necrosis factor receptor type 2) on the development of hypertension in fructose-fed rats (FFR). High fructose feeding and treatment with etanercept (0.3 mg/kg, three times per week) was initiated simultaneously in male Wistar rats. Systolic blood pressure, fasted plasma parameters, insulin sensitivity, vascular reactivity, plasma angiotensin II (Ang II), and norepinephrine were determined following 9 weeks of treatment. FFR exhibited insulin resistance, hyperinsulinemia, hypertriglyceridemia, endothelial dysfunction, and hypertension. Treatment with etanercept prevented the rise in blood pressure without affecting insulin levels, insulin sensitivity, triglycerides, or Ang II levels in FFR. Etanercept treatment improved acetylcholine-induced relaxation and normalized endothelial nitric oxide synthase expression in aortas from FFR. The results of this study suggest that treatment with etanercept prevented the development of hypertension by improving vascular function and restoring endothelial nitric oxide synthase expression in FFR.

In Vitro and In Vivo Pharmacodynamic Properties of Metoprolol in Fructose-fed Hypertensive Rats

This study of metoprolol pharmacokinetic and pharmacodynamic properties investigates cardiac beta1-adrenoceptors activity and its involvement in the hypertensive stage in 6-week-old fructose-fed male Sprague-Dawley rats. A microdialysis probe was inserted in the carotid artery to monitor metoprolol levels, blood pressure, and heart rate after drug administration (3-10 mg/kg intravenously). The relationship between levels and cardiovascular effects was studied using a pharmacokinetic-pharmacodynamic model with effect compartment. Dissociation constant and inverse agonism were evaluated in isolated atria. Metoprolol pharmacokinetics were similar in both groups. Metoprolol induced a greater hypotensive effect in fructose-fed animals (Emax: -24 +/- 1 mm Hg, n = 6, P < 0.05 vs. control) than in control rats (Emax: -14 +/- 1 mm Hg, n = 6). Bradycardic response was similar in both groups; metoprolol chronotropic potency was greater in fructose-fed rats (IC50: 123 +/- 15 ng/mL, P < 0.05 vs. control) compared to control animals (IC50: 216 +/- 36 ng/mL) after administration of 3 mg/kg. Metoprolol constants of dissociation for beta1-adrenoceptors and inverse agonism were similar in both groups. Results demonstrate the beta1-adrenoceptors involvement in the fructose hypertension. A greater potency to metoprolol in vivo chronotropic effect was found in fructose-fed rats. This greater potency was not caused by alteration in the activity of beta1-adrenoceptors.

Endothelin-1 blockade prevents COX2induction and TXA2production in the fructose hypertensive ratThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.

Feeding rats with a high fructose diet results in insulin resistance and hypertension. Fructose-hypertensive rats (FHR) have increased vascular levels of endothelin-1 (ET-1) and thromboxane (TXA2). We have previously shown that chronic treatment with either the dual endothelin receptor blocker, bosentan, or the thromboxane synthase inhibitor, dazmegrel, prevented fructose-induced increases in blood pressure, suggesting that both ET-1 and TXA2 play important roles in the development of hyperinsulinemia/insulin resistance-associated hypertension. In this study, we investigated the potential interrelationship between ET-1 and TXA2 in the development of fructose-induced hypertension in vivo. Male Wistar rats were fed on a high fructose diet for 9 weeks. Either bosentan or dazmegrel treatment (daily by oral gavage) was initiated 3 weeks after the start of fructose feeding for a total duration of 6 weeks. At the end of drug treatment, blood and aorta were collected from each animal. Plasma thromboxane B2 (TXB2), a stable TXA2 metabolite, increased significantly in FHR and was reduced to control level by both chronic bosentan and dazmegrel treatment. Protein expression of cyclooxygenase 2 (COX2) was elevated significantly in FHR aortas and treatment with bosentan and dazmegrel corrected these changes. These results indicate that the actions of ET-1 in the aorta of FHR may be mediated through COX2-derived TXA2. Bosentan may prevent the development of hypertension in fructose-fed rats through inhibition of COX2 induction and subsequently the reduction in plasma TXA2.

Androgens are necessary for the development of fructose-induced hypertension.

Hyperinsulinemia and insulin resistance are closely associated with hypertension in humans and in animal models. Gender differences have been found in the development of hypertension in fructose-fed rats. The objectives of the present study were, first, to clarify whether androgens are required in the development of hyperinsulinemia, insulin resistance, and hypertension in fructose-fed rats, and second, to determine if cyclooxygenase-1 and cyclooxygenase-2 are also increased in the arteries of these rats. Male rats were gonadectomized or sham-operated and fed a 60% fructose diet beginning at age 7 weeks. Blood pressure was measured by a tail-cuff method, and an oral glucose tolerance test was performed to assess insulin sensitivity after 8 weeks of fructose feeding. Cyclooxygenase-1 and cyclooxygenase-2 mRNA expression was also assessed in the thoracic aortae and mesenteric arteries. Gonadectomy prevented hypertension from developing in the fructose-fed rats, but hyperinsulinemia and insulin resistance developed. There was an increase in cyclooxygenase-2 expression in the thoracic aortae and mesenteric arteries of the fructose-fed sham-operated rats while the expression of cyclooxygenase-1 remained unchanged. Gonadectomy prevented the mRNA overexpression of vascular cyclooxygenase-2 in the fructose-fed rats. These results suggest that the presence of androgens is necessary for the development of fructose-induced hypertension. Androgens apparently act as a link between hyperinsulinemia/insulin resistance and hypertension in fructose-hypertensive rats. Furthermore, an increase in the expression of cyclooxygenase-2 is implicated in the development of hypertension. The mechanisms involved require further study.

Potential role of kinins in the effects of taurine in high-fructose-fed rats

The present work investigates the involvement of kinins in the effects of taurine in fructose-fed hypertensive rats. The effects of taurine on blood pressure, plasma glucose, insulin, and the insulin sensitivity index were determined. Angiotensin-converting enzyme (ACE) activity and nitrite content in plasma, plasma and tissue kallikrein activity, and taurine content were also investigated. The blood pressure changes in response to the coadministration of inhibitors of the synthesis of nitric oxide (NO), prostaglandins (PGs), or a kinin receptor blocker along with taurine was also evaluated. Fructose-fed rats had higher blood pressure and elevated plasma levels of glucose and insulin. Kallikrein activity, taurine, and nitrite contents were significantly lower in fructose-fed rats as compared with controls. The increases in systolic blood pressure, hyperglycemia, and hyperinsulinemia were controlled by taurine administration in fructose-fed rats. ACE activity was lower, while nitrite and taurine content and kallikrein activity were higher, in taurine-supplemented rats as compared with fructose-fed rats. A significant increase in blood pressure was observed in rats cotreated with the inhibitors Hoe 140 (a kinin receptor blocker), L-NAME (a NO synthase inhibitor), or indomethacin (a PG synthesis inhibitor) with taurine for 1 week as compared with taurine-treated fructose-fed rats. This suggests that the antihypertensive effect of taurine in fructose-fed rats was blocked by the inhibitors. Augmented kallikrein activity and, hence, increased kinin availability may be implicated in the effects of taurine in fructose-fed hypertensive rats.

Chinese medicine, Jiang-Tang-Ke-Li, improves insulin resistance by modulating muscle fiber composition and muscle tumor necrosis factor-alpha in fructose-fed rats.

Insulin resistance and hyperinsulinemia are common findings in patients with essential hypertension. These impairments in glucose metabolism are commonly associated with diabetes mellitus, hypertension, and dyslipidemia, which are high risk factors of cardiovascular diseases, and recent evidence indicates that they may play a role in the development of coronary artery disease. The aim of this study was to determine the effect of Jiang-Tang-Ke-Li (JTKL), a traditional Chinese medicine used to treat diabetes mellitus in China, on insulin resistance and hypertension in fructose-fed rats (FFR). Systolic blood pressures in the FFR groups were significantly higher than that in the control group, although JTKL had no effect on systolic blood pressure for the last 2 weeks of treatment with the medicine. The average rate of glucose infusion during a glucose clamp, as an index of insulin sensitivity (M value), was significantly lower in the FFR than in the control rats, and treatment with JTKL for 2 weeks significantly increased the M value to that of the control. Treatment with Panax ginseng (PG), a component of JTKL, for 2 weeks also significantly increased the M value of FFR to the control level. The composite ratio of type I fibers in soleus muscle decreased significantly in the FFR compared to that in the control, and treatment with JTKL led to recovery of the composite ratio of type I fibers to the same level as that of the control group. The M value showed a significant positive correlation with the composite ratio of type I fibers and a significant negative correlation with the composite ratio of type II fibers. Tumor necrosis factor (TNF)-alpha levels were significantly higher in the soleus and extensor digitorum longus (EDL) muscles of the FFR than in those of the control rats. Treatment with JTKL for 2 weeks significantly lowered TNF-alpha levels to the control levels. M values showed a significant negative correlation with TNF-alpha in both the soleus and EDL muscles. The results suggest that the Chinese medicine JTKL, which contains PG as one of its valid components, improves insulin resistance by modulating muscle fiber composition and TNF-alpha in skeletal muscles in hypertensive and insulin-resistant FFR.