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Chronically increased levels of high molecular weight advanced glycation end products (HMW-AGEs) are known to induce cardiovascular dysfunction. Whether an acute increase in HMW-AGE levels affects vascular function remains unknown. In this study, we examined whether acute exposure to HMW-AGEs disturbs aortic vasomotor function. Aortae were obtained from healthy male rats and were acutely pre-treated with HMW-AGEs in organ baths. Aortic relaxation responses to cumulative doses of acetylcholine (ACh), in the presence or absence of superoxide dismutase (SOD), were measured after precontraction with phenylephrine (PE). Furthermore, levels of 3-nitrotyrosine were evaluated on aortic paraffine sections. In our study, we show that acute exposure to HMW-AGEs significantly decreases the aortic relaxation response to ACh. SOD pre-treatment prevents acute HMW-AGEs-induced impairment by limiting superoxide formation. In conclusion, our data demonstrate that acute exposure to HMW-AGEs causes adverse vascular remodelling, characterised by disturbed vasomotor function due to increased oxidative stress. These results create opportunities for future research regarding the acute role of HMW-AGEs in cardiovascular dysfunction. [ABSTRACT FROM AUTHOR]

Acid-base conditions modify artery tone and tissue perfusion but the involved vascular-sensing mechanisms and disease consequences remain unclear. We experimentally investigated transgenic mice and performed genetic studies in a UK-based human cohort. We show that endothelial cells express the putative HCO3–-sensor receptor-type tyrosine-protein phosphatase RPTPγ, which enhances endothelial intracellular Ca2+-responses in resistance arteries and facilitates endothelium-dependent vasorelaxation only when CO2/HCO3– is present. Consistent with waning RPTPγ-dependent vasorelaxation at low [HCO3–], RPTPγ limits increases in cerebral perfusion during neuronal activity and augments decreases in cerebral perfusion during hyperventilation. RPTPγ does not influence resting blood pressure but amplifies hyperventilation-induced blood pressure elevations. Loss-of-function variants in PTPRG, encoding RPTPγ, are associated with increased risk of cerebral infarction, heart attack, and reduced cardiac ejection fraction. We conclude that PTPRG is an ischemia susceptibility locus; and RPTPγ-dependent sensing of HCO3– adjusts endothelium-mediated vasorelaxation, microvascular perfusion, and blood pressure during acid-base disturbances and altered tissue metabolism.

This study examined the effects of 12 weeks North-American ginseng supplementation, exercise training, and sedentary behavior on vascular responses in type I diabetic rats. The following hypotheses were tested: (1) ginseng supplementation would result in improved vascular responsiveness and sensitivity; (2) exercise training would result in further improvement in these vascular responses; (3) control rats with no access to exercise would show a depressed vascular response compared to control rats that were not exposed to a sedentary lifestyle. Groups: non-diabetic sedentary control (CS), sedentary diabetic (DS), sedentary diabetic with ginseng supplementation (DS+GS), diabetic with ginseng supplementation and high-intensity endurance exercise (D+GS+EX), and control not exposed to sedentary behavior (C). Diabetes was induced by streptozotocin. Arteries were excised, cleaned, and mounted onto a myography system. Percent vasorelaxation to acetylcholine (ACh) (10-8 M ACh to 10-4 M ACh) of the carotid artery was similar in CS (57 ± 31%), C (66 ± 35%), DS (58 ± 36%), D+GS+Ex (71 ± 37%), and DS+GS (64 ± 37%) (p > 0.05). Percent vasorelaxation of the aorta was smaller in CS (23 ± 17%) compared to C (46 ± 35%), DS (60 ± 40%), D+GS+Ex (64 ± 40%), and DS+GS (56 ± 39%) (p < 0.05), and smaller in C compared to D+GS+Ex (p < 0.05). In the femoral, the percent vasorelaxation was reduced in DS (18 ± 16%) compared to all the other conditions (CS, 43 ± 22%; C, 79 ± 28%; D+GS+Ex, 55 ± 27%; DS+GS, 45 ± 26%; p < 0.05), but larger in C compared to the other conditions (CS, DS, D+GS+Ex, DS+GS; p < 0.05). Diabetes and sedentary lifestyle have detrimental effects on vascular responses that are evident in the femoral arteries of the diabetic rats. Ginseng supplementation restored the loss of sensitivity, with no added vascular protection of exercise training.

Inadequate perfusion of solid cancer tissue results in low local nutrient and oxygen levels and accumulation of acidic waste products. Previous investigations have focused primarily on tumor blood vessel architecture, and we lack information concerning functional differences between arteries that deliver blood to solid cancer tissue versus normal tissue. Here, we use isometric myography to study resistancesized arteries from human primary colon adenocarcinomas and matched normal colon tissue. Vasocontraction of colon cancer feed arteries in response to endothelin-1 and thromboxane stimulation is attenuated compared with normal colon arteries despite similar wall dimensions and comparable contractions to arginine vasopressin and K+-induced depolarization. Acetylcholine-induced vasorelaxation and endothelial NO synthase expression are increased in colon cancer feed arteries compared with normal colon arteries, whereas vasorelaxation to exogenous NO donors is unaffected. In congruence, the differences in vasorelaxant and vasocontractile function between colon cancer feed arteries and normal colon arteries decrease after NO synthase inhibition. Rhythmic oscillations in vascular tone, known as vasomotion, are of lower amplitude but similar frequency in colon cancer feed arteries compared with normal colon arteries. In conclusion, higher NO synthase expression and elevated NO signaling amplify vasorelaxation and attenuate vasocontraction of human colon cancer feed arteries. We propose that enhanced endothelial function augments tumor perfusion and represents a potential therapeutic target. [ABSTRACT FROM AUTHOR]

The tripeptide GVR was previously shown to inhibit ACE and was able to reduce systolic blood pressure in SHRs within 6 h after administration. To further analyse the potential of tripeptide GVR in lowering blood pressure, a long term study was carried out where the tripeptide was orally administered to SHRs for 21 days. Elevated systolic blood pressure was significantly reduced when the peptide was administered at 50 mg/kg body weight and 100 mg/kg body weight. Body weight of the SHRs did not change significantly between the studied groups and the histopathological findings indicated that there were no abnormalities in liver and kidney tissues. From the acute toxicity analysis of this tripeptide, using the Up and Down method revealed that the peptide was non-toxic to SHRs. Tripeptide GVR demonstrated endothelium-dependent vasorelaxation activity using thoracic aortas from SD rats in which vasorelaxation was not observed in denuded aortas. The metabolomic analysis carried out from the sera of SHRs demonstrated changes on metabolites associated with pathways related to renin angiotensin system. As for proteomic analysis, differentially expressed proteins detected were mainly proteins related with inflammation. Based on the results, tripeptide GVR has a potential to ameliorate the elevated blood pressure in SHRs. [ABSTRACT FROM AUTHOR]

Fenugreek is a common herb possessing several bioactive components including diosgenin. Here, dietary fenugreek seed flour and diosgenin were evaluated on a model of endothelium-dependent vasorelaxation by abdominal aortas isolated from rats receiving high-fat, high-sugar diet (HFHSD). 60 male Wistar rats were randomized into six groups: (i) negative control getting conventional rat feed regimen; (ii) positive control receiving HFHSD; (iii) a test group fed 2 g/kg bw/day fenugreek seed flour (containing 10 mg/kg bw/day diosgenin) + HFHSD; (iv) three test groups fed 1, 10 and 50 mg/kg bw/day diosgenin + HFHSD. Alimentary treatments were carried out for six weeks. The abdominal aortas were isolated, and 2 mm wide rings were sectioned off and mounted at a resting tension of 10 mN in organ baths containing Krebs solution (36 °C) exposed to 95% O2 and 5% CO2. After 60-min incubation, a norepinephrine concentration-response (E/c) curve was generated to determine their half-maximal effective concentration (EC50) value. After 60-min wash-out, a pre-contraction with norepinephrine EC50 was made, followed by an acetylcholine E/c curve. Plasma glutathione levels, glutathione-handling enzyme activities and blood antioxidant capacities were also determined. HFHSD significantly decreased the dilatory response to acetylcholine and increased plasma glutathione levels and these effects were significantly reversed by fenugreek seed flour, 10 and 50 mg/kg bw/day diosgenin. Both fenugreek and diosgenin treatments prevent HFHSD-induced endothelial dysfunction and redox changes. As fenugreek treatment was more effective at lower acetylcholine concentrations than diosgenin treatments, components of fenugreek other than diosgenin may contribute to the beneficial effects of dietary fenugreek seed flour. [ABSTRACT FROM AUTHOR]

Objectives The G protein-coupled oestrogen receptor-1 ( GPER-1) agonist G1 induces endothelium-dependent relaxation. Activation of the epidermal growth factor ( EGF) receptor leads to transduction of signals from the plasma membrane for the release of nitric oxide. We tested the hypothesis that G1 induces endothelium-dependent vasorelaxation through activation of the EGF receptor. Methods Rat aortic rings were mounted in organ baths. After pretreatment with various inhibitors, aortic rings contracted with 11,9-epoxymethano-prostaglandin F2α or KCl were subjected to relaxation by G1. Key findings G1 induced endothelium-dependent vasorelaxation, which was attenuated by pretreatment with either L-Nω-nitroarginine methyl ester (L- NAME), an inhibitor of nitric oxide synthase, or (3a S,4 R,9b R)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro- 3 H-cyclopenta[c]quinoline HB-EGF, heparin-binding EGF-like growth factor, a GPER-1 antagonist. Neither a general oestrogen receptor antagonist, ICI 182 780, nor a selective oestrogen receptor-α antagonist, methyl-piperidino-pyrazole dihydrochloride ( MPP), had an effect on G1-induced vasorelaxation. However, pretreatment with EGF receptor blockers, AG1478 or DAPH, resulted in attenuated G1-induced vasorelaxation. In addition, pretreatment with Src inhibitor 4-amino-3-(4-chlorophenyl)-1-(t-butyl)-1 H-pyrazolo[3,4-d]pyrimidine, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine or Akt inhibitor VIII also resulted in attenuated vascular relaxation induced by the cumulative addition of G1. However, neither phosphatidylinositol-3 kinase inhibitors LY294002 and wortmannin nor an extracellular signal-regulated kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene monoethanolate had effect on vascular relaxation induced by the cumulative addition of G1. Conclusions G1 induces endothelium-dependent vasorelaxation through Src-mediated activation of the EGF receptor and the Akt pathway in rat aorta. [ABSTRACT FROM AUTHOR]

The dynamic adjustment and amplitude of the endothelium-dependent vasorelaxation of the carotid, aorta, iliac, and femoral vessels were measured in response to acute low- (LI) or high-intensity (HI) endurance exercise. Vasorelaxation to 10-4M ACh was evaluated in 10 control, 10 LI, and 10 HI rats. Two-millimeter sections of carotid, aorta, iliac, and femoral arteries were mounted onto a myography system. Vasorelaxation responses were modeled as a monoexponential function. The overall τ (control, 10.5 ± 6.0 s; LI, 10.4 ± 5.7 s; HI, 11.0 ± 6.9 s) and time-to-steady-state (control, 47.6 ± 24.0 s; LI, 46.2 ± 22.8 s; HI, 49.1 ± 28.3 s) was similar in LI, HI, and control (P < 0.05). The overall (average of four vessel-type) % vasorelaxation was larger in LI (73 ± 16%) and HI (73 ± 16%) than in control (66 ± 19%) (P < 0.05). The overall rate of vasorelaxation was greater in LI (1.9 ± 0.9%·s-1) and HI (1.9 ± 1.1%·s-1) compared with control (1.6 ± 0.7%·s-1) (P < 0.05). The vessel-specific responses (average response for the three conditions) showed that carotid displayed a slower adjustment (τ, 18.9±4.4 s; time-to-steady-state, 80.4±18.4 s) compared with the aorta (τ, 10.3 ± 3.8 s; time-to-steady-state, 46.3 ± 15.2 s), the iliac (τ, 6.3 ± 2.1 s; time-to-steady-state, 30.3 ± 9.0 s), and the femoral (τ, 6.0 ± 1.9 s; time-to-steady-state, 29.3 ± 8.4 s). The % vasorelaxation was larger in the carotid (82 ± 14%) than in the aorta (67 ± 16%), iliac (61 ± 13%), and femoral (71 ± 19%) (P < 0.05). The rate of vasorelaxation was carotid (1.1 ± 0.2%·s-1), aorta (1.5 ± 0.4%·s-1), iliac (2.2 ± 0.8%·s-1), and femoral (2.6 ± 1.0%·s-1). In conclusion, an acute bout of endurance exercise increased vascular responsiveness. The dynamic and percent adjustments were vessel-specific with vessel function likely determining the response. [ABSTRACT FROM AUTHOR]

It is of interest to investigate whether synthetic thioflavonoids have vasorelaxant actions as natural flavonoids. We tested the hypothesis that 3′,4′-dimethoxythioflavone induces endothelium-dependent vasorelaxation through activation of epidermal growth factor (EGF) receptor. Rat aortic rings were mounted in organ baths and subjected to relaxation upon contraction. 3′,4′-Dimethoxythioflavone induced endothelium-dependent vasorelaxation, which was attenuated by pretreatment with either l- N-nitroarginine methyl ester, an inhibitor of nitric oxide synthase, or 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. 3′,4′-Dimethoxythioflavone-induced vasorelaxation was not affected by pretreatment with a general estrogen receptor antagonist ICI 182,780, a selective estrogen receptor-α antagonist methyl-piperidino-pyrazole dihydrochloride, or a G protein-coupled receptor 30 antagonist G15. However, pretreatment with EGF receptor blockers AG1478 or DAPH, but not with a phosphatidylinositol-3 kinase inhibitor LY294002 or an Akt1/2 kinase inhibitor Akt inhibitor VIII, attenuated 3′,4′-dimethoxythioflavone-induced vasorelaxation. In addition, pretreatment with a Src inhibitor PP2 or an ERK inhibitor U0126 also attenuated vascular relaxation induced by the cumulative addition of 3′,4′-dimethoxythioflavone. However, neither a mitochondrial electron transport inhibitor rotenone, an NADPH oxidase inhibitor apocynin, nor a superoxide dismutase mimetic MnTMPyP affected the vascular relaxation induced by the cumulative addition of 3′,4′-dimethoxythioflavone. In conclusion, 3′,4′-dimethoxythioflavone induces endothelium-dependent vasorelaxation through activation of EGF receptor and Src/ERK pathway in rat aorta. [ABSTRACT FROM AUTHOR]

The rate of adjustment of endothelium-dependent vasorelaxation was examined in the aorta, iliac and femoral arteries of eight control and eight diabetic rats with and without supplementation with vitamin C. Vessels were constricted using 10−5 M phenylephrine (PE) and relaxed with 10−4 M acetylcholine (ACh condition) or 10−4 M ACh plus 10−4 M vitamin C (ACh + vitamin C condition) in a myography system. Vasorelaxation was modelled as a mono-exponential function using a non-linear regression analysis. The adjustment (τ) of vasorelaxation was faster in control (6.6 ± 3.2 s) compared to diabetic rats (8.4 ± 3.4 s) (p < 0.05). The time-to-steady-state tended to be shorter in control (32.0 ± 13.9 s) compared to diabetic rats (38.0 ± 15.0 s) (p = 0.1). ACh + vitamin C did not speed the vasorelaxation response. The τ for vasorelaxation was shorter in the femoral (6.5 ± 2.7 s) and iliac (6.8 ± 2.5 s) compared to the aorta (9.2 ± 4.2 s) (p < 0.05). The rate of vasorelaxation was greater in the femoral (3.2 ± 1.4%·s−1) compared to the iliac (2.0 ± 1.0%·s−1) and aorta (1.1 ± 0.4%·s−1) in both groups and in the iliac compared to the aorta (p < 0.05) in the control group. In conclusion, the vasorelaxation response was vessel specific with a slower rate of adjustment in diabetic compared to control animals. [ABSTRACT FROM PUBLISHER]

Ablating insulin receptors in cardiomyocytes causes subendocardial fibrosis and left ventricular (LV) dysfunction after 4 wk of transverse aortic constriction (TAC). To determine whether these maladaptive responses are precipitated by coronary vascular dysfunction, we studied mice with cardiomyocyte-restricted knock out of insulin receptors (CIRKO) and wild-type (WT) TAC mice before the onset of overt LV dysfunction. Two weeks of TAC produced comparable increases (P < 0.05 vs. respective sham) in heart weight/body weight (mg/g) in WT-TAC (8.03 ± 1.14, P < 0.05 vs. respective sham) and CIRKO-TAC (7.76 ± 1.25, P < 0.05 vs. respective sham) vs. WT-sham (5.64 ± 0.11) and CIRKO-sham (4.64 ± 0.10) mice. In addition, 2 wk of TAC were associated with similar LV geometry and function (echocardiography) and interstitial fibrosis (picrosirius red staining) in CIRKO and WT mice. Responses to acetylcholine (ACh), NG-monomethyl-l-arginine (l-NMMA), and sodium nitroprusside (SNP) were measured in coronary arteries that were precontracted to achieve ∼70% of maximal tension development using the thromboxane A2 receptor mimetic U-46619 (∼3 × 10-6 M). ACh-evoked vasorelaxation was absent in WT-TAC but was present in CIRKO-TAC albeit reduced relative to sham-operated animals. l-NMMA-evoked tension development was similar in vessels from CIRKO-TAC mice but was lower (P < 0.05) in WT-TAC animals vs. the respective sham-operated groups, and SNP-evoked vasorelaxation was similar among all mice. Thus estimates of stimulated and basal endothelial nitric oxide release were better preserved in CIRKO vs. WT mice in response to 2 wk of TAC. These findings indicate that maladaptive LV remodeling previously observed in CIRKO-TAC mice is not precipitated by coronary artery dysfunction, because CIRKO mice exhibit compensatory mechanisms (e.g., increased eNOS transcript and protein) to maintain coronary endothelial function in the setting of pressure overload. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the antihypertensive activity of aqueous extracts obtained from Malaysian coastal seaweeds and to determine the pharmacological mechanisms of the extracts on rat aorta in vitro. Materials and Methods: The antihypertensive activity of 11 species of seaweeds (5 brown, 1 red and 5 green algae) were tested by cumulative addition of the extracts to phenylephrine (PE)-precontracted Wistar-Kyoto (WKY) aortic rings in in vitro isometric contraction studies. Mechanisms for vasorelaxant effect were investigated in the presence of various antagonists. Results: Of the 11 species tested, 2 showed a vasorelaxant effect. Further investigation of the mechanisms of action of the aqueous extract of green alga, Cladophora patentiramea (AECP),showed that the vascular relaxant effect was endothelium- and concentration-dependent. A maximum relaxation of 45.8 ± 4.6% (n = 8, p < 0.001) was obtained at 0.1 mg/ml of extract, after which the response was found to reduce in a concentration-dependent manner to 15.7 ± 4.9% (n = 8, p < 0.001) at the highest extract concentration tested. Pretreatment of endothelium-intact aortic rings with Nω-nitro-L-arginine methyl ester (L-NAME, 30 μM), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 μM) and methylene blue (100 μM) resulted in a complete blockade of AECP-induced vasorelaxation. However, the relaxant effects of the extract were not blocked by atropine (1 μM), indomethacin (10 μM) and glibenclamide (10 μM), although the maximum relaxant responses were enhanced in the presence of glibenclamide. Conclusion: Our data showed that the in vitro vascular relaxant effect of AECPwas mediated through endothelium-dependent nitric oxide-cGMP pathway, and was not associated with the release of vasodilator prostaglandins, activation of muscarinic receptors, or ATP-sensitive potassium channels opening. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Apigenin is shown to have cardiovascular effects, but the effects of apigenin on aortas injured by exogenous oxidants are unknown. The objective of this study was to investigate the effect of apigenin on endothelium-dependent vasorelaxation in isolated rat aortic rings exposed to superoxide anion produced by pyrogallol, and its mechanism. The male Sprague–Dawley rat thoracic aorta was rapidly dissected out and the effect of apigenin on tension of aortic rings pretreated with 500μM pyrogallol, inducing oxidative stress injury, was measured. The activity of nitric oxide synthase (NOS), the level of nitric oxide (NO) and the inhibition of superoxide anion in aortic tissues were measured. We found that pretreatment with pyrogallol concentration-dependently decreased acetylcholine-induced endothelium-dependent vasorelaxation. Apigenin (0.5–72.0μM) evoked a concentration-dependent relaxation in aortas (pD2: 5.304±0.049), which was weakened by l-NAME (the maximal relaxation fell from 87.6±6.7% to 37.1±8.8%, P <0.01), but not by aminoguanidine and indomethacin. Apigenin markedly attenuated the inhibition of vasorelaxation induced by pyrogallol (the maximal relaxation elevated from 55.8%±6.6% to 69.5%±6.4%, and the pD2 increased from 6.559±0.119 to 7.057±0.145, P <0.01) and increased the inhibition of superoxide anion (from 94.6% to 74.5%), the NO level (from 77.1% to 94.4%), and the constitutive NOS activity (from 35.1% to 62.5%). These results indicate that pyrogallol decreased endothelium-dependent vasorelaxation in rat aortas via oxidative stress, which was markedly attenuated by apigenin. This may be mediated by weakening the oxidative stress and the NO reduction. [Copyright &y& Elsevier]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Haemodynamic effects of endothelial stimuli induced by salbutamol and L-arginine in humans have been previously studied predominantly at rest in selected vascular beds. • We studied the effects of salbutamol, L-arginine and nitroglycerin on cardiac and vascular function by continuous recording of pulse wave analysis and impedance cardiography both in the supine position and during passive head-up tilt. WHAT THIS STUDY ADDS • The divergent effects of the research drugs in supine position and during head-up tilt indicate that human haemodynamics should also be studied in the upright position. • Since inhaled salbutamol induced more pronounced changes in haemodynamics, it provides a clinically more applicable tool than infused L-arginine for the assessment of endothelial function in humans. AIMS To examine the effects of salbutamol and L-arginine, two compounds acting largely on the endothelium, and the endothelium-independent agent nitroglycerin on blood pressure, arterial compliance, cardiac function and vascular resistance. METHODS Continuous radial pulse wave analysis, whole-body impedance cardiography, and plethysmographic blood pressure from fingers in the supine position and during head-up tilt were recorded in nine healthy subjects. Data were captured before and after L-arginine (10 mg mg−1 min−1) or saline infusion, salbutamol (400 µg) or placebo inhalation, and sublingual nitroglycerin (0.25 mg) or placebo resoriblet. RESULTS The results of all measurements were comparable before drug administration. The effects of inhaled salbutamol were apparent in the supine position: systemic vascular resistance (−9.2 ± 2.6%) and augmentation index (−4.0 ± 1.5%) decreased, and heart rate (8.6 ± 2.5%) and cardiac output (8.8 ± 3.1%) increased. L-arginine had no clear effects on supine haemodynamics, but during head-up tilt blood pressure was moderately decreased and reduction in aortic reflection time prevented, indicating improved large arterial compliance. Nitroglycerin reduced supine vascular resistance (−6.7 ± 1.8%) and augmentation index (−7.4 ± 1.6%), and increased cardiac output (+9.2 ± 2.7%). During head-up tilt, nitroglycerin increased cardiac output (+10.6 ± 5.6%) and heart rate (+40 ± 7.5%), decreased vascular resistance (−7.8 ± 5.8%) and augmentation index (−18.7 ± 3.2%), and prevented the decrease in aortic reflection time. CONCLUSIONS Inhaled salbutamol predominantly changed supine haemodynamics, whereas the moderate effects of L-arginine were observed during the head-up tilt. In contrast, small doses of nitroglycerin induced major changes in haemodynamics both supine and during the head-up tilt. Altogether, these results emphasize the importance of haemodynamic measurements in both the supine and upright positions. [ABSTRACT FROM AUTHOR]

In healthy individuals, HDL can counteract the inhibition of vasorelaxation induced by oxidised LDL. Several abnormalities such as increased size, glycation and decreased paraoxonase activity have been reported for HDL from type 1 diabetic patients. Thus, we hypothesised that the ability of HDL to protect vessels against impairments of vasorelaxation would be decreased in these patients. We compared the ability of HDL from 18 type 1 diabetic patients and 12 control participants to counteract the inhibition of endothelium-dependent relaxation induced by oxidised LDL on rabbit aorta rings. Serum triacylglycerol and total cholesterol, LDL- and HDL-cholesterol were similar in type 1 diabetic and control participants. Fasting glycaemia and the HDL-fructosamine level were higher in diabetic patients than in controls (9.06 ± 3.55 vs 5.27 ± 0.23 mmol/l, p < 0.005; and 10.2 ± 3.2 vs 7.7 ± 2.5 μmol/g protein, p < 0.05, respectively). HDL composition, size and paraoxonase activity were similar in both groups. HDL from controls reduced the inhibitory effect of oxidised LDL on maximal relaxation ( E max; 79.3 ± 11.8 vs 66.4 ± 11.7%, p < 0.05), whereas HDL from type 1 diabetic patients had no effect ( E max = 70.6 ± 17.4 vs 63.9 ± 17.2%, NS). In type 1 diabetic patients, E max was not correlated with glycaemia or the HDL-fructosamine level. HDL particles from type 1 diabetic patients do not protect against inhibition of endothelium-dependent vasorelaxation induced by oxidised LDL, in contrast to HDL particles from healthy individuals. This defect cannot be explained by abnormalities in HDL composition, size or paraoxonase activity, and may contribute to the early development of atherosclerotic lesions in type 1 diabetic patients. [ABSTRACT FROM AUTHOR]

The article presents the findings of a study on nitric oxide synthase-dependent mechanism of vasorelaxation in small arteries from hypertensive rats. Systolic blood pressure increased in rats which received angiotensin II (ANG) and ANG/high-salt (HS) than with normotensive (NORM) and HS. Third-order mesentric arteries from ANG were less sensitive to acetylcholine (ACh) than arteries from NORM. There was less cyclic guanosine monophosphate (cGMP) content in small mesenteric arteries from ANG.

Abstract: Hypercholesterolemia is a dominant risk factor for the development and progression of atherosclerosis and cardiovascular diseases. Natural compounds have been proved to be useful in lowering serum cholesterol to slow down the progression of cardiovascular diseases. Pueraria lobata is employed clinically to treat cardiovascular diseases in China. In the present study, the atheroscleroprotective potential of the herb''s major active compound, puerarin, was investigated by monitoring serum lipid profile and major enzyme expressions on cholesterol homeostasis in Sprague–Dawley rats fed with control diet, hypercholesterolmic diet or hypercholesterolmic diet plus administration of puerarin (300 mg/kg/day, p.o.) for 4 weeks. Puerarin markedly attenuated the increased total cholesterol induced by hypercholesterolmic diet in both serum and liver. It caused a significant reduction in the atherogenic index. Expression of mRNA for hepatic 7α-hydroxylase (CYP7A1) was significantly enhanced but not for those of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) and lanosterol 14α-demethylase (CYP51). To further explore the atheroscleroprotective potential of puerarin, acetylcholine induced endothelium-dependent vasorelaxation and endothelial nitric oxide synthase (eNOS) expression on isolated thoracic aortas were analyzed. Animals administered with puerarin suppressed the hypercholesterolemic diet induced impairment of eNOS expression, whereas there was no significant difference in the endothelium-dependent vasorelaxation among various groups of animals. These data indicated that puerarin reduced the atherogenic properties of dietary cholesterol in rats. Its hypocholesterolemic function may be due to the promotion of cholesterol and bile acids excretion in liver. Whether puerarin targets directly on cholesterol homeostasis or both cholesterol homeostasis and endothelial function remains to be determined. [Copyright &y& Elsevier]

1. The aim of the present study was to investigate the responses to acetylcholine (ACh; 3 nmol/L−30 µmol/L) and sodium nitroprusside (SNP; 3 nmol/L−30 µmol/L) of precontracted aortic rings from diabetic rats supplemented with docosahexaenoic acid (DHA).2. Diabetes was induced by streptozotocin (STZ; 55 mg/kg). Diabetic and sham rats were fed, over a period of 8 weeks, either control diet or a DHA-supplemented diet. Aortic endothelial fatty acid composition was analysed by gas chromatography. The involvement of endothelial-derived nitric oxide (NO) and cyclo-oxygenase (COX) metabolites in response to ACh was assessed using the NO synthase inhibitorNG-nitro-l-arginine methyl ester (100 µmol/L) and the COX inhibitor indomethacin (1 µmol/L), respectively.3. The DHA-supplemented diet induced a small increase in n-3 polyunsaturated fatty acids (PUFA;P < 0.001) owing to the incorporation of DHA in the endothelial cells of sham animals (1.6 ± 0.2% in the DHA group compared with traces in the control group;P < 0.001) and diabetic animals (1.3 ± 0.2% in the DHA group compared with traces in control group;P < 0.001), without a decrease in n-6 PUFA, despite a small decrease in arachidonic acid content (P < 0.05). Diabetes did not modify the incorporation of DHA in endothelial cells, but did significantly increase the arachidonic acid content (0.6 ± 0.0vs0.4 ± 0.1% in control group in the STZ and sham groups, respectively;P < 0.001). Acetylcholine-induced relaxation was significantly reduced in STZ groups compared with the sham groups (P < 0.001) and the DHA-supplemented diet did not modify these effects. In contrast, neither the DHA-supplemented diet nor diabetes affected the aortic relaxation induced by SNP.NG-Nitro-l-arginine methyl ester strongly inhibited the relaxant effects of ACh in the sham groups (P < 0.001) and abolished ACh-induced relaxation in the STZ groups (P < 0.001). The diet did not modify these effects. In the presence of indomethacin, the relaxation induced by ACh was decreased in the sham groups (P < 0.01), but not in the STZ groups. The DHA-supplemented diet did not have any effect on these responses.4. In conclusion, these results suggest that, in the present study, the endothelial dysfunction occurring in the rat model of STZ-induced diabetes is associated with modifications of both the synthesis of COX derivatives and NO metabolism and is not affected by dietary supplementation with DHA. [ABSTRACT FROM AUTHOR]

Objective: Although HIV Protease inhibitors significantly reduce the viral load, they are associated with increased risk of cardiovascular disease. The aim of this study was to investigate the effects of HIV protease inhibitor ritonavir on vascular endothelial cell function. Methods: Porcine carotid arteries were perfusion-cultured for 24 h as controls or with 15 μM of ritonavir. Vessels were precontracted with norepinephrine followed by endothelium-dependent vasorelaxation with acetylcholine. Rings of vessels were cultured as controls or with ritonavir for 24 h and basal and NADPH-stimulated superoxide levels were determined using lucigenin-enhanced chemiluminescence. Superoxide levels in situ were also examined using dihydroethidium (DHE) staining, and nitrotyrosine levels were examined using a nitrotyrosine antibody. Results: Endothelium-dependent vasorelaxation was significantly reduced in ritonavir-treated vessels compared to controls. There were significant increases in basal and NADPH-stimulated superoxide production in vessel rings treated with ritonavir compared to control vessels. Dihydroethidium staining and nitrotyrosine staining were also elevated in endothelial cells of ritonavir-treated vessels, indicating increased superoxide production and increased oxidative stress, respectively, in ritonavir-treated vessels compared to controls. Conclusions: These data demonstrate that HIV protease inhibitor ritonavir causes a significant reduction in endothelium-dependent vasorelaxation in cultured porcine carotid arteries. Increased oxidative stress may be a possible mechanism of HIV protease inhibitor ritonavir-induced endothelial dysfunction. [Copyright &y& Elsevier]

Proteinase-activated receptor (PAR)-mediated vasorelaxant responses were examined in main pulmonary artery preparations from control rats and rats exposed to hypoxia (10% oxygen) for 1 or 4 weeks to induce pulmonary hypertension. Trypsin and the PAR-2 peptide, SLIGRL, relaxed phenylephrine precontracted preparations, with maximum responses the same as the maximum response to acetylcholine. Responses to trypsin and SLIGRL were abolished by endothelium removal or a nitric oxide (NO) synthase inhibitor, and were, therefore, due to release of endothelium-derived NO. In pulmonary arteries from rats exposed to hypoxia for 1 week, the potencies and maximal responses for acetylcholine and trypsin were markedly reduced compared with data in control rats, but these values were restored to normal in arteries from 4-week hypoxic rats. In contrast, the potency of SLIGRL was unchanged in arteries from either group of hypoxic rats. The data for trypsin and acetylcholine are consistent with previous findings for a variety of endothelium-dependent vasodilators and reflect an impairment of endothelial function in early hypoxic pulmonary hypertension. The data for SLIGRL emphasise that one cannot necessarily predict changes in PAR-2-mediated endothelium-dependent vasorelaxation in disease states from data with the classical endothelium-dependent vasodilator, acetylcholine. [Copyright &y& Elsevier]

6-(Substituted-phenyl)amino-5,8-quinazolinediones (3) were synthesised by regioselective substitution of 5,8-quinazolinedione (5) with appropriate arylamines in the presence of Ce(III) ions. All synthesised 5,8-quinazolinediones 3 showed a potent and efficacious inhibitory effect on the acetylcholine (ACh)-induced vasorelaxation of rat aorta with the endothelium. The quinones 3, at a low concentration of 0.1 μM, reduced the maximal response with increase of EC50 values for ACh. The results indicate that quinones 3 are potent inhibitors of endothelium-dependent vasorelaxation. [Copyright &y& Elsevier]

Sodium fluoride (NaF) produced concentration-dependent relaxation of isolated rabbit ear artery precontracted with norepinephrine. In contrast, an arterial preparation with the endothelium rubbed off did not relax, but contracted in response to NaF. NaF-induced relaxation was not influenced by indomethacin but was inhibited by methylene blue or N-monomethyl-L-arginine. The results indicate that NaF relaxes the artery by releasing a so-called EDRF. [ABSTRACT FROM AUTHOR]

The present study investigated the effects of Cornus mas, Sorbus aucuparia and Viburnum opulus fruit extracts on arginase activity and arterial vasodilation. V. opulus fruit extract exerted the highest vasorelaxant activity in phenylephrine precontracted rat aortic rings (EC 50 = 6.31 ± 1.61 μg/mL) and a significant inhibition of arginase (IC 50 = 71.02 ± 3.06 μg/mL). By contrast, S. aucuparia and C. mas fruit extracts showed no important anti-arginase activity and a significantly weaker activity in the rat aortic rings relaxation assay (EC 50 = 100.9 ± 11.63 and 78.52 ± 8.59 μg/mL, respectively). For all extracts, the main mechanism of vasodilation was proven to be endothelium-dependent. HPLC-ESI-Q-TOF-MS/MS studies revealed a very complex metabolite profiling in all three extracts with chlorogenic acid accounting for 30.89, 0.72 and 2.03 mg/g in V. opulus , C. mas and S. aucuparia fruit extracts, respectively. All extracts were declared non-toxic in the brine shrimp acute toxicity test. Our study highlights potential benefits of V. opulus fruit extract in diseases associated with endothelial dysfunction and impaired vasodilation. • Cornus mas , Sorbus aucuparia and Viburnum opulus fruit extracts were investigated. • Metabolite profiling of fruit extracts was carried out using HPLC-ESI-Q-TOF-MS/MS. • V. opulus fruit extract showed the strongest inhibition of arginase. • V. opulus fruit extract induced the highest endothelium-dependent vasorelaxation. • All three extracts showed no toxic effects on brine shrimps. [ABSTRACT FROM AUTHOR]