Abstract 643: Heterozygous Endothelial Endothelin-1 Overexpression Potentiates Endothelium-Dependent Contractions in the Carotid Arteries of Obese Mice

Elevated plasma levels of the vasoconstrictor peptide endothelin-1 (ET-1) are associated with cardiovascular risk factors such as obesity, diabetes and hypertension, in which endothelium-dependent contractions are prominent. Exogenous ET-1 promotes the release of endothelium-derived contracting factors (EDCF), but the role of endogenously produced ET-1 in these processes is unknown. Therefore, mice with tie-1 promoter driven endothelium-restricted heterozygous overexpression of ppET-1 (TET+/-) and WT littermates were kept on standard chow as lean controls or administered a high fat diet for 30 weeks to induce obesity. At sacrifice, fasting glucose levels were significantly elevated in obese animals (8.3±0.3 vs. 5.3±0.2 mmol/l in lean controls, n =6, P <0.001). Isometric tension was measured in aortic and carotid arterial rings in wire myographs. In phenylephrine-contracted aortic rings, endothelium-dependent and −independent relaxations to acetylcholine and sodium nitroprusside, respectively, were unaltered between groups. In carotid arteries, the potency of phenylephrine to evoke contractions was greater in preparations from obese TET+/- mice ( pD 2 6.71±0.07 vs. lean TET+/- 6.34±0.13, n =5-6, P <0.05), whereas there was no change in the contractile response to the α 1 -adrenergic agonist by diet-induced obesity in WT littermates. The augmented EDCF responses to acetylcholine of quiescent carotid arterial rings of obese animals were further potentiated by TET+/- ( E max 51.3±1.1% vs. 40.6±1.3% KCl in WT obese, n =6, P <0.001). The production of 6-keto PGF 1α − the stable metabolite of prostacyclin − was increased significantly in preparations from obese TET+/- mice (238.4±30.0 vs. 127.0±12.7 pg/mL in obese WT littermates, n =4-6, P <0.05). In the presence of L-NAME, TP receptor activation by U46619 was more effective in obese TET+/- ( E max 151.8±5.4% vs. 126.1±4.7% KCl in WT obese, n =4-6, P <0.05). Overall, TET+/- had no effect on relaxations in obese animals, but contractile responses − EDCF-mediated ones in particular − were facilitated. The present results suggest that this is due to an increased production of vasoconstrictor prostanoids possibly combined with an augmented responsiveness of the underlying vascular smooth muscle.

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Role of Reactive Oxygen Species in Kv Channel Inhibition and Vasoconstriction Induced by TP Receptor Activation in Rat Pulmonary Arteries

Annals of the New York Academy of Sciences ◽

10.1196/annals.1378.053 ◽

2006 ◽

Vol 1091 (1) ◽

pp. 41-51 ◽

Cited By ~ 45

Author(s):

ANGEL COGOLLUDO ◽

GIOVANNA FRAZZIANO ◽

LAURA COBEÑO ◽

LAURA MORENO ◽

FEDERICA LODI ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Pulmonary Arteries ◽

Reactive Oxygen ◽

Receptor Activation ◽

Oxygen Species ◽

Kv Channel ◽

Tp Receptor ◽

Channel Inhibition

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Colonic dysmotility and inflammation associated with high fat diet-induced obesity: role of the enteric glia

Proceedings of The Nutrition Society ◽

10.1017/s0029665120004425 ◽

2020 ◽

Vol 79 (OCE2) ◽

Author(s):

Matteo Fornai ◽

Carolina Pellegrini ◽

Vanessa D'Antongiovanni ◽

Laura Benvenuti ◽

Nunzia Bernardini ◽

...

Keyword(s):

High Fat Diet ◽

Mucosal Barrier ◽

Tlr4 Expression ◽

High Fat ◽

Glucose Levels ◽

Diet Induced Obesity ◽

Epididymal Fat ◽

Junction Protein ◽

Colonic Dysmotility

AbstractIntroductionEnteric glial cells (EGCs) contribute to the regulation of bowel motility, and have been implicated in the onset and development of several digestive disorders. However, the involvement of EGCs in obesity-related intestinal dysmotility is unknown. Accordingly, this study examined the role of EGCs in colonic neuromuscular dysfunctions in a mouse model of diet-induced obesity.Materials and MethodsC57BL/6 male mice (n = 6 per group) were fed with standard diet (SD) or high fat diet (HFD) for 8 weeks. Body and epididymal fat weight, and blood fasting glucose levels were evaluated the day before sacrifice. Colonic longitudinal muscle strips were set up in organ baths with Krebs solution and connected to isometric transducers. The effects of fluorocitrate (FC, gliotoxin) were tested on contractile responses mediated by NK1 tachykininergic receptors upon application of electrical stimuli (0.5 ms, 28 V, 10 Hz) [incubation with atropine, guanethidine, L-NAME, GR159897 and SB218795 (NK2 and NK3 antagonists, respectively)] or exogenous substance P (SP). Colonic levels of interleukin (IL)-1β, IL-6, malondialdehyde (MDA) and occludin (a tight junction protein involved the maintenance of mucosal barrier) were measured. Cultured rat EGCs were exposed to palmitate and lipopolysaccharide (LPS), either alone or in combination, to mimic the exposure to HFD. IL-1β and SP levels were then assessed in cell supernatants, while toll-like receptor 4 (TLR4) expression was evaluated in cell lysates.ResultsHFD-mice displayed increments of body weight, epididymal fat weight and blood glucose levels. In in vitro experiments, electrically induced colonic tachykininergic contractions were enhanced in HFD mice, as compared with SD animals. No differences were observed when comparing contractions to exogenous SP. The increase in electrically evoked tachykininergic contractions was blunted upon incubation with the gliotoxin FC. Exogenous SP-induced contractions were not affected by FC. HFD mice displayed an increase in colonic IL-1β, IL-6 and MDA levels and a reduced occludin expression, as compared with SD mice. Exposure of EGCs to palmitate, alone or in combination with LPS, resulted in a significant increase in TLR4 expression, while LPS alone was without effects. The combination of palmitate and LPS increased significantly IL-1β and SP levels in cell supernatants, while single treatments were without effects.DiscussionHFD is characterized by colonic dysmotility along with bowel inflammation, oxidative stress, and an impairment of mucosal barrier integrity. In this setting, the hyperactivation of EGCs, likely via TLR4, appears to contribute to inflammation and colonic tachykininergic motor dysfunctions.

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Colesevelam improves insulin resistance in a diet-induced obesity (F-DIO) rat model by increasing the release of GLP-1

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00362.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. G419-G424 ◽

Cited By ~ 76

Author(s):

Quan Shang ◽

Monica Saumoy ◽

Jens Juul Holst ◽

Gerald Salen ◽

Guorong Xu

Keyword(s):

Insulin Resistance ◽

Bile Acid ◽

Rat Model ◽

Plasma Glucose ◽

Receptor Activation ◽

High Energy ◽

Farnesoid X Receptor ◽

Oral Glucose ◽

Glucose Levels ◽

Diet Induced Obesity

Bile acid sequestrants have been shown to lower glucose levels in patients with type 2 diabetes. To investigate how colesevelam (CL) HCl improves hyperglycemia, studies were conducted in diet-induced obesity (F-DIO) rats, which develop insulin resistance when fed a high-energy (high fat/high sucrose) diet (HE). The rats were fed HE; HE + 2% CL; HE + 0.02% SC-435 (SC), an apical sodium-dependent bile acid transporter inhibitor; and regular chow (controls). After 4 wk of treatment, both in the HE group and the SC + HE group, plasma glucose and insulin levels remained elevated compared with baseline values throughout an oral glucose tolerance test (OGTT). In contrast, in the CL + HE group, plasma glucose levels returned to baseline by the end of the test, and insulin peaked in 15–30 min and then returned to baseline. CL induced release of glucagon-like peptide-1 (GLP-1) because the area under the curve of plasma total GLP-1 in the CL + HE group was significantly greater than in the HE group during the OGTT. Bile acid concentrations in the portal blood did not decrease in the HE group but declined significantly both in the CL + HE and SC + HE groups with reduced farnesoid X receptor activation compared with controls. We concluded that CL reduces plasma glucose levels by improving insulin resistance in this rat model. It is unlikely that the improvement is attributable to decreased bile acid flux to the liver but is likely secondary to induced GLP-1 secretion, which improves insulin release.

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Role of endothelin during experimental Trypanosoma cruzi infection in rats

Clinical Science ◽

10.1042/cs103s064s ◽

2002 ◽

Vol 103 (s2002) ◽

pp. 64S-67S ◽

Cited By ~ 10

Author(s):

Elizabeth R.S. CAMARGOS ◽

Conceição R.S. MACHADO ◽

Antonio L. TEIXEIRA ◽

Lamara L.V. ROCHA ◽

Anderson J. FERREIRA ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Acute Infection ◽

Receptor Activation ◽

Heart Tissue ◽

Histopathological Analysis ◽

Endothelin 1 ◽

Eta Receptor ◽

Eta Receptor Antagonist ◽

Cruzi Infection

Chagas' disease is caused by the intracellular protozoan Trypanosoma cruzi. Here we have investigated the role of endothelin-1 in T. cruzi acute infection in rats, using the orally active ETA receptor antagonist BSF-461314. Treatment with BSF-461314 markedly increased parasitaemia, but animals managed to control the infection by day 15. Histopathological analysis of heart tissue at the end of the acute phase showed greater numbers of parasite nests in BSF-461314-treated animals. The perfusion of isolated rat hearts from infected animals with bradykinin failed to induce an increase, and actually reduced, coronary blood flow. Pretreatment with BSF-461314 prevented changes in coronary flow induced by T. cruzi infection. Together these results demonstrate that endothelin-1, through ETA receptor activation, contributes to the protective immune response against acute T. cruzi infection. Moreover, these data suggest that endothelin-1 is a mediator of impaired endothelium-dependent vasomotion in the coronary microcirculation associated with acute T. cruzi infection.

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Role of Cl− current in endothelin-1-induced contraction in rabbit basilar artery

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.281.5.h2159 ◽

2001 ◽

Vol 281 (5) ◽

pp. H2159-H2167 ◽

Cited By ~ 12

Author(s):

Yun Dai ◽

John H. Zhang

Keyword(s):

Basilar Artery ◽

Methanesulfonic Acid ◽

Isometric Tension ◽

Channel Blockers ◽

Free Solution ◽

Bicarbonate Buffer ◽

Endothelin 1 ◽

New Zealand White Rabbits ◽

Basilar Arteries

Cl− efflux induces depolarization and contraction of smooth muscle cells. This study was undertaken to explore the role of Cl− channels in endothelin-1 (ET-1)-induced contraction in rabbit basilar artery. Male New Zealand White rabbits ( n = 26), weighing 1.8–2.5 kg, were euthanized by an overdose of pentobarbital. The basilar arteries were removed for isometric tension recording. ET-1 produced a concentration-dependent contraction of the rabbit basilar artery in the normal Cl− Krebs-Henseleit bicarbonate buffer (123 mM Cl−). The ET-1-induced contraction was reduced by the following manipulations: 1) inhibition of Na+-K+-2Cl− cotransporter with bumetanide (3 × 10−5 and 10−4 M), 2) bicarbonate-free solution to disable Cl−/HCO[Formula: see text] exchanger, and 3) preincubation of rings with the Cl− channel blockers niflumic acid, 5-nitro-2-(3-phenylpropylamino)benzoic acid, and indanyloxyacetic acid 94. The ET-1-induced contraction was enhanced by substitution of extracellular Cl− (10 mM) with methanesulfonic acid (113 mM). Cl− channels are involved in ET-1-induced contraction in the rabbit basilar artery.

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Endothelium and aortic contraction to endothelin-1 in the pregnant rat

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y99-150 ◽

2000 ◽

Vol 78 (5) ◽

pp. 372-377 ◽

Cited By ~ 2

Author(s):

Amadou Moctar Dièye ◽

Alexis Gairard

Keyword(s):

Receptor Antagonist ◽

Late Pregnancy ◽

Female Rats ◽

Pregnant Rats ◽

Pregnant Rat ◽

Endothelin 1 ◽

Key Words Endothelin ◽

Vasoconstrictor Peptide ◽

Aortic Contraction

Endothelium-derived factors modulate tone and may be involved in hyporeactivity to vasoconstrictors, such as norepinephrine or angiotensin II, as has been previously described during gestation. The endothelium produces endothelin-1, a major vasoconstrictor peptide, therefore aortic contractions to endothelin-1 (10-10 to 3 ×10-7 M) were used to assess the role of the endothelium in pregnant Wistar rats (at 20 days of gestation). Late pregnancy is characterized by a significantly diminished systolic blood pressure in conscious rats (-17 mmHg, P < 0.001, n = 14). In pregnant and in age-matched nonpregnant female rats, endothelin-1 induced aortic contraction was greater when endothelium was present (at least P < 0.01). Indomethacin significantly reduced this contraction in aortic rings with intact endothelium in all groups. In aortic rings that had endothelium physically removed, contraction to endothelin-1 was greater in pregnant rats than in nonpregnant ones. Indomethacin decreased contraction of aortic rings in pregnant rats only. These results suggest an enhanced synthesis of vasoconstrictors by cyclooxygenases in vascular smooth muscle during pregnancy. In vessels with intact endothelium, we did not find hyporeactivity to endothelin-1 during late pregnancy. Contraction to endothelin-1 involved ETA receptors because it was decreased by BQ-123, an ETA receptor antagonist, whereas there was no significant change when using BQ-788, an ETB receptor antagonist. Key words: endothelin-1, endothelium, contraction, aorta, gestation.

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P737Endothelial ERK2/thromboxane receptor pathway induces endothelial dysfunction, insulin resistance and steatohepatosis through superoxide with high fat high sucrose diet

European Heart Journal ◽

10.1093/eurheartj/ehz747.0341 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Cited By ~ 1

Author(s):

A Sato ◽

Y Satoh ◽

S Endo ◽

T Kimura ◽

A Osaki ◽

...

Keyword(s):

Insulin Resistance ◽

Endothelial Function ◽

Isometric Tension ◽

Superoxide Production ◽

Mice Model ◽

Tp Receptor ◽

High Sucrose Diet ◽

Nafld Activity Score ◽

High Sucrose

Abstract Introduction Metabolic syndrome (MetS) is well known as the risk of cardiovascular diseases associated with endothelial dysfunction and induces steatohepatosis. Insulin resistance is a major character of MetS, which affects intracellular signaling pathways and endothelial function. Extracellular signal-regulated kinase (ERK) is a major component of insulin signal and many of vasoactive peptides, which were released in MetS, can activate it in endothelium. However, the role of endothelial ERK in nitric oxide (NO) bioactivity in MetS in in vivo has been unknown. Purpose The aim of this study is to clarify the role of endothelial ERK2 on NO bioactivity in mice model of MetS. Methods and results We created endothelial specific ERK2 knock out mice (EE2KO) crossing Tie2-Cre mice and ERK2 flox mice and fed them with normal or high-fat/high-sucrose diet (HFHSD) for 24 weeks. Serum glucose and insulin levels and HOMA-IR were lowered in EE2KO with HFHSD without changing body weight. In wild type mice (WT) with HFHSD, nonalcoholic fatty liver disease (NAFLD) activity score, fibrosis score and serum ALT level were increased, all of which were blunted in EE2KO. EE2KO with HFHSD lowered systolic blood pressure (WT: 123.7±5.83 mmHg, EE2KO: 101.4±3.66 mmHg, P<0.01, N=8) without changing heart rate, which was increased to the same levels with L-NAME, an endothelial NO synthase inhibitor, in both groups. Serum NO levels measured with serum nitrite/nitrate concentrations were increased in EE2KO with HFHSD (WT: 23.10±3.74 μmol/l, EE2KO: 41.71±6.73 μmol/l, P<0.05, N=12). Endothelial function was assessed with the isometric tension measurement of aortic rings with acetylcholine (ACh). ACh-induced relaxation was improved in EE2KO with HFHSD. Superoxide production of aorta from EE2KO was lowered than WT with HFHSD in dihydroethidium (DHE) staining. S18886, an antagonist of the thromboxane A2-prostanoid (TP) receptor, decreased superoxide production of aorta in DHE staining resulting in improving endothelial function in the isometric tension measurement of aortic rings. Oral administrations of S18886 decreased systolic blood pressure, serum fasting glucose and insulin levels, and surprisingly improved steatohepatosis by decreasing NAFLD activity score and fibrosis score. Relaxation of aortic rings with ACh Conclusions Endothelial ERK2/TP receptor pathway increases superoxide production and decreased NO bioactivity, resulting in deteriorating endothelial function, insulin resistance and steatohepatosis, which were improved by antagonist of the TP receptor in mice model of MetS. The present study indicates that ERK2/TP pathway could be a therapeutic target for complications of MetS.

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