endothelin-1 and Weight-Gain

Pulmonary arterial hypertension is characterized by high pulmonary blood pressure, vascular remodeling and right ventricular hypertrophy. In the present study, we investigated whether genistein would prevent the development of low temperature-induced pulmonary hypertension in broilers. Hemodynamic parameters, vascular remodeling, the expression of endothelial nitric oxide and endothelin-1 content in lung tissue were evaluated. The results demonstrated that genistein significantly reduced pulmonary arterial hypertension and suppressed pulmonary arterial vascular remodeling without affecting broilers' performance. The beneficial effects appeared to be mediated by restoring endothelial function especially endothelial nitric oxide and endothelin-1, two critical vasoactive molecules that associated with the development of hypertension. Genistein supplementation might be a potential therapeutic strategy for the treatment of pulmonary hypertension.

Topics: Animals; Ascites; Chickens; Cold Temperature; Cyclic GMP; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Genistein; Hemodynamics; Hypertension, Pulmonary; Lung; Male; Neovascularization, Pathologic; Nitric Oxide Synthase Type III; Pericardial Effusion; Phytoestrogens; Poultry Diseases; Weight Gain

In non-alcoholic steatohepatitis (NASH), decreased nitric oxide and increased endothelin-1 (ET-1, also known as EDN1) released by sinusoidal endothelial cells (LSEC) induce hepatic stellate cell (HSC) contraction and contribute to portal hypertension (PH). Statins improve LSEC function, and ambrisentan is a selective endothelin-receptor-A antagonist. We aimed to analyse the combined effects of atorvastatin and ambrisentan on liver histopathology and hemodynamics, together with assessing the underlying mechanism in a rat NASH model. Diet-induced NASH rats were treated with atorvastatin (10 mg/kg/day), ambrisentan (30 mg/kg/day or 2 mg/kg/day) or a combination of both for 2 weeks. Hemodynamic parameters were registered and liver histology and serum biochemical determinations analysed. Expression of proteins were studied by immunoblotting. Conditioned media experiments were performed with LSEC. HSCs were characterized by RT-PCR, and a collagen lattice contraction assay was performed. Atorvastatin and ambrisentan act synergistically in combination to completely normalize liver hemodynamics and reverse histological NASH by 75%. Atorvastatin reversed the sinusoidal contractile phenotype, thus improving endothelial function, whereas ambrisentan prevented the contractile response in HSCs by blocking ET-1 response. Additionally, ambrisentan also increased eNOS (also known as Nos3) phosphorylation levels in LSEC, via facilitating the stimulation of endothelin-receptor-B in these cells. Furthermore, the serum alanine aminotransferase of the combined treatment group decreased to normal levels, and this group exhibited a restoration of the HSC quiescent phenotype. The combination of atorvastatin and ambrisentan remarkably improves liver histology and PH in a diet-induced NASH model. By recovering LSEC function, together with inhibiting the activation and contraction of HSC, this combined treatment may be an effective treatment for NASH patients.

Topics: Alanine Transaminase; Animals; Atorvastatin; Biomarkers; Collagen; Disease Models, Animal; Drug Synergism; Endothelial Cells; Endothelin-1; Enzyme Activation; Hemodynamics; Hepatic Stellate Cells; Insulin Resistance; Liver; Liver Cirrhosis; Nitric Oxide Synthase Type III; Non-alcoholic Fatty Liver Disease; Phenylpropionates; Pyridazines; Weight Gain

Hyperoxia-induced bronchopulmonary dysplasia (BPD) models are essential for better understanding and impacting on long-term pulmonary, cardiovascular, and neurological sequelae of this chronic disease. Only few experimental studies have systematically compared structural alterations with lung function measurements.. In three separate and consecutive series, Sprague-Dawley infant rats were exposed from day of life (DOL) 1 to 19 to either room air (0.21; controls) or to fractions of inspired oxygen (FiO. Exposure to FiO. Our in vivo infant rat model mimics clinical key features of BPD. To the best of our knowledge, this is the first BPD rat model demonstrating an association between lung structure and function. Moreover, we provide additional evidence that infant rats subjected to hyperoxia develop rarefaction of pulmonary vessels, augmented vascular α-SMA, and adaptive cardiac hypertrophy. Thus, our model provides a clinically relevant tool to further investigate diseases related to O

Topics: Animals; Animals, Newborn; Behavior, Animal; Biomarkers; Cardiomegaly; Endothelin-1; Female; Humans; Hyperoxia; Lung; Microvascular Rarefaction; Myocardium; Rats, Sprague-Dawley; Respiratory Mechanics; Social Behavior; Survival Analysis; Vascular Endothelial Growth Factor A; Weight Gain

Kelussia odoratissima Mozzaf, formerly Apium odoratissima, is a plant locally called "Karafs", found in central Zagros region of Iran. Leaves and stems of the plant are traditionally used in the treatment of hypertension and inflammation. Lowering blood pressure effects of Kelussia odoratissima Mozzaf (wild celery) was evaluated in preventing pulmonary hypertension syndrome (PHS) in broiler chickens reared at high altitude (2,100 m).. A total number of 208 day-old male broilers (Ross 308) were randomly assigned to four treatments including different levels of Kelussia odoratissima Mozzaf (0%, 0.25%, 0.5%, and 0.75%) in a 42-day trial.. Body weight gain and feed:gain responses significantly (P<0.05) improved when Kelussia odoratissima Mozzaf was included in broiler diets at 0.75% in the growing stage and throughout the trial. Over-expression of inducible nitric oxide (NO) synthase in the heart was observed in chickens fed Kelussia odoratissima Mozzaf. Birds received Kelussia odoratissima Mozzaf at 0.5% and 0.75% had significantly (P<0.05) higher circulatory concentrations of NO though significantly (P<0.05) lower serum malondialdehyde concentration, hematocrit and heterophil to lymphocyte ratio when compared to the birds fed the control diet. Feeding Kelussia odoratissima Mozzaf at 0.5% and 0.75% prevented from right ventricular hypertrophy and led to a significant decline in mortality from PHS.. It can be concluded that Kelussia odoratissima Mozzaf is a promising medicinal herb to prevent PHS in broiler chickens by improving blood pressure and antioxidant responses.

Topics: Altitude; Animals; Apiaceae; Chickens; Diet; Eating; Endothelin-1; Gene Expression; Heart Ventricles; Hypertension, Pulmonary; Male; Nitric Oxide Synthase Type II; Phytotherapy; Plant Leaves; Plant Shoots; Plants, Medicinal; Superoxide Dismutase; Superoxide Dismutase-1; Weight Gain

To investigate the influence of exposure to high-altitude (HA) hypoxia on the expressions of endothelin-1 (ET-1), endothelin type A (ETA) and endothelin type B (ETB) receptors in broiler chickens, immunohistochemistry studies were performed in the lungs. Six hundred 1-day-old male broiler chickens were randomly divided into two groups: group A, birds maintained under rich oxygen conditions (oxygen content 21%); and group B, birds exposed to HA hypoxia (oxygen content 13%). Our data showed that exposure to altitude elevated ET-1 and ETA gene expressions at 21 and 28 days of age when compared with the rich oxygen group. Meanwhile, a marked decline in ETB expression was observed at 28 days of age in the course of HA, although there were no significant changes (P>0.05) at 7, 14 and 21 days of age. The increased response was accompanied by adverse effects on weekly body weight gain and ascites mortality. These observations suggested that ET-1, ETA and ETB genes are normally expressed in the lungs of birds. Increased levels of ET-1 and ETA and decreased ETB gene expression in the lungs are probably involved in the lung dysfunction of broiler chickens with developmental ascites.

Topics: Altitude; Animals; Ascites; Chickens; Down-Regulation; Endothelin-1; Gene Expression Regulation; Hypoxia; Lung; Male; Oxygen; Random Allocation; Receptors, Endothelin; Up-Regulation; Weight Gain

Rats fed a high fat diet develop increased adiposity and oxidative stress leading to impaired vasodilation. The purpose of the present study was to examine the effects of high fat-induced increases in adiposity and oxidative stress on vasoconstrictor reactivity of isolated mesenteric arteries. We hypothesized that rats with more adiposity would develop oxidative stress-potentiated increases in iNOS-derived nitric oxide leading to diminished vasoconstriction. Male Sprague-Dawley rats were fed either a control (Chow) or high fat diet for 6 weeks. The roles of oxidative stress and iNOS in the impaired vasoconstrictor responses to endothelin-1 were characterized in small mesenteric arteries. Rats fed the HFD developed significantly more adiposity compared to Chow rats. Plasma levels of nitric oxide and the inflammatory factor tumor necrosis factor α were significantly higher in high fat fed rats compared to Chow rats (nitric oxide: 95.36±19.3 vs. 38.96±6.7 μM; tumor necrosis factor α: 598±111.4 vs. 292±71.8 pg/ml, respectively). Despite exhibiting elevated systolic blood pressure compared to Chow rats (153.5±2.4 vs. 137.5±2.7 mm Hg), endothelin-1 mediated vasoconstriction was impaired in isolated mesenteric arteries from high fat fed rats but was normalized by individual or combined inhibition of nitric oxide synthase, iNOS, or oxidative stress. Therefore, oxidative stress and iNOS are involved in the attenuation of endothelin-1 mediated vasoconstriction observed in isolated mesenteric arteries from high fat fed rats.

Topics: Adiposity; Animals; Blood Pressure; Dietary Fats; Endothelin-1; Feeding Behavior; In Vitro Techniques; Inflammation; Male; Mesenteric Arteries; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type II; Nitrites; Oxidative Stress; Rats; Rats, Sprague-Dawley; Vasoconstriction; Weight Gain

Nephrotic syndrome induced by adriamycin (ADR) is an experimental model of glomerulosclerosis in humans. The AT(1) receptor for angiotensin II (Ang II) is involved in the renal expression of the nuclear factor-kappa B (NF-ΚB) during this nephrosis. NF-ΚB is a transcription factor for proinflammatory effects of Ang II; however, there is no information about the role of this receptor in the renal proinflammatory events in ADR nephrosis.. To determine the role of Ang II in ADR nephrosis, Sprague-Dawley rats were treated with ADR (6 mg/kg iv). One ADR group received oral losartan treatment (15 mg/kg gavage) 3 days before ADR injection and then daily for 4 weeks, and the other group water. Animals were sacrificed at week 4 and renal macrophage infiltration, ICAM-1, superoxide anion (O(2(-))) and Ang II expressions were analysed by indirect immunofluorescence and histochemical techniques.. ADR rats showed increased expression of ICAM-1, Ang II, O(2(-)) and macrophage infiltration, events that were diminished by losartan treatment. Ang II expression remained unaltered after antagonist treatment. Proteinuria was reduced after 3 weeks of treatment.. These data suggest that Ang II plays a role in the inflammatory events during ADR-induced nephrosis, probably mediated by AT(1) receptors.

Topics: Angiotensin II; Animals; Cholesterol; Disease Models, Animal; Doxorubicin; Endothelin-1; Fluorescent Antibody Technique; Inflammation; Inflammation Mediators; Kidney; Losartan; Male; Nephrosis; Proteinuria; Rats; Rats, Sprague-Dawley; Time Factors; Triglycerides; Weight Gain

The effect of chronic cigarette smoking on endothelin modulation of vascular contraction, and CYP enzyme levels was studied in 20 male Sprague-Dawley rats. The animals were divided equally into smoking and non-smoking groups. The smoking group was exposed to 6 research cigarettes per rat per day 5 days a week for 16 weeks. The control group was sham smoked. Functional contractile studies were performed in aortas and carotid arteries to determine the regulation of vascular tone by basal release of endothelin. Liver samples were analyzed for CYP1A1 and CYP1A2 gene expression by RT-PCR. Plasma samples were assessed for endothelin-1 (ET-1) level by enzyme immuno assay (EIA). Treatment of aortas and carotid arteries with bosentan, the dual endothelin receptor antagonist, caused a significant reduction in constrictor responses of smoking rats, indicating, increase greater regulation of tone by endothelin in smoker rats compared to controls. There was a greater expression of the cytochrome P450-liver enzymes (CYP1A1 and CYP1A2) in smoker rats. Body weight gain was also significantly decreased in smoker rats. We conclude that increased endothelin release in smoker rats significantly contributes to increased arterial tone and so contribute to the cardiovascular pathophysiology associated with cigarette smoking, such as increased vascular muscularization, increased contraction, decreased dilation and possibly vasospasm.

Topics: Animals; Aorta, Thoracic; Bosentan; Cardiovascular Diseases; Carotid Arteries; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Cytochromes; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Induction; Liver; Male; Models, Animal; Nicotiana; Nitric Oxide; Random Allocation; Rats; Rats, Sprague-Dawley; Smoke; Smoking; Sulfonamides; Time Factors; Vasoconstriction; Weight Gain

1. In the present study, we investigated the role of endothelin ET(B) receptors in gender differences in the development of deoxycorticosterone acetate (DOCA)-salt-induced hypertension by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the ET(B) receptor gene. 2. In wild-type rats, the elevation of systolic blood pressure (SBP) by DOCA-salt treatment for 4 weeks was extremely lower in females than in males, but this gender difference was partially attenuated in ovariectomized (OVX) animals. These alterations of SBP corresponded with vascular superoxide () production. 3. In homozygous (sl/sl) group, the SBP of male, intact female and OVX rats was markedly elevated by DOCA-salt treatment to the same extent, indicating that the gender difference in DOCA-salt-induced hypertension was abolished by the genetic ET(B) receptor deficiency. There were similar increases in the vascular endothelin (ET)-1 content in the three DOCA-salt-treated animal groups, but vascular production in male and OVX rats was much higher than that in intact females. 4. Daily oral administration of ABT-627, an ET(A) receptor antagonist, to sl/sl rats for 2 weeks suppressed the DOCA-salt-induced hypertension more efficiently in intact female rats than in male animals. 5. Thus, vascular oxidative stress is related, at least in part, to differences in the development of DOCA-salt-induced hypertension between male and female rats, but this gender difference is abolished by the genetic ET(B) receptor deficiency, suggesting that ET(B) receptor-mediated vasoprotective actions contribute to the gender differences seen. In addition, in both sexes, vascular ET-1 overproduction and the ET(A) receptor-mediated action seem to be responsible for the enhanced susceptibility to DOCA-salt hypertension in genetic ET(B) receptor deficiency.

Topics: Animals; Aorta, Thoracic; Atrasentan; Blood Pressure; Desoxycorticosterone; Dopamine beta-Hydroxylase; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hypertension; Injections, Subcutaneous; Male; Mice; Mice, Knockout; Mice, Transgenic; Organ Size; Ovariectomy; Pyrrolidines; Rats; Receptor, Endothelin B; Sex Factors; Superoxides; Uterus; Weight Gain

Impaired placentation and oxidative stress are proposed to play major roles in the pathogenesis of placental dysfunction and pre-eclampsia. This study was carried out to evaluate if inhibited angiogenesis by Suramin injections in early pregnancy may cause a condition resembling pre-eclampsia in rats. Rats of two different Sprague-Dawley strains, U and H, were given intraperitoneal injections of Suramin or saline in early pregnancy. The outcome of pregnancy was evaluated on gestational day 20. Suramin injections caused increased blood pressure and decreased renal blood flow in the U rats. In both rat strains Suramin decreased the placental blood flow and caused fetal growth retardation. In both strains the placental concentration of the isoprostane 8-epi-PGF2alpha was increased, indicating oxidative stress. The serum concentration of Endothelin-1 was increased in the U rats. The U strain had a lower basal placental blood flow, and the effects of Suramin were more pronounced in this strain. We conclude, that Suramin injections to pregnant rats cause a state of placental insufficiency, which partly resembles human pre-eclampsia. The induction of this condition is at least partly mediated by oxidative stress, and is subject to varied genetic susceptibility.

Topics: Angiogenesis Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Electrolytes; Endothelin-1; Female; Humans; Isoprostanes; Lipids; Nitrites; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Proteinuria; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Renal Circulation; Suramin; Weight Gain

The aim was to assess the developmental and biochemical effects resulting from separate and combined exposures to radiation and noise in adult male Sprague-Dawley rats. For 21 days, animals were exposed daily (1) to whole-body 121 kVp X-ray exposure (cumulative dose=5 Gy), (2) to random intermittent noise band-limited between 0.4 and 20 kHz; 2 h day(-1) 86 decibels (dB) and (3) to combined exposures. Control animals were housed under ambient noise conditions 55 dB A-weighted (dBA) and sham-exposed to X-rays. Body weight gain was significantly reduced in animals exposed to either X-rays or noise, and the loss was more pronounced in animals exposed to both conditions. Neither plasma adrenocorticotropic hormone (ACTH) nor corticosterone was altered by the treatment conditions. This study corroborated previous reports that ionizing radiation exposure increased plasma levels of 8-hydroxy-2'-deoxyguanosine (8-OHDG), but no effect was observed in animals co-exposed to chronic noise. Plasma big-endothelin-1 (Big ET-1) was significantly reduced in animals exposed to a combination of noise and X-rays. The results indicated that (1) adaptation to chronic noise appeared to occur at the level of the hypothalamic pituitary adrenal (HPA) response, in spite of a compromise in overall body weight gain; and (2) ionizing radiation exposure might alter systems activated by stressor exposure and/or act independently to influence health outcomes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adrenal Glands; Adrenocorticotropic Hormone; Animals; Corticosterone; Deoxyguanosine; Endothelin-1; Male; Noise; Rats; Rats, Sprague-Dawley; Weight Gain; X-Rays

In vitro studies suggest that collecting duct-derived (CD-derived) endothelin-1 (ET-1) can regulate renal Na reabsorption; however, the physiologic role of CD-derived ET-1 is unknown. Consequently, the physiologic effect of selective disruption of the ET-1 gene in the CD of mice was determined. Mice heterozygous for aquaporin2 promoter Cre recombinase and homozygous for loxP-flanked exon 2 of the ET-1 gene (called CD-specific KO of ET-1 [CD ET-1 KO] mice) were generated. These animals had no CD ET-1 mRNA and had reduced urinary ET-1 excretion. CD ET-1 KO mice on a normal Na diet were hypertensive, while body weight, Na excretion, urinary aldosterone excretion, and plasma renin activity were unchanged. CD ET-1 KO mice on a high-Na diet had worsened hypertension, reduced urinary Na excretion, and excessive weight gain, but showed no differences between aldosterone excretion and plasma renin activity. Amiloride or furosemide reduced BP in CD ET-1 KO mice on a normal or high-Na diet and prevented excessive Na retention in salt-loaded CD ET-1 KO mice. These studies indicate that CD-derived ET-1 is an important physiologic regulator of renal Na excretion and systemic BP.

Topics: Aldosterone; Amiloride; Animals; Blood Pressure; Diuretics; Endothelin-1; Furosemide; Heterozygote; Homozygote; Hypernatremia; Hypertension; In Situ Hybridization; Kidney Tubules, Collecting; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; RNA, Messenger; Sodium Chloride, Dietary; Weight Gain

Effects of sitaxsentan (TBC11251), an orally active, highly selective antagonist of endothelin A receptors, were examined on the development and maintenance of pulmonary hypertension, pulmonary vascular remodeling, and cardiac hypertrophy in the rat. The pulmonary vasoconstrictor response to acute hypoxia (10% O(2)for 90 min) was prevented with sitaxsentan (5 mg/kg infused iv 10 min prior to the onset of hypoxia) while BQ-788 (a specific endothelin B receptor antagonist) was without effect. The same dose of sitaxsentan delivered iv 50 min after the onset of hypoxia reversed the established pulmonary vasoconstriction. In a 2-week model of hypoxia using 10% O(2), treatment with sitaxsentan (15 mg/kg per day in drinking water) attenuated pulmonary hypertension and the associated right ventricular hypertrophy, and prevented the remodeling of small pulmonary arteries (50-100 microM) without affecting systemic arterial blood pressure or heart rate. Institution of sitaxsentan treatment (15 and 30 mg/kg per day in drinking water) for 4 weeks after 2 weeks of untreated hypoxia produced a significant, dose dependent reversal of the established pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling despite continued hypoxic exposure. Sitaxsentan blocked increased plasma endothelin levels in the prevention protocol but did not affect the established elevated levels in the intervention study. Sitaxsentan dose dependently (10 and 50 mg/kg per day in the drinking water) attenuated right ventricular systolic pressure, right heart hypertrophy, and pulmonary vascular remodeling observed 3 weeks after a single subcutaneous injection of monocrotaline. These findings support the hypothesis that endothelin-1 plays a significant role in the development of pulmonary hypertension, pulmonary vascular remodeling, and the associated cardiac hypertrophy, and further suggest that specific endothelin-A receptor blockade may be useful in the treatment of pulmonary hypertension of diverse etiologies.

Topics: Animals; Cardiomegaly; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypertrophy; Hypoxia; Isoxazoles; Male; Monocrotaline; Oxygen; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Thiophenes; Vasoconstriction; Weight Gain

Recently, we have shown that chronic administration of N-Nitro-L-Arginine Methyl Ester (L-NAME, an inhibitor of nitric oxide synthase) precipitates stroke in stroke-prone spontaneously hypertensive rats (SHRSP). Enalapril maleate, an angiotensin converting enzyme inhibitor was shown to delay the onset of such stroke. In the present study, five groups of 4-week-old SHRSP were used. Three groups of SHRSP were made diabetic using streptozotocin (100 mg/kg i.p.). One week later, the SHRSP from groups I (non-diabetic) and III (diabetic) chronically received L-NAME (0.5 g/L) in saline as drinking water. Two SHRSP groups, II (non-diabetic) and IV (diabetic) received L-NAME (0.5 g/L) and enalapril maleate (20 mg/L) in saline as drinking water. Control SHRSP (group C; diabetic) received only saline to drink. SHRSP groups I and III developed stroke in 10+/-2 and 11+/-2 days, respectively. The average stroke-free period in groups II and IV was 19+/-2 and 28+/-2 days, respectively. Protective effect of streptozotocin-induced diabetes disappeared when SHRSP drinking L-NAME and enalapril, concurrently received subcutaneous injections of insulin (2 units daily per 100 g rat). Present data suggest that experimental diabetes delays the onset of L-NAME-induced stroke in SHRSP only in the absence of angiotensin converting enzyme activity. In addition, diabetes-induced enhancement of stroke-protective effect of enalapril appears to be independent of reduction in mean and systolic blood pressures.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cerebrovascular Disorders; Diabetes Mellitus, Experimental; Enalapril; Endothelin-1; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Inbred SHR; Streptozocin; Weight Gain