scholarly journals Effects of the Dual Endothelin Receptor Antagonist Aprocitentan on Body Weight and Fluid Homeostasis in Healthy Subjects on a High Sodium Diet

2020 ◽  
Author(s):  
Pierre Gueneau de Mussy ◽  
Patricia N. Sidharta ◽  
Gregoire Wuerzner ◽  
Marc P. Maillard ◽  
Nicolas Guérard ◽  
...  
Keyword(s):  
Body Weight ◽  
Receptor Antagonist ◽  
Healthy Subjects ◽  
Endothelin Receptor Antagonist ◽  
Endothelin Receptor ◽  
High Sodium ◽  
Fluid Homeostasis ◽  
Sodium Diet ◽  
High Sodium Diet

scholarly journals The Main and Interactive Effects of Fat and Sodium Contents of the Diet on Characteristics of Metabolic Syndrome in Male Wistar Rats (P08-038-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Alireza Jahan-Mihan ◽  
Kea Schwarz ◽  
Leila Nynia ◽  
Tatyana Kimble
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
High Fat Diet ◽  
Sodium Content ◽  
Fat Content ◽  
High Fat ◽  
High Sodium ◽  
Sodium Diet ◽  
Male Wistar Rats ◽  
High Sodium Diet

Abstract Objectives The objective of this study was to investigate the main and interactive effects of fat and sodium content of the diet on food intake, body weight and composition, glucose metabolism and blood pressure in male Wistar rats. Methods Male Wistar Rats (n = 48, initial body weight: 115.30 ± 1.73 g) were allocated into 4 groups (n = 12/group) and received one of the following diets: Normal sodium normal fat (NSNF), normal sodium high fat (NSHF), high sodium normal fat (HSNF), high sodium high fat (HSHF) diet for 12 weeks. Body weight (BW) and food intake (FI) were measured weekly. Short-term food intake (1, 2 and 12 hours food intake after 12 hours fasting) was measured at week 6. Body composition and organs’ weight were measured at week 12. Systolic (SBP) and diastolic (DBP) blood pressure, pulse and fasting blood glucose (FBG) were measured and oral glucose tolerance test (OGTT) was conducted at weeks 1, 4, 8 and 12. Results Regardless of sodium content, a greater FI (both gram and cal) was observed in rats fed normal fat diet compared with those fed high fat diet. Consistently, FI (g) at 1, 2 and 12 hours was higher in rats fed a normal fat diet. However, no difference in calorie intake was observed at any time point. Higher BW and fat (%) was observed in high fat diet groups. Moreover, greater kidneys’ weights was observed in high sodium diet groups. Fasting blood glucose was higher in rats fed a normal sodium diet compared with those fed a high sodium diet while the tAUC glucose response to glucose preload was higher in rats fed a high fat diet compared with those fed a normal fat diet which is consistent with higher body weight in high fat diet groups. Regardless of fat content of the diet, pulse was higher in rats fed a high sodium diet compared with those fed a normal sodium diet. No effect of either dietary sodium or fat content of the diet on SBP or DBP was observed. Conclusions Fat but not sodium content of the diet is a determining factor in regulation of FI and BW. Moreover, both fat and sodium content of the diet influence the glucose metabolism potentially through different mechanisms. While pulse is influenced by sodium content, the results of this study do not support the effect of sodium or fat content of the diet on either SBP or DBP. Funding Sources UNF, Brooks College of Health internal grant.

scholarly journals The Endothelin Receptor Antagonist Macitentan Ameliorates Endothelin-Mediated Vasoconstriction and Promotes Neuroprotection of Retinal Ganglion Cells in Rats

2020 ◽  
Author(s):  
Dorota L. Stankowska ◽  
Wei Zhang ◽  
Shaoqing He ◽  
Vignesh R. Krishnamoorthy ◽  
Payton Harris ◽  
...  
Keyword(s):  
Body Weight ◽  
Receptor Antagonist ◽  
Intravitreal Injection ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Endothelin Receptor Antagonist ◽  
Brown Norway ◽  
Retinal Ganglion ◽  
Endothelin Receptor ◽  
Norway Rats

AbstractPurposeTo determine if dietary administration of the dual ETA/ ETB receptor antagonist, macitentan, could protect retinal ganglion cells (RGCs) following endothelin-1 (ET-1) mediated vasoconstriction in Brown Norway rats.MethodsAdult male and female Brown Norway rats were either untreated or treated with macitentan (5 mg/kg body weight) once a day for 3 days followed by intravitreal injection of either 4 μl of 500 μM ET-1 (2 nmole/eye) or vehicle in one eye. Imaging of the retinal vasculature using fluorescein angiography was carried out at various time points, including, 5, 10, 15, 25 and 30 minutes. Following the imaging of the vasculature, rats were either treated with macitentan (5 mg/kg/body weight in dietary gels) or untreated (control gels without medication). Following treatments, rats were euthanized, retinal flat mounts were prepared, immunostained for RGC marker Brn3a, imaged and surviving RGCs were counted in a masked manner.ResultsVasoconstrictive effects following intravitreal ET-1 injection were greatly reduced in rats administered with macitentan in the diet prior to the ET-1 administration. ET-1 intravitreal injection produced a 31% loss of RGCs which was significantly reduced in macitentan-treated rats. Following ET-1 administration, GFAP immunostaining was increased in the ganglion cell layer as well as in the retrolaminar region, suggestive of astrocytic activation by ET-1 administration. RGC numbers in macitentan treated and ET-1 injected rats were similar to that observed in control retinas.ConclusionsET-1-mediated neurodegeneration could occur through both vascular and cellular mechanisms. The endothelin receptor antagonist, macitentan, has neuroprotective effects in retinas of Brown Norway rats that occurs through different mechanisms, including, enhancement of RGC survival and reduction ET-1 mediated vasoconstriction.

Protective Effects of Delapril, Indapamide and Their Combination Chronically Administered to Stroke-Prone Spontaneously Hypertensive Rats Fed a High-Sodium Diet

1997 ◽  
Vol 93 (5) ◽  
pp. 401-411 ◽  
Author(s):  
Giuseppe Biagini ◽  
Michele Zoli ◽  
Carla Torn ◽  
Sabina Boschi ◽  
Giuseppe Vantaggiato ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Fluid Intake ◽  
Vascular Lesions ◽  
Heart Weight ◽  
Protective Effects ◽  
Spontaneously Hypertensive ◽  
High Sodium ◽  
Sodium Diet ◽  
High Sodium Diet

1. Stroke-prone spontaneously hypertensive rats (SHRsp) have been used widely to test agents putatively capable of vascular protection. These animals present an accelerated time course of hypertension and a reduced life-span. When fed a high-sodium diet from the eighth week of life, a further acceleration in blood pressure increase is obtained, and rats start to die after 5 weeks of diet as a consequence of cerebral haemorrhage. In this model, angiotensin-converting enzyme (ACE) inhibitors were repeatedly proved to prevent vascular lesions and death. Notably, this effect was independent of any hypotensive effect. On the contrary, diuretics were shown not to be equally effective. A combination of ACE inhibitors and diuretics, although known to have synergistic effects in the therapy of hypertension, has never previously been tested. 2. Our aim was to study the effects of long-term treatment with the ACE inhibitor delapril (12 mg day−1 kg−1), the thiazide-like diuretic indapamide (1 mg day−1 kg−1), and their combination (12 and 1 mg day−1 kg−1 respectively), on the survival of SHRsp rats fed a high-sodium diet from the eighth week of life onwards. The effects of the treatments on blood pressure, body weight, food and fluid intake, diuresis, proteinuria and the appearance of lesion signs and death were assessed weekly. When control rats reached 50% mortality, they were killed, together with some drug-treated rats, to compare lesions in brain and kidney. The other drug-treated rats continued treatments until 50% mortality was reached in two treatment groups. 3. All drug treatments were able to delay death significantly when compared with control rats, which reached 50% mortality after 6 weeks of salt loading. This event was preceded by a highly significant increase in proteinuria, diuresis and fluid intake that took place 3 weeks after the increase in blood pressure over the initial range. In delapril- or indapamide-treated SHRsp these changes were never seen, even when animals started to die. In the combination-treated group, a significant increase (P < 0.01) in fluid intake and diuresis, but not proteinuria, was observed from the third week of treatment onwards. 4. Treatment with delapril or indapamide did not block the progressive increase in blood pressure as observed in control animals. However, the increase in blood pressure was markedly retarded with respect to control rats. At variance with this, in combination-treated animals blood pressure levels were maintained until the end of the experiment within the 99% confidence interval initially observed in control animals. 5. Infarctual and haemorrhagic cerebral lesions were observed in 38% of control rats; no lesions were noted in brains of age-matched rats receiving a drug treatment. Kidneys from control animals presented major degenerative lesions of glomeruli and arteries, characterized by fibrinoid necrosis. This condition was absent in drug-treated animals, which presented minor signs of ischaemic lesion. Heart hypertrophy, when heart weight was expressed as a percentage of body weight, was similar in saline-, delapril- or indapamide-treated rats. At variance with this, in combination-treated animals the heart weight to body weight ratio was significantly (P < 0.01) lower than in the other groups. 6. In conclusion, the diuretic indapamide showed similar protective effects as the ACE inhibitor delapril on acute vascular lesions and survival of SHRsp. Moreover, their combination synergized in preventing heart hypertrophy consequent to long-term hypertension. This result is probably related to the enhanced diuresis and the better control of blood pressure levels selectively found in combination-treated animals.

Investigation of the Effects of Ketoconazole on the Pharmacokinetics of Macitentan, a Novel Dual Endothelin Receptor Antagonist, in Healthy Subjects

2013 ◽  
Vol 52 (8) ◽  
pp. 685-692 ◽  
Author(s):  
Jacob Atsmon ◽  
Jasper Dingemanse ◽  
Dimitri Shaikevich ◽  
Inna Volokhov ◽  
Patricia N. Sidharta
Keyword(s):  
Receptor Antagonist ◽  
Healthy Subjects ◽  
Endothelin Receptor Antagonist ◽  
Endothelin Receptor
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