Enhanced AT1 receptor-mediated vasocontractile response to ANG II in endothelium-denuded aorta of obese Zucker rats

2007 ◽  
Vol 292 (4) ◽  
pp. H1722-H1727 ◽  
Author(s):  
Athar H. Siddiqui ◽  
Tahir Hussain
Keyword(s):  
Isometric Tension ◽  
No Synthase ◽  
Receptor Protein ◽  
Zucker Rats ◽  
No Production ◽  
Ang Ii ◽  
No Donor ◽  
Obese Rats ◽  
Obese Zucker Rats

In the present study, we tested the hypothesis that ANG II causes a greater vasoconstriction in obese Zucker rats, a model of type 2 diabetes, with mild hypertension. Measurement of isometric tension in isolated aortic rings with intact endothelium revealed a modest but not significantly greater ANG II-induced contraction in obese than lean rats. Removal of endothelium or inhibition of nitric oxide (NO) synthase by NG-nitro-l-arginine methyl ester (l-NAME) enhanced 1) ANG II-induced contraction in both lean and obese rats, being significantly greater in obese rats (Emax g/g tissue, denuded: lean 572 ± 40 vs. obese 664 ± 16; l-NAME: lean 535 ± 14 vs. obese 818 ± 23) and 2) ANG II sensitivity in obese compared with lean rats, as revealed by the pD2 values. Endothelin-1 and KCl elicited similar contractions in the aortic rings of lean and obese rats. ACh, a NO-dependent relaxing hormone, produced greater relaxation in the aortic rings of obese than lean rats, whereas sodium nitroprusside, an NO donor, elicited similar relaxations in both rat strains. The expression of the ANG type 1 (AT1) receptor protein and mRNA in the endothelium-intact aorta was significantly greater in obese than lean rats, whereas the endothelium-denuded rings expressed modest but not significantly greater levels of AT1 receptors in obese than lean rats. The endothelial NO synthase protein and mRNA expression levels were higher in the aorta of obese than lean animals. We conclude that, although ANG II produces greater vasoconstriction in obese rat aortic rings, enhanced endothelial AT1 receptor-mediated NO production appears to counteract the increased ANG II-induced vasoconstriction, suggesting that arterial AT1 receptor may not be a contributing factor to hypertension in this model of obesity.

scholarly journals High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT2R-MasR axis in obese Zucker rats

2012 ◽  
Vol 303 (3) ◽  
pp. F412-F419 ◽  
Author(s):  
Preethi Samuel ◽  
Quaisar Ali ◽  
Rifat Sabuhi ◽  
Yonnie Wu ◽  
Tahir Hussain
Keyword(s):  
Sodium Intake ◽  
Zucker Rats ◽  
Kidney Cortex ◽  
Complex Nature ◽  
Ang Ii ◽  
Pronounced Increase ◽  
High Sodium ◽  
High Sodium Intake ◽  
Obese Rats ◽  
Obese Zucker Rats

High sodium intake is known to regulate the renal renin-angiotensin system (RAS) and is a risk factor for the pathogenesis of obesity-related hypertension. The complex nature of the RAS reveals that its various components may have opposing effects on natriuresis and blood pressure regulation. We hypothesized that high sodium intake differentially regulates and shifts a balance between opposing components of the renal RAS, namely, angiotensin-converting enzyme (ACE)-ANG II-type 1 ANG II receptor (AT1R) vs. AT2-ACE2-angiotensinogen (Ang) (1–7)-Mas receptor (MasR), in obesity. In the present study, we evaluated protein and/or mRNA expression of angiotensinogen, renin, AT1A/BR, ACE, AT2R, ACE2, and MasR in the kidney cortex following 2 wk of a 8% high-sodium (HS) diet in lean and obese Zucker rats. The expression data showed that the relative expression pattern of ACE and AT1BR increased, renin decreased, and ACE2, AT2R, and MasR remained unaltered in HS-fed lean rats. On the other hand, HS intake in obese rats caused an increase in the cortical expression of ACE, a decrease in ACE2, AT2R, and MasR, and no changes in renin and AT1R. The cortical levels of ANG II increased by threefold in obese rats on HS compared with obese rats on normal salt (NS), which was not different than in lean rats. The HS intake elevated mean arterial pressure in obese rats (27 mmHg) more than in lean rats (16 mmHg). This study suggests that HS intake causes a pronounced increase in ANG II levels and a reduction in the expression of the ACE2-AT2R-MasR axis in the kidney cortex of obese rats. We conclude that such changes may lead to the potentially unopposed function of AT1R, with its various cellular and physiological roles, including the contribution to the pathogenesis of obesity-related hypertension.

scholarly journals Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II

2010 ◽  
Vol 299 (5) ◽  
pp. F1164-F1170 ◽  
Author(s):  
Xiaoyan Wang ◽  
Fengmin Li ◽  
Pedro A. Jose ◽  
Carolyn M. Ecelbarger
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Receptor Expression ◽  
Female Rats ◽  
Male Rats ◽  
Zucker Rats ◽  
Protein Levels ◽  
Obese Rats ◽  
Obese Zucker Rats

Dopamine produced by renal proximal tubules increases sodium excretion via a decrease in renal sodium reabsorption. Dopamine natriuresis is impaired in obese Zucker rats; however, the mechanism is not fully understood. To test the hypothesis that renal expression of one or more of the subtypes are altered in these rats, we measured whole kidney protein levels by immunoblotting of D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R) dopamine receptors in both male and female obese and lean Zucker rats. In obese males on 1% NaCl diet, D1R, D2R, D4R, and D5R were decreased, while D3R was increased, relative to lean rats. Under a 4% NaCl diet, D2R and D3R levels in obese rats were restored to lean levels. 4% NaCl diet reduced D5R in both body types, relative to 1% NaCl diet. Female rats had higher expression of D1R and D3R than did male; however, the sex difference for D1R was markedly blunted in obese rats. In obese rats, dietary candesartan (angiotensin II type 1 receptor blocker) normalized downregulated D1R and D2R, but either decreased (D3R), did not affect (D4R), or further downregulated (D5R) the other subtypes. Candesartan also decreased D4R in lean rats. In summary, reduced renal protein levels of D1R, D2R, D4R, and D5R in obese Zucker rats could induce salt sensitivity and elevate blood pressure. Increased angiotensin II type 1 receptor activity may be mechanistically involved in the decreased expression of D1R and D2R in obese rats. Finally, reduced D1R and D3R in male rats may contribute to sex differences in blood pressure.

scholarly journals Mechanisms of dysregulation of 11 beta-hydroxysteroid dehydrogenase type 1 in obese Zucker rats

2000 ◽  
Vol 167 (3) ◽  
pp. 533-539 ◽  
Author(s):  
DE Livingstone ◽  
CJ Kenyon ◽  
BR Walker
Keyword(s):  
Weight Gain ◽  
Hydroxysteroid Dehydrogenase ◽  
Zucker Rats ◽  
Tissue Specific ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
The Difference ◽  
Underlying Mechanisms ◽  
Omental Fat

Obesity has been associated with alterations in glucocorticoid metabolism in both man and rodents, but the underlying mechanisms remain undefined. We have previously reported tissue-specific alterations in 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) in obese Zucker rats predicting that reactivation of corticosterone is decreased in liver but increased in omental fat. The mechanisms of dysregulation of 11 beta-HSD1 in obesity are not known, and in this study we have investigated the potential role of glucocorticoids and insulin. In one experiment lean and obese Zucker rats were adrenalectomised, and in a second experiment they were sensitised to insulin by treatment with either metformin or rosiglitazone. Adrenalectomy (ADX) of obese animals attenuated weight gain, normalised hepatic 11 beta-HSD1 kinetics by an effect on V(max) (V(max)in sham-operated animals, 6.6+/-1.1 nmol/min per mg in lean vs 3.4+/-0.6 in obese, P<0.01; in ADX animals 5.9+/-1.1 in lean vs 6.9+/-1.8 in obese, NS), and reversed the difference in omental fat 11 beta-HSD1 activity (18.9+/-4.2% in lean ADX vs 8.2+/-2.3 in obese ADX, P=0.03). Both metformin and rosiglitazone improved insulin sensitivity in obese, but not lean animals, and had no effect on 11 beta-HSD1 activity in either liver or fat. However, both treatments normalised adrenal hypertrophy in obese animals (48+/-29 mg in obese vehicle vs 37+/-1.2 in metformin and 38+/-1.8 in rosiglitazone treated, both P<0.01), and rosiglitazone tended to attenuate hypercorticosteronaemia in obese rats. Neither treatment attenuated weight gain; in fact, weight gain was enhanced by rosiglitazone in obese rats. In summary, altered 11 beta-HSD1 activity in obese Zucker rats is reversible following adrenalectomy, but the mechanism is unclear since adrenalectomy also normalises many other metabolic abnormalities. The current study suggests that hyperinsulinaemia is not responsible for tissue-specific dysregulation of 11 beta-HSD1. However, insulin sensitisation did reverse adrenal hypertrophy, suggesting that hyperinsulinaemia may be a key factor contributing to activation of the hypothalamic- pituitary-adrenal (HPA) axis in obesity independently of tissue-specific changes in 11 beta-HSD1.

Renal dopamine D1 receptor dysfunction is acquired and not inherited in obese Zucker rats

2004 ◽  
Vol 287 (1) ◽  
pp. F109-F116 ◽  
Author(s):  
Anees Ahmad Banday ◽  
Tahir Hussain ◽  
Mustafa F. Lokhandwala
Keyword(s):  
G Protein ◽  
D1 Receptor ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Zucker Rats ◽  
Receptor Function ◽  
Rat Serum ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Renal Dopamine

In essential hypertension, the defect in renal dopamine (DA) D1 receptor function is intrinsic to proximal tubules as this phenomenon is also seen in primary proximal tubule cultures from spontaneously hypertensive rats (SHR) and essential hypertensive patients. Previously, a defect was reported in renal D1 receptor function in obese Zucker rats. In the present study, we sought to determine whether this D1 receptor dysfunction is intrinsic in these animals. In primary proximal tubular epithelial cells (PTECs) from lean and obese rats, DA inhibited Na-K-ATPase (NKA) activity in PTECs from both groups of rats. Basal NKA activity, D1 receptor protein expression, and their coupling to G proteins were similar in cells from both groups. However, when PTECs from lean and obese rats were cultured in 20% serum from obese rats, DA failed to inhibit NKA activity, which was accompanied by a reduction in D1 receptor expression and a defect in D1 receptor-G protein coupling. No such defects in the inhibitory effect of DA on NKA activity, D1 receptor numbers, or coupling were seen when PTECs from both lean and obese rats were grown in 20% serum from lean or rosiglitazone-treated obese (RTO) rats. RTO rat serum had normal blood glucose and reduced plasma levels of insulin compared with serum from obese rats. Furthermore, chronic insulin treatment of PTECs from lean and obese rats caused an attenuation in DA-induced NKA inhibition, a decrease in D1 receptor expression, and D1 receptor-G protein uncoupling. These results suggest that defective D1 receptor function in obese Zucker rats is not inherited but contributed to by hyperinsulinemia and/or other circulating factors associated with obesity.

scholarly journals Obese Zucker Rats Have Reduced Mineralocorticoid Receptor and 11β-Hydroxysteroid Dehydrogenase Type 1 Expression in Hippocampus—Implications for Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in Obesity

Endocrinology ◽  
2003 ◽  
Vol 144 (7) ◽  
pp. 2997-3003 ◽  
Author(s):  
Cecilia Mattsson ◽  
Maggie Lai ◽  
June Noble ◽  
Eoin McKinney ◽  
Joyce L. Yau ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Glucocorticoid Receptors ◽  
Hydroxysteroid Dehydrogenase ◽  
Male Rats ◽  
Zucker Rats ◽  
Mrna Levels ◽  
Hypothalamic Pituitary Adrenal ◽  
Obese Rats ◽  
Obese Zucker Rats

Abstract Obese Zucker rats have elevated basal corticosterone levels and an increased stress response suggestive of an increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. We hypothesized that altered central expression of glucocorticoid receptors (GR), mineralocorticoid receptors (MR), and/or 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) contribute to these changes. In brains from young adult male rats, in situ hybridization and Western blotting showed that obese rats had normal hippocampal GR mRNA and protein levels. In contrast, in obese rats, 11βHSD1 mRNA levels were reduced in a subpopulation of hippocampal cells in the main neuronal layers (by 37–47%, P &lt; 0.05), whereas 11βHSD1 levels in sparse high-expressing cells did not differ. MR mRNA was decreased in all regions of the hippocampus (by 37–49%, P &lt; 0.05 for CA1–2 and P &lt; 0.01 for dentate gyrus) and in frontal cortex (by 16%, P &lt; 0.05) in obese rats. In whole hippocampal homogenates, however, neither the protein concentration of MR by Western blot nor activity of 11βHSD1 was measurably different between the phenotypes. To test the functional importance of lower central MR expression, groups of lean and obese rats were given spironolactone before restraint stress. In vehicle-treated animals, obese rats had higher plasma corticosterone levels than lean rats after stress (by ANOVA, P &lt; 0.05). Spironolactone markedly increased the corticosterone response in both groups, but the incremental rise was smaller in the obese rats, so that spironolactone abolished the differences between groups. We conclude that lower levels of MR, but not GR, contribute to the increased HPA activity in the obese Zucker rats and that this seems more influential during stress than in the basal state. This may be exacerbated by impaired local regeneration of corticosterone by 11βHSD1. These abnormalities could contribute to the subtle changes in the HPA axis in rodent and human obesity.

Interactions between nitric oxide and renal nerves in the excretion of a saline load in obese Zucker rats

2001 ◽  
Vol 101 (3) ◽  
pp. 275-283 ◽  
Author(s):  
Orawan WONGMEKIAT ◽  
Edward J. JOHNS
Keyword(s):  
Nitric Oxide ◽  
Sympathetic Nerves ◽  
Urinary Sodium Excretion ◽  
No Synthase ◽  
Zucker Rats ◽  
Renal Nerves ◽  
Renal Nerve ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Renal Innervation

The present study investigated the potential role of nitric oxide (NO) and its interaction with renal sympathetic nerves in modulating the excretory responses to an acute saline volume expansion (VE), of 10% of body weight, in the innervated and denervated kidneys of both lean and obese Zucker rats. This was done using the NO synthase inhibitors NG-nitro-l-arginine methyl ester (l-NAME), 7-nitroindazole and aminoguanidine. In lean rats, cumulative urinary sodium excretion (cuUNaV) after 40 min of VE in the innervated kidney was enhanced by 48% in l-NAME-treated rats compared with that in untreated rats, but this was not the case for the denervated kidney. VE in untreated obese rats raised cuUNaV to a lesser extent than in the untreated lean rats, by 36% and 46% in the denervated and innervated kidneys respectively (both P < 0.001). l-NAME treatment of obese rats increased cuUNaV after VE compared with that in untreated obese rats, by 48% in the denervated kidney and by 136% in the innervated kidney (both P < 0.001). The magnitude of cuUNaV after VE in both kidneys of 7-nitroindazole-treated obese rats was not different from that in untreated obese rats. However, cuUNaV was raised (P < 0.01) by 56% in the innervated, but not the denervated, kidney of aminoguanidine-treated obese rats. These data show that NO is partially involved in mediating the reflex renal responses to VE in Zucker rat strains. NO, possibly generated by endothelial NO synthase, exerts its effects in obese rats through a renal-nerve-independent mechanism, while the effect of NO generated by inducible NO synthase requires intact renal innervation.

Abstract 1137: Switch From Nitric Oxide To Hydrogen Peroxide Mediated Dilation In Coronary Arterioles Of Obese Rats

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Marta Focardi ◽  
Marina Ziche ◽  
Mario Marzilli
Keyword(s):  
Endothelial Function ◽  
Caloric Intake ◽  
Zucker Rats ◽  
No Production ◽  
Obese Rats ◽  
Before And After ◽  
Obese Zucker Rats ◽  
Carb Diet ◽  
Coronary Endothelial Dysfunction ◽  
Coronary Arterioles

Background. Obesity is associated with coronary endothelial dysfunction, an early marker of atherosclerosis; but impaired endothelial function in obese Zucker rats appears not to be mediated by NO production. Hypothesis: We tested the hypothesis that endothelial derived hyperpolarizing factor (EDHF) is responsible for endothelial dilation in obese rats. Methods: We used 4 groups of male Zucker rats: lean and obese on normal and low carb diets. Rats were fed ad libitum for 3 weeks; caloric intake and weight gain were similar. Coronary arterioles were cannulated and pressurized for diameter measurements. Vasodilation to acetylcholine (Ach) and flow was determined before and after incubation with L-NAME (10 μm), an inhibitor of NO synthase, plus the cyclooxygenase inhibitor indomethacin (Indo; 10 μm), after tetraethylammonium (TEA 1 mM), a non-selective K + channel antagonist, and after catalase, a H 2 O 2 scavenger (CAT; 500 U/ml). Results Acetylcholine-induced vasodilation was impaired in obese rats compared to lean (41%; n=5 vs 87%; n=3; p<0.05) and did not change after L-NAME+Indo incubation in obese both on normal (47 ± 19%; n = 4 vs . 40 ± 13%; n = 4; p =ns) and low carb diet (51 ± 1%; n = 3 vs . 59 ± 6%; n = 3; p =ns). Flow-induced dilation was impaired in obese rats compared to lean (38%;n=5 vs 78%; n=2;p<0.05) and this dilation was not affected by L-NAME+Indo incubation in obese both on normal (45±12%; n=4 vs 48±10% n=4; p =ns) and low carb diet (53±14%; n=3 vs 61±12% n=3; p =ns). Importantly, TEA incubation decreased Ach dilation both in obese on normal (41±11%; n=5 vs 13±7% n=5; p< 0.05) and low carb diet (76±25%; n=3 vs 22±18% n=3; p< 0.05). Similar results were obtained during flow-induced dilation in obese both on normal (37±17%; n=5 vs 14±7% n=5; p< 0.05) and low carb diet (54±14%; n=3 vs 15±3% n=3; p< 0.05). Catalase administration blocked both FID and Ach dilation in obese both on normal (FID 45±15% vs 5±3% n=3; p< 0.05; Ach 39±14% vs 12±5% n=3; p<0.05) and low carb diet (FID 52±19% vs 18±7% n=2; p< 0.05; Ach 75±35% vs 15±2% n=2; p< 0.05). Conclusions: Endothelial dependent vasodilation of coronary arterioles in obese Zucker rats is mediated by H 2 O 2 and increases in endothelial function in obese rats on a low carb diet is mediated by increased H 2 O 2 -induced dilation.

scholarly journals Beneficial Effects of Cornelian Cherries on Lipid Profile and NO/ROS Balance in Obese Zucker Rats: Comparison with CoQ10

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1922 ◽  
Author(s):  
Ezgi Dayar ◽  
Martina Cebova ◽  
Jan Lietava ◽  
Elena Panghyova ◽  
Olga Pechanova
Keyword(s):  
Nadph Oxidase ◽  
Lipid Profile ◽  
Plasma Lipid ◽  
Heart Weight ◽  
Zucker Rats ◽  
Control Group ◽  
No Production ◽  
Beneficial Effects ◽  
Obese Rats ◽  
Obese Zucker Rats

Cornelian cherries (CCs) belong to promising anti-obesity substances. We aimed to study effects of coenzyme Q10 (CoQ10) and two varieties of CCs on lipid profile, ROS, and nitric oxide (NO) production in obese rats. Male Zucker rats were divided into the control group and groups treated with CoQ10 (30mg/kg/day), or CC varieties: Koralovij Marka (KM) and Wild Type (WT) (5 g/kg/day, n = 6 in each group) for 6 weeks. Blood pressure (BP), bodyweight, relative heart weight, and plasma lipid profile were determined. NOS activity and expressions of eNOS, SOD, and NADPH oxidase were determined in the left ventricle (LV) and aorta. Among CC groups, KM decreased bodyweight and WT relative heart weight. Neither CoQ10 nor CCs affected BP. CoQ10 did not affect lipid profile and NOS activity either in the LV or aorta. On the other hand, WT decreased cholesterol and LDL levels. KM and WT increased NOS activity in the aorta, while not affecting the activity in the LV. KM increased eNOS expression and did not affect ROS production, while WT increased SOD and decreased NADPH oxidase without affecting eNOS expressions in both tissues. In conclusion, CCs showed better beneficial effects than CoQ10 in all parameters studied.

scholarly journals Role of Neural NO Synthase (nNOS) Uncoupling in the Dysfunctional Nitrergic Vasorelaxation of Penile Arteries from Insulin-Resistant Obese Zucker Rats

PLoS ONE ◽  
2012 ◽  
Vol 7 (4) ◽  
pp. e36027 ◽  
Author(s):  
Ana Sánchez ◽  
Cristina Contreras ◽  
María Pilar Martínez ◽  
Belén Climent ◽  
Sara Benedito ◽  
...  
Keyword(s):  
No Synthase ◽  
Zucker Rats ◽  
Insulin Resistant ◽  
Obese Zucker Rats ◽  
Penile Arteries

scholarly journals Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats

2005 ◽  
Vol 153 (6) ◽  
pp. 963-969 ◽  
Author(s):  
Dorte X Gram ◽  
Anker J Hansen ◽  
Michael Wilken ◽  
Torben Elm ◽  
Ove Svendsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Sensory Nerve ◽  
Zucker Rats ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Nerve Activity ◽  
Calcitonin Gene ◽  
Obese Rats ◽  
Obese Zucker Rats

Objective: It has earlier been demonstrated that capsaicin-induced desensitization improves insulin sensitivity in normal rats. However, whether increased capsaicin-sensitive nerve activity precedes the onset of insulin resistance in diet-induced obesity – and therefore might be involved in the pathophysiology – is not known. Further, it is of relevance to investigate whether capsaicin desensitization improves glycaemic control even in obese individuals and we therefore chose the obese Zucker rats to test this. Design and methods: Plasma levels of calcitonin gene-related peptide (CGRP; a marker of sensory nerve activity) was assessed in 8-week-old Zucker rats. To investigate whether capsaicin desensitization (100 mg/kg at 9 weeks of age) would also ameliorate glycaemia in this non-diabetic model, we assessed oral glucose tolerance at 7 weeks after capsaicin. Results: It was found that plasma CGRP levels were elevated in obese Zucker rats prior to the onset of obesity (16.1±3.4 pmol/l in pre-obese Zucker rats vs 6.9±1.1 pmol/l in lean littermates; P = 0.015) despite similar body weights. Furthermore, capsaicin desensitization reduced both fasting blood glucose (4.3±0.2 mmol/l vs 5.1±0.2 mmol/l in controls; P = 0.050) as well as the mean blood glucose level during an oral glucose tolerance test (OGTT) (6.8±0.3 mmol/l vs 8.6±0.5 mmol/l in control obese rats; P = 0.024) whereas the plasma insulin levels during the OGTT were unchanged. However this did not lead to an improvement in insulin resistance or to a reduction of tissue triglyceride accumulation in muscle or liver. Conclusion: We concluded that capsaicin-induced sensory nerve desensitization improves glucose tolerance in Zucker rats. Since, in this study, plasma CGRP levels, a marker of sensory nerve activity, were increased in the pre-obese rats, our data support the hypothesis that increased activity of sensory nerves precedes the development of obesity and insulin resistance in Zucker rats.

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