Estrogen has opposing effects on vascular reactivity  in obese, insulin-resistant male Zucker rats

We hypothesized that estradiol treatment would improve vascular dysfunction commonly associated with obesity, hyperlipidemia, and insulin resistance. A sham operation or 17β-estradiol pellet implantation was performed in male lean and obese Zucker rats. Maximal vasoconstriction (VC) to phenylephrine (PE) and potassium chloride was exaggerated in control obese rats compared with lean rats, but estradiol significantly attenuated VC in the obese rats. Estradiol reduced the PE EC50 in all groups. This effect was cyclooxygenase independent, because preincubation with indomethacin reduced VC response to PE similarly in a subset of control and estrogen-treated lean rats. Endothelium-independent vasodilation (VD) to sodium nitroprusside was similar among groups, but endothelium-dependent VD to ACh was significantly impaired in obese compared with lean rats. Estradiol improved VD in lean and obese rats by decreasing EC50 but impaired function by decreasing maximal VD. The shift in EC50 corresponded to an upregulation in nitric oxide synthase III protein expression in the aorta of the estrogen-treated obese rats. In summary, estrogen treatment improves vascular function in male insulin-resistant, obese rats, partially via an upregulation of nitric oxide synthase III protein expression. These effects are counteracted by adverse factors, such as hyperlipidemia and, potentially, a release of an endothelium-derived contractile agent.

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Endothelial cell transfusion ameliorates endothelial dysfunction in 5/6 nephrectomized rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00132.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. H1256-H1264 ◽

Cited By ~ 5

Author(s):

Maricica Pacurari ◽

Dongqi Xing ◽

Rob H. P. Hilgers ◽

Yuan Yuan Guo ◽

Zhengqin Yang ◽

...

Keyword(s):

Nitric Oxide ◽

Chronic Kidney Disease ◽

Endothelial Dysfunction ◽

Nitric Oxide Synthase ◽

Kidney Disease ◽

Endothelial Nitric Oxide Synthase ◽

Vascular Function ◽

Vascular Reactivity ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Endothelial dysfunction is prevalent in chronic kidney disease. This study tested the hypothesis that transfusion of rat aortic endothelial cells (ECs) ameliorates endothelial dysfunction in a rat model of chronic kidney disease. Male Sprague-Dawley rats underwent sham surgery or 5/6 nephrectomy (Nx). Five weeks after Nx, EC (1.5 × 106 cells/rat) or vehicle were transfused intravenously. One week later, vascular reactivity of mesenteric artery was assessed on a wire myograph. Sensitivity of endothelium-dependent relaxation to acetylcholine and maximum vasodilation were impaired by Nx and improved by EC transfusion. Using selective pharmacological nitric oxide synthase isoform inhibitors, we demonstrated that the negative effect of Nx on endothelial function and rescue by EC transfusion are, at least in part, endothelial nitric oxide synthase mediated. Plasma asymmetric dimethylarginine was increased by Nx and decreased by EC transfusion, whereas mRNA expression of dimethylarginine dimethylaminohydrolases 1 (DDAH1) was decreased by Nx and restored by EC transfusion. Immunohistochemical staining confirmed that local expression of DDAH1 is decreased by Nx and increased by EC transfusion. In conclusion, EC transfusion attenuates Nx-induced endothelium-dependent vascular dysfunction by regulating DDAH1 expression and enhancing endothelial nitric oxide synthase activity. These results suggest that EC-based therapy could provide a novel therapeutic strategy to improve vascular function in chronic kidney disease.

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Modulation of noradrenaline-induced vasoconstriction in isolated perfused mesenteric arterial beds from obese Zucker rats in the presence and absence of insulin

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y02-015 ◽

2002 ◽

Vol 80 (3) ◽

pp. 171-179 ◽

Cited By ~ 17

Author(s):

Yi He ◽

Kathleen M MacLeod

Keyword(s):

Nitric Oxide ◽

Insulin Resistance ◽

Receptor Antagonist ◽

Vascular Reactivity ◽

Zucker Rats ◽

Insulin Resistant ◽

Significant Difference ◽

Obese Rats ◽

Obese Zucker Rats ◽

Presence And Absence

The genetically obese Zucker rat (fa/fa) is an insulin-resistant animal model with early-onset severe hyperinsulinemia that eventually develops mild hypertension. Thus, it represents a model in which the effect of hyperinsulinemia insulin resistance associated with hypertension on vascular reactivity can be examined. The purpose of this study was to investigate the contribution of endogenous nitric oxide (NO) and prostaglandins to reactivity to noradrenaline (NA) in the presence and absence of insulin in mesenteric arterial beds (MAB) from 25-week-old obese Zucker rats and their lean, gender-matched littermates. In the absence of insulin, bolus injection of NA (0.990 nmol) produced a dose-dependent increase in perfusion pressure in MAB from both lean and obese rats. Although there was no significant difference in NA pD2 (log ED50) values, the maximum response of MAB from obese rats to NA was slightly but significantly reduced compared with that of MAB from lean rats. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 300 µM) enhanced and indomethacin (20 µM) inhibited pressor responses to NA in MAB from both obese and lean rats. Perfusion with insulin (200 mU/L, a level similar to that in obese rats in vivo) potentiated only the responses of the obese MAB to the two lowest doses of NA tested (0.9 and 3 nmol). In the presence of L-NMMA, insulin further potentiated the NA response in MAB from obese rats. Indomethacin, the prostaglandin H2/thromboxane A2 receptor antagonist SQ 29548 (0.3 µM), and the nonselective endothelin-1 (ET-1) receptor antagonist bosentan (3 µM) all abolished insulin potentiation of the NA response in obese MAB. These data suggest that concurrent release of NO and vasoconstrictor cyclooxygenase product(s) in MAB from both obese and lean Zucker rats normally regulates NA-induced vasoconstrictor responses. Furthermore, insulin increases the release of contracting cyclooxygenase product(s) and enhances reactivity to low doses of NA in MAB from obese rats. The effects of insulin may be partially mediated by ET-1 via ET receptors and are buffered to some extent by concomitant NO release. This altered action of insulin may play a role in hypertension in this hyperinsulinemic insulin-resistant model.Key words: hyperinsulinemia, insulin resistance, hypertensive Zucker obese rat, mesenteric arterial bed, noradrenaline.

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Adventitial Gene Transfer of Recombinant Endothelial Nitric Oxide Synthase to Rabbit Carotid Arteries Alters Vascular Reactivity

Circulation ◽

10.1161/01.cir.96.7.2254 ◽

1997 ◽

Vol 96 (7) ◽

pp. 2254-2261 ◽

Cited By ~ 56

Author(s):

Iftikhar J. Kullo ◽

Geza Mozes ◽

Robert S. Schwartz ◽

Peter Gloviczki ◽

Thomas B. Crotty ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Gene Transfer ◽

Endothelial Nitric Oxide Synthase ◽

Vascular Reactivity ◽

Carotid Arteries ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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Effect of magnesium supplementation on blood pressure and vascular reactivity in nitric oxide synthase inhibition-induced hypertension model

Clinical and Experimental Hypertension ◽

10.3109/10641963.2015.1036063 ◽

2015 ◽

Vol 37 (8) ◽

pp. 633-642 ◽

Cited By ~ 5

Author(s):

Filiz Basralı ◽

Günnur Koçer ◽

Pınar Ülker Karadamar ◽

Seher Nasırcılar Ülker ◽

Leyla Satı ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Nitric Oxide Synthase ◽

Vascular Reactivity ◽

Magnesium Supplementation ◽

Induced Hypertension ◽

Oxide Synthase

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Inducible Nitric-oxide Synthase and Nitric Oxide Donor Decrease Insulin Receptor Substrate-2 Protein Expression by Promoting Proteasome-dependent Degradation in Pancreatic β-Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m110.192732 ◽

2011 ◽

Vol 286 (33) ◽

pp. 29388-29396 ◽

Cited By ~ 21

Author(s):

Toshihiro Tanioka ◽

Yoshiaki Tamura ◽

Makiko Fukaya ◽

Shohei Shinozaki ◽

Ji Mao ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Protein Expression ◽

Inducible Nitric Oxide Synthase ◽

Nitric Oxide Donor ◽

Insulin Receptor Substrate ◽

Β Cells ◽

Pancreatic Β Cells ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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Arginase Inhibitor 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside Activates Endothelial Nitric Oxide Synthase and Improves Vascular Function

Planta Medica ◽

10.1055/s-0042-111014 ◽

2016 ◽

Vol 83 (03/04) ◽

pp. 210-216 ◽

Cited By ~ 1

Author(s):

Bonggu Yi ◽

Minh Nguyen ◽

Moo-Ho Won ◽

Young Kim ◽

Sungwoo Ryoo

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Vascular Function ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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Nitric oxide synthase and arginase expression changes in the rat perirhinal and entorhinal cortices following unilateral vestibular damage: A link to deficits in object recognition?

Journal of Vestibular Research ◽

10.3233/ves-2004-14601 ◽

2004 ◽

Vol 14 (6) ◽

pp. 411-417 ◽

Cited By ~ 2

Author(s):

Ping Liu ◽

Catherine M. Gliddon ◽

Libby Lindsay ◽

Cynthia L. Darlington ◽

Paul F. Smith

Keyword(s):

Nitric Oxide ◽

Object Recognition ◽

Nitric Oxide Synthase ◽

Protein Expression ◽

Medial Temporal Lobe ◽

Contralateral Side ◽

Arginase Ii ◽

Neurochemical Changes ◽

Oxide Synthase ◽

Vestibular Damage

Previous studies have shown that peripheral vestibular damage causes long-term neurochemical changes in the hippocampus which may be related to spatial memory deficits. Since recent studies have also demonstrated deficits in non-spatial object recognition memory following vestibular lesions, the aim of the present study was to extend these investigations into the perirhinal cortex (PRC), which is known to be important for object recognition, and the related entorhinal cortex (EC). We examined the effects of unilateral vestibular deafferentation (UVD) on the expression of four enzymes associated with neuronal plasticity, neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), arginase I and arginase II (AI and II), in the rat EC and PRC using Western blotting. Tissue was collected at 10 hs, 50 hs and 2 weeks post-UVD. In the EC and PRC, nNOS protein expression decreased on the contralateral side at 2 weeks post-UVD but not before. At the same time, eNOS protein expression increased in both regions on the contralateral side. In the EC, AII protein expression increased on the ipsilateral side at 2 weeks post-UVD. In the PRC, AI increased and decreased on the contralateral and ipsilateral sides (respectively) at 2 weeks post-UVD. AII showed a bilateral increase in the PRC at 2 weeks post-UVD. These results demonstrate changes in NOS and arginase protein expression in the PRC and EC following UVD, which are unlikely to be due to the initial severity of the vestibular syndrome because they develop well after vestibular compensation has taken place. Neurochemical changes in these regions of the medial temporal lobe may be implicated in the development of object recognition deficits that contribute to cognitive dysfunction following peripheral vestibular damage.

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Hypertension in insulin-resistant Zucker obese rats is independent of sympathetic neural support

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1992.262.3.e368 ◽

1992 ◽

Vol 262 (3) ◽

pp. E368-E371 ◽

Cited By ~ 7

Author(s):

M. B. Zemel ◽

J. D. Peuler ◽

J. R. Sowers ◽

L. Simpson

Keyword(s):

Angiotensin Ii ◽

Neural Activity ◽

Vascular Reactivity ◽

Zucker Rats ◽

Ganglionic Blockade ◽

Intravenous Injections ◽

Insulin Resistant ◽

Arterial Blood ◽

Obese Rats ◽

Blood Pressure Responses

We have previously reported that insulin-resistant Zucker obese rats exhibit hypertension associated with impaired vascular smooth muscle (VSM) Ca2+ transport and proposed that this results from failure of insulin to regulate VSM Ca2+ transport in insulin resistance. However, hypertension in insulin-resistant states is generally attributed to hyperinsulinemia, with a consequent stimulation of sympathetic neural activity. Accordingly, the present study was conducted to determine whether the hypertension observed in Zucker obese rats compared with their lean controls was dependent on either increased sympathetic neural activity or exaggerated vascular reactivity. Intra-arterial blood pressure responses to ganglionic blockade with Ecolid (chlorisondamine chloride) and to graded intravenous injections of angiotensin II and norepinephrine were compared in 6- to 8-wk-old male Zucker rats and their lean controls (n = 10/group). The obese rats exhibited significant hypertension before ganglionic blockade (P less than 0.001), and this difference was largely sustained during ganglionic blockade (P less than 0.005). Furthermore, the obese rats exhibited greater pressor sensitivity to both angiotensin II and to norepinephrine during ganglionic blockade (P less than 0.01). Thus enhanced pressor sensitivity, independent of sympathetic neural activity, appears to support hypertension in Zucker obese rats.

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Stimulation of the endogenous hydrogen sulfide synthesis suppresses oxidative–nitrosative stress and restores endothelial-dependent vasorelaxation in old rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2019-0411 ◽

2020 ◽

Vol 98 (5) ◽

pp. 275-281 ◽

Cited By ~ 2

Author(s):

L.A. Mys ◽

N.A. Strutynska ◽

Y.V. Goshovska ◽

V.F. Sagach

Keyword(s):

Nitric Oxide ◽

Hydrogen Sulfide ◽

Nitric Oxide Synthase ◽

Vascular Reactivity ◽

Nitrosative Stress ◽

Rat Aorta ◽

Aortic Tissue ◽

Old Rats ◽

Oxide Synthase ◽

Stimulation Of

Hydrogen sulfide (H2S) is an endogenous gas transmitter with profound effects on the cardiovascular system. We hypothesized that stimulation of H2S synthesis might alleviate age-associated changes in vascular reactivity. Pyridoxal-5-phosphate (PLP), the coenzyme of H2S-synthesizing enzymes, was administrated to old male Wistar rats per os at a dose of 0.7 mg/kg body mass once a day for 2 weeks. H2S content in the aortic tissue, markers of oxidative stress, inducible nitric oxide synthase (iNOS) and constitutive nitric oxide synthase (cNOS), arginase activities, and endothelium-dependent vasorelaxation of the aortic rings were studied. Our results showed that PLP restored endogenous H2S and low molecular weight S-nitrosothiol levels in old rat aorta to the levels detected in adults. PLP significantly reduced diene conjugate content, hydrogen peroxide and peroxynitrite generation rates, and iNOS and arginase activity in the aortic tissue of old rats. PLP also greatly improved acetylcholine-induced relaxation of old rat aorta (47.7% ± 4.8% versus 18.4% ± 4.1% in old rats, P < 0.05) that was abolished by NO inhibition with N-nitro-l-arginine methyl ester hydrochloride (L-NAME) or H2S inhibition with O-carboxymethylhydroxylamine (O-CMH). Thus, PLP might be used for stimulation of endogenous H2S synthesis and correction of oxidative and nitrosative stress and vessel tone dysfunction in aging and age-associated diseases.

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