Defective Endothelium-Dependent Relaxation in Fructose-Hypertensive Rats

Verma, Subodh; Bhanot, Sanjay; Yao, Linfu; McNeill, John H.

doi:10.1016/0895-7061(95)00392-4

Cited by 92 publications

(54 citation statements)

References 39 publications

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“…Plasma insulin levels were markedly elevated in OZR and more moderately increased in FF-LZR compared with LZR. These data are consistent with the literature values (7,16,20) and indicate that fructose feeding induced a state of moderate insulin resistance, whereas obesity induces a more severe form. Plasma cholesterol and triglycerides were significantly elevated in both OZR and FF-LZR, consistent with insulin resistance.…”

Section: Resultssupporting

confidence: 82%

“…Insulin resistance is considered an emerging risk factor for vascular disease and has been documented to impair nitric oxide (NO)-dependent mesenteric vasodilation in animal models of insulin resistance (20,(22)(23)(24). Given that NO is a major contributor to absorptive functional hyperemia (1,9,12,17) and flow-mediated regulation (2,12,19), it raises the question of how the mesenteric circulation compensates for the impaired dilator response caused by insulin resistance against the elevated metabolic demands associated with increased ingestion of food in obese or hyperphagic individuals.…”

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confidence: 99%

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Reduced constrictor reactivity balances impaired vasodilation in the mesenteric circulation of the obese Zucker rat

Romanko¹,

Stepp²

2005

American Journal of Physiology-Heart and Circulatory Physiology

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Romanko, Olga P., and David W. Stepp. Reduced constrictor reactivity balances impaired vasodilation in the mesenteric circulation of the obese Zucker rat. Am J Physiol Heart Circ Physiol 289: H2097-H2102, 2005. First published June 10, 2005; doi:10.1152/ajpheart.00213.2005.-Obesity causes whole body insulin resistance and impaired vasodilation to nitric oxide (NO). Because NO is a major contributor to the regulation of mesenteric blood flow, the mesenteric circulation of obese animals is faced with reduced capacity to increase flow and increased demand for flow associated with elevated consumption of food. This study hypothesized that insulin resistance impairs NO-mediated dilation but that constrictor reactivity would be reduced to compensate in obese animals. We further hypothesized that elevated superoxide levels caused impaired responses to NO in insulin resistance. Vasodilator reactivity and vasoconstrictor reactivity of mesenteric resistance arteries from lean (LZR) and obese (OZR) Zucker rats were examined in vitro using videomicroscopy. Insulin resistance independent of obesity was induced via fructose feeding in LZR (FF-LZR). Endothelium-dependent NO-mediated dilation was reduced in OZR and FF-LZR compared with LZR. Impairments in NO-mediated dilation were reversed with 1 mM tempol, a SOD mimetic. Constrictor reactivity to norepinephrine was reduced in OZR but not in FF-LZR relative to LZR. Basal mesenteric vascular resistance was similar in LZR and OZR despite impaired NO-dependent dilation in OZR. Mesenteric vascular resistance was increased in FF-LZR relative to LZR. These data indicate that there is reduced constrictor reactivity in OZR that may offset the impaired NO-mediated dilation and preserve mesenteric blood flow in hyperphagic, obese animals. microcirculation; adrenergic; nitric oxide; superoxide OBESITY IS AN EMERGING EPIDEMIC in Western cultures, especially in the United States, where an estimated 180 million people are overweight. The causes of obesity vary but include metabolic impairment, a high-fat diet, and overeating (hyperphagia). Functional hyperemia of the gut is required for food absorption and thus weight gain, but the effects of obesity and chronic hyperphagia on mesenteric perfusion are incompletely understood.Obesity also induces whole body insulin resistance, resulting in impaired control of plasma glucose, hyperinsulinemia, and chronic triglyceride dyslipidemia. Insulin resistance is considered an emerging risk factor for vascular disease and has been documented to impair nitric oxide (NO)-dependent mesenteric vasodilation in animal models of insulin resistance (20,(22)(23)(24). Given that NO is a major contributor to absorptive functional hyperemia (1, 9, 12, 17) and flow-mediated regulation (2,12,19), it raises the question of how the mesenteric circulation compensates for the impaired dilator response caused by insulin resistance against the elevated metabolic demands associated with increased ingestion of food in obese or hyperphagic individuals. Potential mechanisms in...

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Section: Resultssupporting

confidence: 82%

mentioning

confidence: 99%

Reduced constrictor reactivity balances impaired vasodilation in the mesenteric circulation of the obese Zucker rat

Romanko¹,

Stepp²

2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…Vagal dysfunction in fructose-fed female rats www.bjournal.com.br which was observed in the fructose-fed group of the present study, and hyperinsulinemia are the main causes for increased AP in the fructose model, and they are possibly responsible for sympathetic nervous system activation (6), impairment of endothelium-dependent relaxation (12,14) and dysfunction in angiotensin-renin system (5). This is the first study to evaluate cardiac autonomic control in female rats after high fructose consumption, using an invasive method.…”

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confidence: 93%

Parasympathetic dysfunction is associated with insulin resistance in fructose-fed female rats

Brito

Ponciano

Figueroa

et al. 2008

Braz J Med Biol Res

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The objective of the present study was to identify metabolic, cardiovascular and autonomic changes induced by fructose overload administered in the drinking water of rats for 8 weeks. Female Wistar rats (200-220 g) were divided into 2 groups: control (N = 8) and fructose-fed rats (N = 5; 100 mg/L fructose in drinking water for 8 weeks). The autonomic control of heart rate was evaluated by pharmacological blockade using atropine (3 mg/kg) and propranolol (4 mg/kg). The animals were submitted to an intravenous insulin tolerance test (ITT) and to blood glucose measurement. The fructose overload induced a significant increase in body weight (~10%) and in fasting glycemia (~28%). The rate constant of glucose disappearance (KITT) during ITT was lower in fructose-fed rats (3.25 ± 0.7%/min) compared with controls (4.95 ± 0.3%/min, P < 0.05) indicating insulin resistance. The fructose-fed group presented increased arterial pressure compared to controls (122 ± 3 vs 108 ± 1 mmHg, P < 0.05) and a reduction in vagal tonus (31 ± 9 vs 55 ± 5 bpm in controls, P < 0.05). No changes in sympathetic tonus were observed. A positive correlation, tested by the Pearson correlation, was demonstrable between cardiac vagal tonus and KITT (r = 0.8, P = 0.02). These data provided new information regarding the role of parasympathetic dysfunction associated with insulin resistance in the development of early metabolic and cardiovascular alterations induced by a high fructose diet.

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“…Thus the effect of insulin resistance on vascular signaling mechanisms is an area of increasing scrutiny. Insulin-resistant states and diabetes are associated with reduced endothelium-dependent relaxation, and this dysfunction of the endothelium is highly correlated with future cardiovascular events (1,14,34,49). In the obese Zucker rat (OZR), we previously showed that endothelium-dependent relaxation is impaired (14); however, the mechanisms underlying reduced synthesis or action of nitric oxide (NO) remain to be established.…”

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confidence: 99%

Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90

Fulton

Harris

Kemp

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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.-Previously, using an animal model of syndrome X, the obese Zucker rat (OZR), we documented impaired endothelium-dependent vasodilation. The aim of this study was to determine whether reduced expression or altered posttranslational regulation of endothelial nitric oxide synthase (eNOS) underlies the vascular dysfunction in OZR rats. There was no significant difference in the relative abundance of eNOS in hearts, aortas, or skeletal muscle between lean Zucker rats (LZR) and OZR regardless of age. There was no difference in eNOS mRNA levels, as determined by real-time PCR, between LZR and OZR. The inability of insulin resistance to modulate eNOS expression was also documented in two additional in vivo models, the ob/ob mouse and the fructose-fed rat, and in vitro via adenoviral expression of protein tyrosine phosphatase 1B in endothelial cells. We next investigated whether changes in the acute posttranslational regulation of eNOS occurs with insulin resistance. Phosphorylation of eNOS at S632 (human S633) and T494 was not different between LZR and OZR; however, phosphorylation of S1176 was significantly enhanced in OZR. Phosphorylation of S1176 was not different in the ob/ob mouse or in fructose-fed rats. The association of heat shock protein 90 with eNOS, a key regulatory step controlling nitric oxide and aberrant O 2 Ϫ production, was not different between OZR and LZR. Taken together, these results suggest that changes in eNOS expression or posttranslation regulation do not underlie the vascular dysfunction seen with insulin resistance and that other mechanisms, such as altered localization, reduced availability of cofactors, substrates, and the elevated production of O 2 Ϫ , may be responsible. syndrome X; Zucker; obesity INSULIN RESISTANCE, a prediabetic condition associated with obesity, is increasing at an alarming rate in Western cultures (26,30). Diabetes increases the incidence of many vasculopathies, including atherosclerosis, microvascular disease, and poor wound healing (44, 47). Of even greater concern is the mounting evidence that insulin-resistant states, independent of frank diabetes, also promote vascular dysfunction (43, 52). Thus the effect of insulin resistance on vascular signaling mechanisms is an area of increasing scrutiny. Insulin-resistant states and diabetes are associated with reduced endothelium-dependent relaxation, and this dysfunction of the endothelium is highly correlated with future cardiovascular events (1,14,34,49). In the obese Zucker rat (OZR), we previously showed that endothelium-dependent relaxation is impaired (14); however, the mechanisms underlying reduced synthesis or action of nitric oxide (NO) remain to be established.Endothelium-dependent relaxation is mediated by the synthesis and subsequent diffusion of NO from the endothelium to the underlying smooth muscle (21, 35). Of the three NO synthases (NOS), the endothelial isoform (eNOS) is uniquely positioned within the vascular endothelium and alone is responsible for endothelium-dependent NO-mediated relaxation (20)....

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Defective Endothelium-Dependent Relaxation in Fructose-Hypertensive Rats

Cited by 92 publications

References 39 publications

Reduced constrictor reactivity balances impaired vasodilation in the mesenteric circulation of the obese Zucker rat

Reduced constrictor reactivity balances impaired vasodilation in the mesenteric circulation of the obese Zucker rat

Parasympathetic dysfunction is associated with insulin resistance in fructose-fed female rats

Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90

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