Reduction of Capillary Permeability in the Fructose-Induced Hypertensive Rat

Chakir, M

doi:10.1016/s0895-7061(97)00411-1

Cited by 18 publications

(11 citation statements)

References 25 publications

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“…While the pathophysiological mechanisms responsible for elevated blood pressure and hyperinsulinemia in fructose-treated animals are not completely understood, elevated sympathetic nervous system activity (Verma et al, 1999), impaired endothelium-dependent dilation (Richey et al, 1998), reduction of capillary permeability (Chakir et al, 1998) and elevated vascular expression of ET-1 and ET A receptor genes (Juan et al, 1998) have all been implicated. A direct relationship between hypertension and hyperinsulinemia has not yet been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Increased Endothelial Nitric-Oxide Synthase Expression Reduces Hypertension and Hyperinsulinemia in Fructose-Treated Rats

Zhao¹,

Xu²,

Cui³

et al. 2008

J Pharmacol Exp Ther

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Endothelial dysfunction and decreased production of nitric oxide (NO) by endothelial NO synthase (eNOS) are implicated in the pathogenesis of hypertension and insulin resistance. Because the potential influence of increased eNOS expression/ activity on these parameters is unclear, the present study examined the effects of eNOS gene therapy on insulin resistance and blood pressure alterations in a fructose-induced hypertension model in rats. As predicted, 2 weeks of fructose consumption in the drinking water resulted in elevated systolic blood pressure and insulin resistance. These and other physiologic alterations were reversed within 2 weeks after a single intravenous injection of a vector containing the human eNOS cDNA (pcDNA3.1-eNOS), whereas injection of an empty vector (pcDNA3.1) was without effect. In support of the beneficial effects of pcDNA3.1-eNOS treatment being because of enhanced eNOS expression and activity, increased eNOS protein levels were documented in aorta, liver, kidney, and heart of fructose-treated rats injected with pcDNA3.1-eNOS, and corresponding elevations in nitrite/nitrate and cGMP concentrations were observed in urine. Furthermore, pcDNA3.1-eNOS treatment prevented fructose-induced decreases in expression levels of insulin receptor substrate-1, the p110 catalytic subunit of phosphatidylinositol 3-kinase, phosphorylated Akt, and phosphorylated AMP-activated protein kinases in liver, aorta, and skeletal muscle. The results of this study cumulatively indicate that gene therapy with human eNOS decreased fructose-induced hypertension and insulin resistance in rats and suggest potential signaling pathways that mediate these effects. These data highlight the potential utility of eNOS gene therapy in the treatment of hypertension and insulin resistance.Nitric oxide (NO), a potent vasodilator constitutively produced by endothelial nitric-oxide synthase (eNOS), is thought to be the endothelium-derived relaxing factor that mediates relaxation in response to acetylcholine, bradykinin, and substance P in vascular beds (Rees and Moncada, 1989). eNOS is the predominant vascular NO synthase isoform and is responsible for the majority of NO production in the vasculature (Moncada and Higgs, 2006). In addition to its effects on the regulation of blood pressure and regional blood flow, NO influences vascular smooth muscle proliferation and inhibits platelet aggregation and leukocyte adhesion (Moncada and Higgs, 2006).A number of lines of evidence implicate eNOS-derived NO as a pivotal regulator of blood pressure, vascular tone, and vascular homeostasis. In vivo inhibition of NO synthase activity by nonhydrolyzable analogs of L-arginine results in a dramatic increase in mean arterial blood pressure (Desjardins and Balligand, 2006), whereas mice genetically deficient in eNOS have impaired endothelium-dependent vasodilator responses to acetylcholine and are hypertensive (Huang et

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Section: Discussionmentioning

confidence: 99%

Increased Endothelial Nitric-Oxide Synthase Expression Reduces Hypertension and Hyperinsulinemia in Fructose-Treated Rats

Zhao¹,

Xu²,

Cui³

et al. 2008

J Pharmacol Exp Ther

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“…The precise pathophysiological mechanism(s) responsible for the elevated blood pressure in fructose-fed animals are poorly understood, but several possible causes have been suggested. For example, fructose-induced hypertension in rats may result from an increase in sympathetic nervous system activity, 16 impaired endothelium-dependent vasodilation, 17 reduced capillary permeability, 18 and/or elevated vascular expression of ET-1 and ET A -R genes. 19 In this regard, we demonstrated that vascular levels of ET-1 and ET A -R transcripts were increased and urinary ET-1 levels were elevated after fructose feeding.…”

Section: Discussionmentioning

confidence: 99%

Gene Therapy With Human Tissue Kallikrein Reduces Hypertension and Hyperinsulinemia in Fructose-Induced Hypertensive Rats

et al. 2003

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Abstract-This study investigates gene therapy with human tissue kallikrein as a treatment for fructose-induced hypertension in rats. Hypertension was induced by addition of 10% fructose to drinking water. Fructose-fed rats also had increased serum insulin and triglycerides, decreased urine osmolarity, increased urine volume and endothelin-1, and increased aortic endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 mRNA levels. Fructose-induced hypertensive and control rats were injected intravenously with a construct containing the human tissue kallikrein cDNA. Two weeks after injection of hypertensive rats, systolic blood pressure and serum insulin levels normalized, urine osmolarity increased, urine endothelin-1 levels decreased, and aortic endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 mRNA levels decreased. In contrast, injection of the human tissue kallikrein cDNA had minimal effect on blood pressure or insulin levels in control rats. These results suggest that gene therapy with human tissue kallikrein may have potential as a treatment for hypertension and associated insulin resistance. Moreover, our data suggest that the beneficial effects of human tissue kallikrein on these parameters are associated with changes in endothelin-1, endothelin-A receptor, and angiotensin II receptor Key Words: kinins Ⅲ diabetes mellitus Ⅲ hypertension, renal Ⅲ endothelin Ⅲ receptors, endothelin Ⅲ angiotensin II H ypertension is a chronic disease of major public health importance. Hypertension affects Ϸ50 million individuals in the United States and Ϸ1 billion individuals worldwide. The relation between blood pressure and risk of cardiovascular events is continuous, consistent, and independent of other risk factors. The higher the blood pressure, the higher the chance of myocardial infarction, heart failure, stroke, and kidney disease. 1 Tissue kallikrein is a serine protease that converts kininogen to the peptide hormone kinin. Kinin is a potent vasodilator that plays important roles in controlling vascular tone, local blood flow, electrolyte and glucose transport, pain, inflammation, and vascular permeability. 2 Tissue kallikrein is significantly reduced in the urine of patients with hypertension 3 and in kidneys and urine of hypertensive rats. 4 In addition, transient hypotension can be induced by repeated administration of high doses of tissue kallikrein. 5 These results suggest that tissue kallikrein may be involved in blood pressure homeostasis and chronic disease processes related to development and maintenance of systemic hypertension.Genetic studies confirm the putative role of tissue kallikrein in hypertension and suggest that gene therapy might be feasible and efficacious. For example, mice lacking the kallikrein gene are hypertensive, 6 and gene transfer can lower blood pressure in hypertensive animals. 7-9 Drug therapy for hypertension can effectively reduce blood pressure; however, medication side effects are common and maintenance of normal blood pressure requires dail...

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“…Wascher et al, in a model of isolated perfused rat hearts, found that transfer of insulin across the endothelium is substantially delayed in obese insulin-resistant JCR:LAcp rats (17). In addition, the kinetics of interstitial insulin were found to be slower in a model of artificially hyperinsulinemic dogs (18), and capillary permeability was reported to be reduced in the insulin-resistant fructoseinduced hypertensive rats (19). These results suggest that alteration of receptor-mediated part of transendothelial insulin transport may contribute to the defective insulin-mediated vasodilation in these states.…”

Section: Oxidative Stress and Insulin Actionmentioning

confidence: 99%

Stress and Vascular Responses: Oxidative Stress and Endothelial Dysfunction in the Insulin-Resistant State

et al. 2003

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Abstract. Although insulin-resistant states have been associated with endothelial dysfunction due to increased vascular oxidative stress, the underlying mechanisms are pooly understood. Recent experimental evidence suggests that tetrahydrobiopterin (BH 4 ), the natural and essential cofactor of NO synthases (NOS), plays a crucial role not only in increasing the rate of NO generation by NOS but also in controlling the formation of superoxide anion (O 2 -) in endothelial cells. Because insulin resistance has been suggested to be a significant contributing factor in the development of abnormal pteridine metabolism and endothelial dysfunction, we investivated pteridine content and NO/ O 2 -production with the use of isolated thoracic aortas obtained from fructose-induced insulin-resistant rats. Under insulin-resistant conditions where BH 4 levels are suboptimal, the production of O 2 -by NOS leads to endothelial dysfunction. Furthermore, oral supplementation of BH 4 restores endothelial function and relieved oxidative tissue damage, at least in part, through activation of endothelial NOS (eNOS) in the aorta of insulin-resistant rats. These results indicate that insulin resistance may be a pathogenic factor for endothelial dysfunction through impaired eNOS activity and increased oxidative breakdown of NO due to enhanced formation of O 2 -, which are caused by relative deficiency of BH 4 in vascular endothelial cells.

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Reduction of Capillary Permeability in the Fructose-Induced Hypertensive Rat

Cited by 18 publications

References 25 publications

Increased Endothelial Nitric-Oxide Synthase Expression Reduces Hypertension and Hyperinsulinemia in Fructose-Treated Rats

Increased Endothelial Nitric-Oxide Synthase Expression Reduces Hypertension and Hyperinsulinemia in Fructose-Treated Rats

Gene Therapy With Human Tissue Kallikrein Reduces Hypertension and Hyperinsulinemia in Fructose-Induced Hypertensive Rats

Stress and Vascular Responses: Oxidative Stress and Endothelial Dysfunction in the Insulin-Resistant State

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