Cardiac Microvasculature in DOCA-Salt Hypertensive Rats

Larouche, Isabelle; Schiffrin, Ernesto L.

doi:10.1161/01.hyp.34.4.795

Cited by 36 publications

(19 citation statements)

References 42 publications

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“…For example, chronic administration of ET A receptor antagonist in normotensive rats has no effect on arterial pressure, suggesting that ET may not play a major role in regulating basal arterial pressure [63]. Also, the ET A antagonist A127722 slightly lowers blood pressure in DOCA-salt hypertensive rats [81]. Additionally, administration of BQ123 slightly lowers the blood pressure in SHR and DOCA-salt hypertensive rats, but not in renovascular hypertension.…”

Section: Effects Of Et Antagonists In Hypertensionmentioning

confidence: 99%

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Hynynen

Khalil²

2006

PRC

107

105

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The discovery of endothelin two decades ago has now evolved into an intricate vascular endothelin (ET) system. Several ET isoforms, receptors, signaling pathways, agonists, antagonists, and clinical applications have been identified and documented in first-rate patents. The role of ET as one of the most potent endothelium-derived vasoconstricting factors is now complemented by a newly discovered role in vascular relaxation. ET synthesis is initiated by the transcription of ET genes in endothelial cells and the generation of the gene products preproET and big ET, which are further cleaved by specific ET converting enzymes into ET-1, -2, -3 and -4 isoforms. ET isoforms bind with different affinities to ET A and ET B2 receptors in vascular smooth muscle, and stimulate [Ca 2+ ] i , protein kinase C, mitogen-activated protein kinase and other signaling mechanisms of smooth muscle contraction, growth and proliferation. ET also binds to endothelial ET B1 receptors, which mediate the release of vasodilator substances such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor. Endothelial ET B1 receptors may also function in ET re-uptake and clearance. Although the effects of ET on vascular function and growth are well-recognized, the role of ET and its receptors in the regulation of blood pressure and in the pathogenesis of hypertension is not clearly established. Salt-dependent hypertension in experimental animals and some forms of moderate to severe hypertension in human may show elevated levels of plasma or vascular ET; however, other forms of hypertension show normal ET levels. The currently available ET receptor antagonists reduce blood pressure in some forms of experimental hypertension. Careful examination of recent patents may identify more effective and specific modulators of the vascular ET system for clinical use in human hypertension.

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Section: Effects Of Et Antagonists In Hypertensionmentioning

confidence: 99%

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Hynynen

Khalil²

2006

PRC

107

105

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“…A number of hypertensive animal models [1][2][3] and patients with essential hypertension 4 exhibit a reduction in microvessel length density in tissues such as skeletal muscle, skin, conjunctiva, and myocardium. This phenomenon, designated as structural or anatomic rarefaction, leads to an increase in peripheral vascular resistance and localized reduction in oxygen delivery to the tissue.…”

mentioning

confidence: 99%

Oxidative Stress Promotes Endothelial Cell Apoptosis and Loss of Microvessels in the Spontaneously Hypertensive Rats

Kobayashi

DeLano

Schmid‐Schönbein

2005

ATVB

116

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Objective-Endothelial cell apoptosis caused by oxidative stress may lead to the loss of microvessels (rarefaction) in hypertension. We examine here the effects of antioxidants on cell apoptosis and rarefaction. Methods and Results-The juvenile spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were treated with superoxide scavengers, Tempol or Tiron, during growth. After the treatment, oxidative stress status, endothelial cell apoptosis rate, and microvessel length density in skeletal muscle and mesentery were evaluated in comparison with age-matched controls. Untreated 16-week-old SHR had higher oxidative stress (PϽ0.01) and cell apoptosis rate (PϽ0.05) and lower microvessel length density (371Ϯ17 mm/mm 3 [PϽ0.01]) compared with age-matched WKY rats (435Ϯ15 mm/mm 3 ). In the SHR, but not in WKY rats, systemically applied antioxidants attenuated oxidative stress and cell apoptosis rate (PϽ0.05 versus untreated controls) and prevented the loss of microvessels (411Ϯ15 Key Words: arterial hypertension Ⅲ capillary Ⅲ endothelial cell apoptosis Ⅲ microvessels Ⅲ oxidative stress Ⅲ rarefaction Ⅲ superoxide A number of hypertensive animal models 1-3 and patients with essential hypertension 4 exhibit a reduction in microvessel length density in tissues such as skeletal muscle, skin, conjunctiva, and myocardium. This phenomenon, designated as structural or anatomic rarefaction, leads to an increase in peripheral vascular resistance and localized reduction in oxygen delivery to the tissue. 5 Substantial evidence indicates that microvascular rarefaction is associated with the pathogenesis of hypertension and may be accompanied by parenchymal cell death. 6,7 The disappearance of microvessels in hypertensive subjects may be a secondary event after blood pressure elevation. 8 However, recent research in man demonstrates microvascular rarefaction in pre-established stage of hypertensive subjects who still maintain near normal blood pressure. 9 In addition, the loss of microvessels is implicated in development of nonhypertensive pathologic conditions including diabetic organ failure. 10 These findings seem to suggest that factors other than elevated arterial pressure may promote the disappearance of microvessels. Accumulating evidence indicates that the increase in endothelial cell apoptosis in microvessels may cause rarefaction in hypertensive subjects, although the mechanism of enhanced cell apoptosis is still undergoing investigation. 11,12 We hypothesize that oxidative stress promotes endothelial cell apoptosis in microvessels and induces rarefaction in the spontaneously hypertensive rats (SHR). In the SHR, microvascular endothelium is exposed to enhanced oxidative stress due to an increase in xanthine-oxidase 13 and NADPH-oxidase activity 14 and/or a reduction in superoxide-dismutase activity. 15 Reactive oxygen species (ROS) modulate diverse functions and exert secondary effects on microvessels, eg, an inhibition of endothelium-dependent vasodilation 16 and a promotion of leukocyte adhesion to e...

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“…8 Moreover, in these experimental models, ET-1 receptor antagonists also regressed vascular growth and inflammation and improved endothelial dysfunction. 8,9 Interestingly, PPAR-␥ activators are able to suppress ET-1 secretion from endothelial and vascular smooth muscle cells. 10,11 In addition, ET-1 production by endothelial cells can be activated by many factors, such as insulin or thrombin, through c-jun fixation on the activator protein-1 site of the prepro-ET-1 promoter.…”

mentioning

confidence: 99%

Effect of Peroxisome Proliferator–Activated Receptor-α and -γ Activators on Vascular Remodeling in Endothelin-Dependent Hypertension

Iglarz

Touyz

Amiri

et al. 2003

ATVB

Self Cite

177

125

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Objective-Peroxisome proliferator-activated receptors (PPARs) may modulate in vitro the vascular production of vasoactive peptides such as endothelin-1 (ET-1). Thus, we investigated in vivo the interaction between PPARs and ET-1 in deoxycorticosterone acetate (DOCA)-salt rats that overexpress vascular ET-1. Methods and Results-Unilaterally nephrectomized 16-week-old Sprague-Dawley rats (Uni-Nx) were divided into 4 groups (nϭ6 each): control group, DOCA-salt group, DOCA-saltϩPPAR-␥ activator (rosiglitazone, 5 mg · kg). Systolic blood pressure was significantly increased in the DOCA-salt group (240Ϯ11 vs 121Ϯ2 mm Hg in Uni-Nx, PϽ0.01). Progression of hypertension was partially prevented by coadministration of rosiglitazone (172Ϯ3 mm Hg vs DOCA-salt, PϽ0.05) but not by fenofibrate. Both PPAR activators abrogated the increase in prepro-ET-1 mRNA content in the mesenteric vasculature of DOCA-salt rats. The media-to-lumen ratio was increased in DOCA-salt rats (10.3Ϯ0.9% vs 4.9Ϯ0.5% in Uni-Nx rats, PϽ0.01). Rosiglitazone and fenofibrate prevented the hypertrophic remodeling observed in DOCA-salt rats without affecting vascular stiffness. Rosiglitazone but not fenofibrate prevented endothelial dysfunction in pressurized mesenteric arteries. Finally, both rosiglitazone and fenofibrate prevented the vascular increase in superoxide anion production induced in DOCA-salt animals. Conclusions-PPAR-␣ and -␥ activators were able to modulate endogenous production of ET-1 and had beneficial vascular effects in endothelin-dependent hypertension. Key Words: PPAR activators Ⅲ rosiglitazone Ⅲ fenofibrate Ⅲ resistance arteries Ⅲ DOCA-salt P eroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors that have recently been found to be involved in the homeostasis of vascular biology. 1 Indeed, PPAR-␣ and -␥ isoforms have been characterized in multiple vascular cell types in rats and humans. [2][3][4][5][6] Moreover, PPAR activators prevent in vitro vascular smooth muscle cell growth 4 and inflammatory response 5 and also induce apoptosis, 6 suggesting at least a potential role in vascular remodeling.A recent study from our laboratory demonstrated that both PPAR-␣ and -␥ activators prevent vascular remodeling in angiotensin II-infused rats. 7 As angiotensin II, endothelin-1 (ET-1) is a potent vasoconstrictor. It is produced within the vascular wall and plays a critical role in vascular hypertrophy in many models of hypertension, such as deoxycorticosterone acetate (DOCA)-salt rats or stroke-prone spontaneously hypertensive rats. 8 Indeed, in those models of hypertension in which ET-1 plays a vasoconstrictor role, ET-1 was overexpressed in the vessel wall, and systolic blood pressure (SBP) was lowered by endothelin receptor antagonists. 8 Moreover, in these experimental models, ET-1 receptor antagonists also regressed vascular growth and inflammation and improved endothelial dysfunction. 8,9 Interestingly, PPAR-␥ activators are able to suppress ET-1 secretion from endothelial and vascular smo...

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Cardiac Microvasculature in DOCA-Salt Hypertensive Rats

Cited by 36 publications

References 42 publications

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Oxidative Stress Promotes Endothelial Cell Apoptosis and Loss of Microvessels in the Spontaneously Hypertensive Rats

Effect of Peroxisome Proliferator–Activated Receptor-α and -γ Activators on Vascular Remodeling in Endothelin-Dependent Hypertension

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