Oxygen-Derived Free Radical-Induced Vasoconstriction by Thromboxane A2 in Aorta of the Spontaneously Hypertensive Rat

Hibino, Michitaka; Okumura, Kenji; Iwama, Yoshio; Mokuno, Shinji; Osanai, Hiroyuki; Matsui, Hideo; Toki, Yukio; Itō, Takayuki

doi:10.1097/00005344-199904000-00013

Cited by 41 publications

(33 citation statements)

References 28 publications

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“…This could explain why Raynaud's disease is more common in women than men, why the severity of the disease is greater between menarche and menopause, 9 and why unopposed estrogen therapy in post-menopausal women is positively associated with the disease. 82 Consistent with the proposal that a vasoconstrictor COX product accentuates vasoconstriction in Raynaud's disease, is the finding that the TXA 2 synthesis inhibitor dazoxiben shortened the duration of vasospasm evoked by cooling in patients with Raynaud's disease. By contrast, in a subsequent clinical trial performed with dazoxiben, there was no reduction in the number of vasospasm episodes 83 and a similar finding was made in a different trial when a specific TXA 2 receptor antagonist was used.…”

Section: The Nature Of the Vasoconstrictor Cox Productssupporting

confidence: 63%

Mechanisms of Raynaud’s disease

2005

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Raynaud's phenomenon is due to transient cessation of blood flow to the digits of the hands or feet. An attack of Raynaud’s phenomenon is classically manifested as triphasic color changes. The white phase is due to excessive vasoconstriction and cessation of regional blood flow. This phase is followed by a cyanotic phase, as the residual blood in the finger desaturates. The red phase is due to hyperemia as the attack subsides and blood flow is restored. An attack is frequently associated with pain and/or paresthesia due to sensory nerve ischemia. Variants of Raynaud’s phenomenon include acrocyanosis and primary livedo reticularis, each of which is associated with reduced skin blood flow, exacerbated by cold or emotional upset. Raynaud’s phenomenon in the absence of other disorders is primary Raynaud’s phenomenon, or Raynaud’s disease. The mechanisms of Raynaud’s disease include increased activation of the sympathetic nerves, in response to cold or emotion; an impaired habituation of the cardiovascular response to stress may contribute. In addition, there appears to be a local fault, which is likely multifactorial. This local fault is due to an alteration in vascular function rather than vascular structure. The alteration in vascular function may be related to increased sensitivity to cold of the adrenergic receptors on the digital artery vascular smooth muscle. In some cases, locally released or systemically circulating vasoconstrictors may participate, including endothelin, 5-hydroxytryptamine and thromboxane. A deficiency or increased degradation of nitric oxide, possibly due to increased oxidative stress, may be involved in some cases. These recent pathophysiological insights may lead to new therapeutic options.

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Section: The Nature Of the Vasoconstrictor Cox Productssupporting

confidence: 63%

Mechanisms of Raynaud’s disease

2005

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“…However, arachidonic acid metabolites are clearly involved in the regulation of blood pressure. 12-lipoxygenase (45), cysteinyl leukotrienes (58,59), and 20-hydroxyeicosatetreonoic acid (60) all influence blood pressure in the SHR, whereas TXA 2 , a potent vasoconstrictor (61), is elevated in the aorta of young SHR (44). Arachidonic acid released as the precursor to these products is therefore likely to be liberated by another PLA 2 enzyme, probably cPLA 2 -IV either from endothelial or vascular smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

Levick¹,

Loch²,

Rolfe³

et al. 2006

The Journal of Immunology

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The development of fibrosis in the chronically hypertensive heart is associated with infiltration of inflammatory cells and cardiac hypertrophy. In this study, an inhibitor of the proinflammatory enzyme, group IIA human secretory phospholipase A2 (sPLA2-IIA), has been found to prevent collagen deposition as an important component of cardiovascular remodeling in a rat model of developing chronic hypertension. Daily treatment of young male spontaneously hypertensive rats (SHR) with an sPLA2-IIA inhibitor (KH064, 5-(4-benzyloxyphenyl)-4S-(phenyl-heptanoylamino)-pentanoic acid, 5 mg/kg/day p.o.) prevented increases in the content of perivascular (SHR 20.6 ± 0.9%, n = 5; SHR+KH064 14.0 ± 1.2%, n = 5) and interstitial (SHR 7.9 ± 0.3%, n = 6; SHR+KH064 5.4 ± 0.7%, n = 6) collagen in the left ventricle of rat hearts, but did not affect numbers of infiltrating monocytes/macrophages, left ventricular hypertrophy (SHR 2.88 ± 0.08, n = 12; SHR+KH064 3.09 ± 0.08 mg/g body weight, n = 9), increased systolic blood pressure, or thoracic aortic responses. This selective antifibrotic activity suggests that sPLA2-IIA may have an important but specific role in cardiac fibrosis, and that its inhibitors could be useful in dissecting molecular pathways leading to fibrotic conditions.

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“…But the mechanisms that lead to such vascular complications in hypertension are still uncertain. A number of studies indicate that elevated oxygen free radical production may play a role in experimental models of hypertension (12,23,25,26,29,36,44,47) and in human hypertensive individuals (21, 31). Oxygen free radicals such as superoxide, hydrogen peroxide, hydroxyl radical, or peroxynitrite may cause local vascular damage while at the same time producing the hallmarks of hypertension, i.e., increased vascular tone, reduced fluid shear stress response, and arterial pressure elevation (8,9,19,53).…”

mentioning

confidence: 99%

Control of oxidative stress in microcirculation of spontaneously hypertensive rats

DeLano¹,

Balete²,

Schmid‐Schönbein³

2005

American Journal of Physiology-Heart and Circulatory Physiology

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One mechanism for organ damage in individuals with arterial hypertension may be due to oxygen free radical production. This study was designed to localize free radicals in a microvascular network of mature spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Because glucocorticoids play a role in pressure elevation of SHRs, we investigated their role in microvascular free radical formation. Oxygen radical production in mesentery was detected by tetranitroblue tetrazolium reduction to formazan aided by digital light-absorption measurements. Formazan deposits were observed in the endothelial cells and lumens of all microvessels and in lymphatic endothelia but were fewer in tissue parenchyma. The formazan distribution in younger (14 -16 wk old) WKY rats and SHRs was heterogeneous with low values in capillaries and small arterioles/venules (Ͻ30 m) but enhanced deposits in larger venules. Adrenalectomy served to reduce the formazan density in SHRs to the level of WKY rats, whereas dexamethasone supplementation of the adrenalectomized rats caused elevation in the larger venules of SHRs. In older (40 wk old) SHRs, formazan levels were elevated in all hierarchies of microvessels. After pressure reduction was employed with chronic hydralazine treatment, the formazan deposits were reduced in all locations of the microcirculation in both WKY rats and SHRs. Elevated formazan deposits were also found in lymphatic endothelium. These results suggest that oxygen free radical production is elevated in both high-and lowpressure regions of SHR microcirculation via a process that is controlled by glucocorticoids. Older SHRs have higher formazan levels than younger SHRs in all microvessels. Chronic hydralazine treatment, which serves to reduce arterial blood pressure, attenuates tetranitroblue tetrazolium reduction in WKY rats and SHRs even in venules of the microcirculation, which has no micropressure elevation. Free radical production may be a more global condition in SHRs and may not be limited to arteries and arterioles. mesentery; arteriole; capillary; venule; superoxide; nitroblue tetrazolium; dexamethasone; Wistar-Kyoto; adrenalectomy; hydralazine ELEVATION OF ARTERIAL blood pressure is accompanied by a significant risk factor for cardiovascular complications such as stroke, myocardial infarction, atherosclerosis, or renal failure. But the mechanisms that lead to such vascular complications in hypertension are still uncertain. A number of studies indicate that elevated oxygen free radical production may play a role in experimental models of hypertension (12,23,25,26,29,36,44,47) and in human hypertensive individuals (21, 31). Oxygen free radicals such as superoxide, hydrogen peroxide, hydroxyl radical, or peroxynitrite may cause local vascular damage while at the same time producing the hallmarks of hypertension, i.e., increased vascular tone, reduced fluid shear stress response, and arterial pressure elevation (8,9,19,53).Free radicals in hypertension may be derived from a variety of cells in vivo...

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Oxygen-Derived Free Radical-Induced Vasoconstriction by Thromboxane A2 in Aorta of the Spontaneously Hypertensive Rat

Cited by 41 publications

References 28 publications

Mechanisms of Raynaud’s disease

Mechanisms of Raynaud’s disease

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

Control of oxidative stress in microcirculation of spontaneously hypertensive rats

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