Dependence of Elevated Mesenteric Arteriolar Tone on Glucocorticoids in Spontaneously Hypertensive Rats

Suzuki, Hidekazu; Zweifach, Benjamin W.; Schmid-Schönbein, Greet W.

doi:10.1159/000179080

Cited by 21 publications

(22 citation statements)

References 26 publications

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“…This evidence, combined with the fact that prehypertensive individuals may already be producing enhanced free radical production before blood pressure elevation, suggests that there may be systemic mechanisms that control free radical production in addition to just pressure elevation. The fact that SHRs have an enhanced level of glucocorticoid and mineralocorticoid receptors (7) and after adrenalectomy their blood pressure responds significantly more strongly to glucocorticoids (46) is in line with this hypothesis. Comparing adrenalectomy and hydralazine treatment in SHRs, it is noteworthy that both serve to reduce TNBT reduction and blood pressure, but hydralazine is not specific to SHRs and instead affects free radical production in the normotensive WKY rats as well on both the arteriolar and venular sides.…”

Section: Discussionmentioning

confidence: 57%

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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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Section: Discussionmentioning

confidence: 57%

“…This sensitivity may be one of the underlying processes in hypertension. Blood pressures of SHRs may also be hyperresponsive to mineralocorticoid and its metabolites (10,13), a trend that is not uniformly confirmed (46). Blood pressure is significantly elevated by aldosterone supplementation in adrenalectomized SHRs (10,37).…”

Section: Discussionmentioning

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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“…Finally, prenatal exposure to elevated glucocorticoids increases both glucocorticoid levels and the risk of hypertension in adulthood (6, 49). Data from experimental animals further support a role for glucocorticoids in the development of hypertension (8,25,26,28,36,57,65).There are also genetic links between GRs and human hypertension. Watt et al (67) reported that 27% of a group of patients with essential hypertension whose parents also had essential hypertension were homozygous for a 4.5-kb allele of the GR gene.…”

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confidence: 87%

Glucocorticoids act in the dorsal hindbrain to increase arterial pressure

Scheuer¹,

Bechtold²,

Shank³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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are present at a high density in the nucleus of the solitary tract (NTS), an area of the dorsal hindbrain (DHB) that is critical for blood pressure regulation. However, whether these receptors play any role in the regulation of blood pressure is unknown. We tested the hypothesis that glucocorticoids act in the DHB to increase arterial pressure using two experimental strategies. In one approach, we implanted pellets of corticosterone (Cort) or sham pellets onto the DHB over the NTS. Compared with rats with sham pellets, rats with DHB Cort pellets had an increased (P Ͻ 0.05) mean arterial pressure (111 Ϯ 2 vs. 104 Ϯ 1 mmHg) and heart rate (355 Ϯ 9 vs. 326 Ϯ 5 beats/min) after 4 days. In the second approach, we implanted subcutaneous Cort pellets to increase the systemic Cort concentration and then subsequently implanted pellets of the GR antagonist mifepristone (Mif; previously RU-38486) or sham pellets onto the DHB. Two days of DHB Mif treatment reduced (P Ͻ 0.05) mean arterial pressure in those rats with elevated plasma Cort levels (118 Ϯ 2 vs. 108 Ϯ 1 mmHg for sham vs. Mif DHB pellets). Cort and Mif pellets placed on the dura had no effects on arterial pressure or heart rate, ruling out systemic cardiovascular effects of the steroids. DHB Cort treatment had no effects on plasma Cort concentration or adrenal weight, indicating that the contents of the DHB Cort pellet did not diffuse into the systemic circulation or into the forebrain areas that regulate plasma Cort concentration in concentrations sufficient to produce physiological effects. Immunohistochemistry for the occupied GRs demonstrated that the Cort and Mif from the DHB pellets were delivered to the DHB with minimal diffusion to the ventral hindbrain or forebrain. We conclude that glucocorticoids act in the DHB to increase arterial pressure.corticosterone; nucleus of the solitary tract; brain; hypertension GLUCOCORTICOIDS ARE IMPORTANT for the maintenance of normal baseline arterial pressure in both rats and humans. Adrenal insufficiency or blockade of type II glucocorticoid receptors (GRs) can lower blood pressure (18,22,61). The effects of adrenalectomy to lower blood pressure can be reversed by glucocorticoid, but not mineralocorticoid, replacement (61). It is also established that elevated glucocorticoids produce doserelated increases in arterial pressure, and sufficiently high levels of glucocorticoids, due to either exogenous administration or endogenous overproduction, cause hypertension in both experimental animals and humans (22,43,44,54). Long-term administration of glucocorticoids, commonly prescribed because of their anti-inflammatory and immunosupressive therapeutic effects, results in a 20% incidence of iatrogenic hypertension (23). There is also increasing evidence that prolonged mild elevations in glucocorticoids or increased sensitivity to the actions of glucocorticoids promote the development and maintenance of essential hypertension. Several studies have reported elevations in plasma and/or urinary glucocorticoids in essential hyperte...

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“…Previous investigations focused on the microcirculation of hypertensives have reported morphological changes in the wall of arterioles (1) as well as changes in the overall makeup of the arteriolar network (2-4), which could account for the elevation in peripheral resistance. An abovenormal level of arteriolar tone can be demonstrated in the microcirculation of SHR down to the smallest precapillary ramifications of the terminal arterioles in different tissues (5)(6)(7)(8).…”

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confidence: 99%

Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats

Suzuki

DeLano

Parks

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

237

173

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Recent evidence in vivo indicates that spontaneously hypertensive rats (SHR) exhibit an increase in oxyradical production in and around microvascular endothelium. This study is aimed to examine whether xanthine oxidase plays a role in overproduction of oxidants and thereby may contribute to hypertensive states as a consequence of the increasing microvascular tone. The xanthine oxidase activity in SHR was inhibited by dietary supplement of tungsten (0.7 g͞kg) that depletes molybdenum as a cofactor for the enzyme activity as well as by administration of (؊)BOF4272 [(؊)-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo(1,5-␣)-1,3,5-triazine-4-monohydrate], a synthetic inhibitor of the enzyme. The characteristic elevation of mean arterial pressure in SHR was normalized by the tungsten diet, whereas Wistar Koto (WKY) rats displayed no significant alteration in the pressure. Multifunctional intravital videomicroscopy in mesentery microvessels with hydroethidine, an oxidant-sensitive f luoroprobe, showed that SHR endothelium exhibited overproduction of oxyradicals that coincided with the elevated arteriolar tone as compared with WKY rats. The tungsten diet significantly repressed these changes toward the levels observed in WKY rats. The activity of oxyradical-producing form of xanthine oxidase in the mesenteric tissue of SHR was Ϸ3-fold greater than that of WKY rats, and pretreatment with the tungsten diet eliminated detectable levels of the enzyme activity. The inhibitory effects of the tungsten diet on the increasing blood pressure and arteriolar tone in SHR were also reproducible by administration of (؊)BOF4272. These results suggest that xanthine oxidase accounts for a putative source of oxyradical generation that is associated with an increasing arteriolar tone in this form of hypertension.

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Dependence of Elevated Mesenteric Arteriolar Tone on Glucocorticoids in Spontaneously Hypertensive Rats

Cited by 21 publications

References 26 publications

Control of oxidative stress in microcirculation of spontaneously hypertensive rats

Control of oxidative stress in microcirculation of spontaneously hypertensive rats

Glucocorticoids act in the dorsal hindbrain to increase arterial pressure

Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats

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