Modification of leukocyte adhesion in spontaneously hypertensive rats by adrenal corticosteroids

Abstract

Leukocyte adhesion is a key factor in the pathogenesis of organ injury following a variety of stimuli. In this study we have addressed the role of leukocyte adhesion in hypertensives as a risk factor for organ injury. In the spontaneously hypertensive rat (SHR), the number of circulating leukocytes and their level of activation are significantly increased compared with its normotensive control, the Wistar-Kyoto rat (WKY). We have demonstrated that elevated levels of glucocorticoid in SHR suppress P-selectin-mediated leukocyte-endothelial interaction in the microcirculation. It is possible that the disturbance in leukocyte-endothelial interactions may result in an elevated number of leukocytes in the circulation. The aim of the present study was to investigate the contribution of the adrenal glands to the disturbance in leukocyte behavior in SHR by subjecting the animals to bilateral adrenalectomy and investigating the effect of hydrocortisone. In addition, we have studied by immunohistochemistry the expression of the endothelial adhesion molecule, P-selectin, in response to histamine in the mesenteric venules of normal and adrenalectomized SHR and WKY. The elevated blood pressure, above-normal leukocyte counts, and elevated number of activated neutrophils (nitroblue tetrazolium test) in SHR were blunted after adrenalectomy. The blunted histamine-induced leukocyte-endothelial interaction in the mesenteric venules of SHR was restored after adrenalectomy. Treatment with hydrocortisone significantly attenuated the elevated leukocyte adhesion in the adrenalectomized SHR as well as in WKY. The suppressed P-selectin expression in SHR mesentery was restored after adrenalectomy. In conclusion, the subnormal leukocyte-endothelial interaction in response to an inflammatory stimulation in SHR is abolished after adrenalectomy, suggesting a relationship between the altered leukocyte adhesiveness and the adrenal corticosteroids in hypertensives.

Impairment of selectin-mediated leukocyte adhesion to venular endothelium in spontaneously hypertensive rats.

“…The results of the present study demonstrate that SHR exhibits impairment of leukocyte rolling and adhesion in postcapillary venules treated with histamine, which is known to elicit significant leukocyte rolling in normotensive rats (6,23,28,29). These findings provide several possible explanations as to why (35), which may serve as a possible explanation for reduction of neutrophil adhesion elicited by FMLP or platelet activating factor (5).…”

“…To elucidate the endothelial P-selectin expression in WKY and SHR, immunohistochemical analysis was carried out according to a previously modified method (22,23). Briefly, 30 min after the histamine superfusion, the blood supply to the intestine was ligated close to the abdominal aorta and then cut (24).…”

“…Vascular tissue samples were taken after intravenous infusion of the anti-P-selectin mAb PB11.3 (2 mg/kg) 50 min before fixation. The circulating mouse mAb could attach only to luminal P-selectin and was subsequently detected with an anti-mouse IgG antibody as described elsewhere (22,23). The mesenteric tissues were immediately immersed in absolute methanol (-20°C) and allowed to stand for 12 h at -20°C.…”

Corticosteroid receptors, macrophages and cardiovascular disease

“…While the precise mechanisms responsible for glucocorticoid-induced hypertension remain to be elucidated, evidence suggests that the impaired leukocyte-endothelial interactions in spontaneous hypertensive rats (SHR) are glucocorticoid dependent (Suzuki et al 1994). Furthermore, these effects are abolished by adrenalectomy or treatment with the GR antagonist RU486 (Suzuki et al 1995). Oxidative stress and nitric oxide deficiency are emerging as key components in the pathogenesis of glucocorticoid-induced hypertension (Ong et al 2008).…”

Control of oxidative stress in microcirculation of spontaneously hypertensive rats

“…Adrenalectomy serves to normalize blood pressure in SHRs to the level of their normotensive Wistar-Kyoto (WKY) controls, whereas supplementation of adrenalectomized SHRs leads to significantly elevated blood pressure compared with WKY rats (1,24,30,45). There are still few studies that serve to explore to what degree glucocorticoids influence free radical formation in SHRs (44).…”