Mechanisms of Oxidative Stress-Induced Increase in Salt Sensitivity and Development of Hypertension in Sprague-Dawley Rats

Abstract

Abstract-High salt intake produces vascular changes that contribute to the development of hypertension in salt-sensitive individuals. Because reactive oxygen species play a role in the pathogenesis of cardiovascular diseases, we investigated whether oxidative stress contributes to salt-sensitive hypertension. Sprague-Dawley rats were divided in different groups and received tap water (vehicle), 30 mmol/L of L-buthionine sulfoximine ([BSO] an oxidant), high salt ([HS] 1% NaCl), and BSO plus HS without and with antioxidant tempol (1 mmol/L) in drinking water for 12 days. Compared with vehicle, BSO treatment caused oxidative stress and mild increase in blood pressure. Thoracic aortic rings from BSO-treated rats exhibited decreased response to endothelium-independent vasorelaxants. In HS-treated rats, the response to vasoactive agents, as well as blood pressure, was unaffected. Concomitant treatment of rats with BSO and HS produced a marked increase in blood pressure and a decreased response to both endothelium-dependent and endothelium-independent vasorelaxants with an increase in EC 50 . Incubation of aortic tissue from BSO-treated rats with sodium nitroprusside showed decreased cGMP accumulation, whereas HS rats had decreased basal NO synthase activity. Tempol decreased oxidative stress, normalized blood pressure, and restored NO signaling and responses to vasoactive compounds in BSO and BSO plus HS rats. We conclude that BSO increases oxidative stress and reduces NO signaling, whereas HS reduces NO levels by decreasing the NO synthase activity. These phenomena collectively result in reduced responsiveness to both endothelium -dependent and endothelium-independent vasorelaxants and may contribute to salt-sensitive hypertension. Key Words: acetylcholine Ⅲ hypertension Ⅲ oxidative stress Ⅲ salt sensitivity Ⅲ tempol E ndothelial cells modulate the reactivity of the underlying vascular smooth muscle cells by releasing endotheliumderived relaxing factors. 1,2 Previous studies have demonstrated that elevated dietary salt intake leads to an impaired relaxation of blood vessels to endothelium-dependent relaxations induced by a variety of vasodilator agents. 3-9 A possible contributor to impaired vascular relaxation to dilator stimuli in animals on a high-salt diet is an impaired function of the endothelium. 3-9 Impaired endothelium-dependent dilation in vessels of animals on a high-salt diet could occur either because the acetylcholine (Ach)-mediated production of NO by the endothelium is impaired or because of the failure of NO to cause vasodilation. [3][4][5][6][7][8][9] NO is a major regulator of vascular tone in humans. 10 Decreased production or bioavailability, or decreased vascular response to NO, has been implicated in the pathogenesis of human hypertension. 11,12 An increase in blood pressure (BP) in response to dietary sodium (salt sensitivity) is a well-documented phenomenon in humans and is considered to be an important factor in the pathogenesis of hypertension. 4 In animal models of salt-sensitive hypertens...

Oxidative Stress Causes Renal Angiotensin II Type 1 Receptor Upregulation, Na + /H + Exchanger 3 Overstimulation, and Hypertension

“…However, Tempol significantly reduced both oxidative stress and blood pressure, but it failed to completely normalize the BSO effects, probably because of its inability to normalize glutathione levels, in BSO-treated rats. 31 Nevertheless, these data confirm previous findings that oxidative stress could be an independent risk factor to the development of hypertension by exaggerating AT 1 R expression, response, and stimulation of renal sodium transporters. 1,30,[32][33][34] Ang II via AT 1 Rs activates serine/threonine and tyrosine kinase pathways, both of which can regulate NHE3 activity.…”

Oxidative Stress Causes Renal Dopamine D1 Receptor Dysfunction and Salt-Sensitive Hypertension in Sprague-Dawley Rats

“…Studies from our laboratory also showed that, during oxidative stress, HS intake attenuated the vasodepressor responses to endothelialdependent and -independent vasoactive compounds despite NO synthase upregulation. 46 Taken together, these data show that the increased salt sensitivity in conditions associated with oxidative stress may be contributed by both renal and extrarenal signaling molecules responsible for sodium homeostasis and vascular tone.…”

Antihypertensive effects and mechanisms of chlorogenic acids

“…A positive relationship between oxidative stress and blood pressure were demonstrated in some models of experimental hypertension. 42 For example, an upregulation of reactive oxygen species appeared to precede the development of hypertension, 43,44 and an antioxidant regimen arrested the process. 44,45 In vasculature, the major source of reactive oxygen species was from a family of non-phagocytic NAD(P)H oxidases, which comprised a catalytic core (Nox/p22 phox ) and several cytosolic subunits (p47 phox , p67 phox , p40 phox , Rac).…”