ET _A Receptor Blockade Decreases Vascular Superoxide Generation in DOCA-Salt Hypertension

Abstract

Abstract-Development and progression of end-organ damage in hypertension have been associated with increased oxidative stress. Superoxide anion accumulation has been reported in deoxycorticosterone acetate (DOCA)-salt hypertension, in which endothelin-1 plays an important role in cardiovascular damage. We hypothesized that blockade of ET A receptors in DOCA-salt rats would decrease oxidative stress. Key Words: endothelin Ⅲ receptors, endothelin Ⅲ deoxycorticosterone Ⅲ hypertension, arterial Ⅲ oxidative stress R eactive oxygen species (ROS), such as superoxide anion (⅐O 2 Ϫ ), hydrogen peroxide, and peroxynitrite (ONOO Ϫ ), are generated as intermediates in reduction-oxidation reactions. The major source of ROS in the vasculature is the nonmitochondrial NADPH oxidase. Under physiological conditions, ROS production is inactivated by an elaborate cellular and extracellular antioxidant defense system, of which glutathione peroxidase is a major component. In pathological conditions, increased generation of ROS and/or depletion of the antioxidant capacity results in increased bioavailability of ROS, referred to as oxidative stress. 1 There is increasing evidence that oxidative stress plays a pathological role in hypertension. 2 Several recent studies have provided compelling evidence for increased ROS generation in the vascular tissues of hypertensive rats. Enhanced ⅐O 2 Ϫ production has been demonstrated in mesenteric arterioles of SHR in vivo. 3 Likewise, increased ⅐O 2 Ϫ generation has been reported in cultured aortic endothelial cells from SHR compared with WKY. 4 Oxidative stress has been implicated in a variety of other hypertensive models including Angiotensin II (Ang II)-induced hypertension, 5,6 Dahl salt-sensitive hypertension, 7 and in human essential hypertension. 8 By promoting NO inactivation, lipid peroxidation, DNA damage, and protein modification, oxidative stress plays a key role in endothelial dysfunction and end-organ damage. Furthermore, ROS activate many redox-sensitive, growth-related intracellular signaling pathways in vascular smooth muscle and endothelial cells, which is particularly important in altered proliferation and hypertrophy, contributing to vascular remodeling, a characteristic feature of hypertensive disease. 9,10 Cytokines, growth factors, and vasoactive agents such as Ang II regulate the activity and expression of enzymes involved in ROS production. 1 In Ang II-dependent models of hypertension, vascular production of ⅐O 2 Ϫ is increased through activation of vascular NADPH oxidase. 5,6 Indeed,

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“…Callera et al 26 showed that in a deoxycorticosterone acetate-salt hypertension rat model, vascular superoxide production was increased by activation of the endothelin system. Zalba et al 27 demonstrated increased production of superoxide anion in SHRs.…”

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“…Also, in vivo blockade of ET A receptors in DOCA-salt hypertensive rats results in reduction in oxidative stress, supporting a role for ET-1 in the generation of reactive oxygen species. Since oxidative stress influences specific signaling pathways and redox-sensitive genes that coordinate several responses in the cardiovascular system including VSM growth and endothelial cell function, and because each of these alterations could be produced by ET-1, oxidative stress may play a role in the cardiovascular changes observed in DOCA-salt hypertension as a result of ET-1 overexpression/actions [83].…”

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“…51 Similarly, chronic ET-1 infusion is associated with Despite mixed results using the antioxidant tempol, there is clear evidence that ET stimulates superoxide production through an NADPH oxidase-dependent manner in DOCA-salt hypertensive rats. 55,56 Because ET A receptor blockade and superoxide scavenging can attenuate the hypertension associated with DOCA-salt treatment, it is reasonable to hypothesize that ETdependent hypertension could be inhibited by disruption of NADPH oxidase subunit assembly with the inhibitor, apocynin. Elmarakby et al have recently demonstrated that apocynin inhibits the increase in oxidative stress associated with chronic ET-1 infusion, yet the resulting hypertension was unaffected.…”

“…55,56 Because ET A receptor blockade and superoxide scavenging can attenuate the hypertension associated with DOCA-salt treatment, it is reasonable to hypothesize that ETdependent hypertension could be inhibited by disruption of NADPH oxidase subunit assembly with the inhibitor, apocynin. Elmarakby et al have recently demonstrated that apocynin inhibits the increase in oxidative stress associated with chronic ET-1 infusion, yet the resulting hypertension was unaffected.…”