There is sexual dimorphism in vascular reactivity and in receptor gene expression to Ang II in SHR. We conclude that estrogen modulates AT(1) and AT(2) receptor gene expression and that this might explain at least partially the lower blood pressure observed in female SHR.

Activation of Toll-like receptors (TLR) induces gene expression of proteins involved in the immune system response. TLR4 has been implicated in the development and progression of cardiovascular diseases. Innate and adaptive immunity contribute to hypertension-associated end-organ damage, although the mechanism by which this occurs remains unclear. In the present study we hypothesize that inhibition of TLR4 decreases blood pressure and improves vascular contractility in resistance arteries from spontaneously hypertensive rats (SHR). TLR4 protein expression in mesenteric resistance arteries was higher in 15 weeks-old SHR than in same age Wistar controls or in 5 weeks-old SHR. In order to decrease activation of TLR4, 15 weeks-old SHR and Wistar rats were treated with anti-TLR4 antibody or non-specific IgG control antibody for 15 days (1µg per day, i.p.). Treatment with anti-TLR4 decreased mean arterial pressure as well as TLR4 protein expression in mesenteric resistance arteries and interleukin-6 (IL-6) serum levels from SHR when compared to SHR treated with IgG. No changes in these parameters were found in Wistar treated rats. Mesenteric resistance arteries from anti-TLR4-treated SHR exhibited decreased maximal contractile response to noradrenaline compared to IgG-treated-SHR. Inhibition of cyclooxygenase-1 (Cox) and Cox-2, enzymes related to inflammatory pathways, decreased noradrenaline responses only in mesenteric resistance arteries of SHR treated with IgG. Cox-2 expression and thromboxane A2 release were decreased in SHR treated with anti-TLR4 compared with IgG-treated-SHR. Our results suggest that TLR4 activation contributes to increased blood pressure, low grade inflammation and plays a role in the augmented vascular contractility displayed by SHR.

Our data show that intrauterine undernutrition: (1) induces hypertension both in the male and female offspring, hypertension being more severe in male than in female rats; (2) alters endothelium-dependent responses in aortas from the resulting offspring. The endothelial dysfunction is associated with a decrease in activity/expression of eNOS in aortas from male offspring. The mechanism involved in altered response to ACh in female offspring might be a consequence of reduction in estrogen levels leading to reduced eNOS activity.

Mechanisms underlying production of vascular free radicals are unclear. We hypothesized that changes in blood flow might serve as a physiological stimulus for endothelial free radical release. Intact isolated aortas from 45 rabbits were perfused with the spin trap a-phenyl-N-tertbutylnitrone (PBN, 20 mmol/L) and formed radical adducts detected by electron paramagnetic resonance spectroscopy (EPR). Sequential perfusion at 2, 7.5, and 12 mL/min changed cumulative vascular PBN radical adduct yields, respectively, from 3.2+0.9 to 4.1±0.7 (P<.05) and 7.0±1.5 (P<.005) pmol/mg with endothelium and from 3.6±1.6 to 3.8±1.4 and 2.2±0.8 pmol/mg without endothelium (P=NS). In endothelialized aortas, superoxide dismutase (SOD) completely blocked flow-induced free radical production, whereas inactivated SOD, indomethacin, and the nitric oxide synthetase antagonist nitro-L-arginine methyl ester (L-NAME) had no effect; relaxations to acetylcholine remained unchanged with higher flows. To assess the role of flow on in vivo radical production, femoral arterial plasma levels of the ascorbyl radical, a stable ascorbate oxidation product, were measured by direct EPR in 56 other rabbits. Ascorbyl levels were assessed at baseline (30.2±0.7 nmol/L) and at peak-induced iliac flow changes. Flow increases from 25% to 100% due to saline injections through an extracorporeal aortic loop induced significant dose-dependent increases in ascorbyl levels (n=5). In addition, after papaverine bolus injections, flow increased by 114±8% versus baseline, and ascorbyl levels increased by 5.4±0.7 nmol/L (n=31, P<.001); similar results occurred with adenosine, isoproterenol, or hyperemia after 30-second occlusions (P<.05, n=4 or 5 in each group). Active SOD completely blocked papaverine-induced ascorbyl radical increase, despite preserved flow response (Aascorbyl=0.02±1.6 nmol/L, P=NS); inactivated SOD, catalase, indomethacin, and L-NAME had no effect. Blood flow decreases of 65% to 100% due to phenylephrine or 60-second balloon occlusions were accompanied by an average decrease of 4.4 nmol/L (P<.05) in ascorbyl levels. No change in ascorbyl signal was observed when rabbit blood alone was submitted to in vitro flow increases through a tubing circuit. Thus, increases in blood flow trigger vascular free radical generation; such a response seems to involve endothelium-derived superoxide radicals unrelated to cyclooxygenase or nitric oxide synthetase activities. This mechanism may contribute to explain vascular free radical generation in physiological or pathological circumstances. (Circ Res. 1994;74:700-709.) Key Words * ascorbyl radical * superoxide dismutase * nitric oxide * endothelium * oxidative stress T he identification of the gaseous free radical nitric oxide (QN=O) as a major signal transducer molecule and endothelium-derived vascular relaxing factor1 suggests that oxyreduction reactions are important effector steps for autocrine or paracrine regulation of vessel tone, permeability, and structure in physiological or pathological conditio...

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,