Chronic Treatment With Acetylcholinesterase Inhibitors Attenuates Vascular Dysfunction in Spontaneously Hypertensive Rats.

Background: Acetylcholinesterase inhibition prevents autonomic imbalance, reduces inflammation, and attenuates the development of hypertension. Considering that vascular dysfunction is a crucial feature of arterial hypertension, we investigated the effects of chronic administration of acetylcholinesterase inhibitors-pyridostigmine or donepezil-on vascular reactivity of spontaneously hypertensive rats (SHR).

Methods: Endothelium-dependent relaxant responses to acetylcholine (ACh) and contractile responses induced by electric field stimulation (EFS) and alpha-adrenergic agonist were studied in mesenteric resistance arteries from SHR and Wistar Kyoto rats.

Vascular proinflammatory responses by aldosterone are mediated via c-Src trafficking to cholesterol-rich microdomains: role of PDGFR.

Aims: We demonstrated c-Src activation as a novel non-genomic signalling pathway for aldosterone in vascular smooth muscle cells (VSMCs). Here, we investigated molecular mechanisms and biological responses of this phenomenon, focusing on the role of lipid rafts/caveolae and platelet-derived growth factor receptor (PDGFR) in c-Src-regulated proinflammatory responses by aldosterone.

Methods And Results: Studies were performed in cultured VSMCs from Wistar-Kyoto (WKY) rats and caveolin-1 knockout (Cav 1(-/-)) and wild-type mice.

Diacylglycerol Kinase Inhibition and Vascular Function.

Diacylglycerol kinases (DGKs), a family of lipid kinases, convert diacylglycerol (DG) to phosphatidic acid (PA). Acting as a second messenger, DG activates protein kinase C (PKC). PA, a signaling lipid, regulates diverse functions involved in physiological responses.

Angiotensin II chronic infusion induces B1 receptor expression in aorta of rats.

We investigated whether angiotensin II infusion modulates in vivo the kinin B1 receptor expression and the mechanisms involved in this process. We also evaluated the role of the B1 receptor activation in aorta. Wistar rats received 400 ng/kg per minute of angiotensin II or saline (control rats) infusion during 14 days through an osmotic minipump.

Enalapril and losartan restored blood pressure and vascular reactivity in intrauterine undernourished rats.

Epidemiological studies suggest that intrauterine undernutrition plays an important role in the development of arterial hypertension and endothelial dysfunction in adulthood. We have evaluated the effect of the Renin Angiotensin System inhibition on the blood pressure and the mesenteric arteriolar reactivity of the intrauterine undernourished rats. Wistar rats were fed either normal or 50% of the normal intake diets, during the whole gestational period.

Long-term effects of intrauterine malnutrition on vascular function in female offspring: implications of oxidative stress.

Maternal malnutrition is known to impair fetal growth and predispose to the development of hypertension and type 2 diabetes. Recently, studies have demonstrated that intrauterine malnutrition is followed later in male offspring by oxidative stress characterized by increased superoxide generation due to activation of NADPH oxidase and reduced antioxidant defenses. However, few studies have investigated the mechanisms involved in endothelial dysfunction in female offspring.

Endothelin receptor antagonists: another potential alternative for cardiovascular diseases.

Endothelin-1 (ET-1), the predominant isoform of the endothelin peptide family, has potent vasoconstrictor, mitogenic, pro-inflammatory and antinatriuretic properties which have been implicated in the pathophysiology of a number of cardiovascular diseases. ET-1 effects are mediated through activation of the G-protein-coupled ETA and ETB receptors, which are found in a variety of cells including endothelial, vascular smooth muscle and mesangial cells. Overexpression of ET-1 has been consistently described in salt-sensitive models of hypertension and in models of renal failure, and has been associated with disease progression.

Losartan attenuates the antimigratory effect of diclofenac in spontaneously hypertensive rats.

Many patients with hypertension, particularly elderly patients, take nonsteroidal antiinflammatory drugs (NSAIDs) and antihypertensive agents. However, few studies describe the effect of the association of antihypertensive agents with NSAIDs on inflammatory response in hypertension. To investigate this, spontaneously hypertensive rats (SHRs) were treated with either diclofenac alone or diclofenac combined with losartan (an AT1 angiotensin II antagonist).

Angiotensin II-induced venoconstriction involves both AT1 and AT2 receptors and is counterbalanced by nitric oxide.

The venoconstrictor effect of Angiotensin II (Ang II) was investigated in the rat mesenteric venules and portal vein. Mesenteric venules were perfused at a constant rate and reactivity to Ang II (0.1 nmol) was evaluated as changes in the perfusion pressure.

Role of PGI2 and effects of ACE inhibition on the bradykinin potentiation by angiotensin-(1-7) in resistance vessels of SHR.

The present study determined the participation of PGI2 in the angiotensin-(1-7) [Ang-(1-7)]/bradykinin (BK) interaction, in the presence and absence of Angiotensin Converting Enzyme (ACE) inhibition, trying to correlate it with tissue levels of both peptides. The isolated mesenteric arteriolar bed of Spontaneously Hypertensive Rats (SHR) was perfused with Krebs or Krebs plus enalaprilat (10 nM), and drugs were injected alone or in association. BK (10 ng)-induced relaxation was potentiated by Ang-(1-7) (2.

A lower ratio of AT1/AT2 receptors of angiotensin II is found in female than in male spontaneously hypertensive rats.

Objective: Sexual dimorphism has been observed in arterial hypertension. Blood pressure levels are lower in female than in male spontaneously hypertensive rats (SHR). Angiotensin II (Ang II) plays a major role in the regulation of blood pressure.

Tetrahydrobiopterin improves endothelial dysfunction and vascular oxidative stress in microvessels of intrauterine undernourished rats.

In the present study, we investigated the effects of the exogenous application of tetrahydrobiopterin on the endothelium-dependent vasorelaxation and superoxide anion generation in the mesenteric microvessels of intrauterine undernourished rats. In addition, we investigated the presence of peroxynitrite in these rats by evaluation of nitrotyrosine-containing proteins, a stable end-product of peroxynitrite oxidation. For this, female pregnant Wistar rats were fed either normal or 50% of the normal intake diets during the whole gestational period.

Changes in the vascular beta-adrenoceptor-activated signalling pathway in 2Kidney-1Clip hypertensive rats.

1. beta-Adrenoceptor (beta-AR)-mediated vasodilation, which plays an important physiological role in the regulation of vascular tone, is decreased in two-kidney, one clip (2K-1C) renal hypertension. In this study, downstream pathways related to vascular beta-AR activation were evaluated in 2K-1C rats.

Gender differences in superoxide generation in microvessels of hypertensive rats: role of NAD(P)H-oxidase.

Objective: This study is aimed to explore whether gender plays a role in the generation of nitric oxide (NO) and superoxide anion (O(2)(-)) in microvessels of hypertensive rats (SHR), as well as the potential mechanisms involved in these effects.

Methods And Results: NO generation in mesenteric arterioles was evaluated by measuring NO synthase (NOS) activity and protein expression. Oxidative stress was studied in vivo in mesenteric arterioles from male and female SHR by hydroethidine microfluorography.

Enalapril interferes with the effect of diclofenac on leucocyte-endothelium interaction in hypertensive rats.

Nonsteroidal anti-inflammatory drugs are known to attenuate the effects of some antihypertensive agents. However, the effect these drugs have on leukocyte migration when combined with antihypertensive agents has not been studied. To investigate this effect, we treated spontaneously hypertensive rats with saline, diclofenac, enalapril, or diclofenac combined with enalapril and observed leukocyte-endothelium interaction.

Relative contribution of estrogen withdrawal and gonadotropins increase secondary to ovariectomy on prostaglandin generation in mesenteric microvessels.

Recent studies have established that ovariectomy impairs endothelial function, partially by increasing vasoconstrictor prostaglandins generation. Because ovariectomy causes concomitant lack of estrogen and increase of gonadotropins (ie, LH and FSH), in this study we explored the relative role of estrogen and LH/FSH in modulating vasoconstrictor prostaglandins generation in mesenteric arteriolar bed of SHR. Endothelium-dependent relaxation to acetylcholine (ACh) and bradykinin (Bk) was markedly reduced in ovariectomized (OVX) compared with SHR in physiological estrus (OE).

Intrauterine undernutrition--renal and vascular origin of hypertension.

A large number of clinical and experimental studies supports the hypothesis that intrauterine undernutrition is an important determinant of hypertension, coronary heart disease and non-insulin-dependent diabetes in the adult offspring. In this review, the renal and vascular repercussions of maternal undernutrition are emphasized, and the physiopatologic mechanisms discussed. The origin of hypertension is detailed based upon the findings of kidney functional parameters and endothelium function studies.

NADPH oxidase and enhanced superoxide generation in intrauterine undernourished rats: involvement of the renin-angiotensin system.

Objective: We previously reported that intrauterine undernutrition increased the oxidative stress by decreasing superoxide dismutase activity. In the present study, we tested whether NADPH oxidase, xanthine oxidase, cyclooxygenase or nitric oxide synthase are responsible for the increased O(2)(-) generation observed in rats submitted to intrauterine undernutrition. In addition, we investigated the effect of angiotensin II (ANG II) on O(2)(-) production via activation of NADPH oxidase.

Vitamins C and E improve endothelial dysfunction in intrauterine-undernourished rats by decreasing vascular superoxide anion concentration.

Epidemiological studies suggest that intrauterine undernutrition plays an important role in the development of arterial hypertension in adulthood. Ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) have antioxidant properties that could improve redox-sensitive vascular changes associated with hypertension. The authors determined whether vitamins C and E treatments ameliorate the hypertension and vascular function in male rats submitted to intrauterine undernutrition.

Enhanced oxidative stress as a potential mechanism underlying the programming of hypertension in utero.

Maternal undernutrition during critical periods of organ development is known to impair fetal growth and predispose to the development of adulthood diseases, such as hypertension, coronary heart disease and type II diabetes that are linked to low birth weight and are characterized by endothelial dysfunction. Increased oxidative stress, in rats submitted to intrauterine undernutrition, provides a potential explanation for the endothelial dysfunction development. The aim of this study was to determine the oxidative stress and its consequence on mesenteric arteriolar responses to vasoactive agents in offspring from diet-restricted dams.

Intrauterine undernutrition: expression and activity of the endothelial nitric oxide synthase in male and female adult offspring.

Objective: Epidemiological studies suggest that intrauterine undernutrition plays an important role in the development of arterial hypertension in adulthood. In an attempt to define the mechanisms whereby blood pressure may be raised, we have hypothesized that arteries from offspring of nutritionally restricted dams exhibit abnormalities in the endothelial function and in nitric oxide synthesis. In order to investigate the existence of potential gender differences on the effects of intrauterine undernutrition, both male and female offspring of pregnant Wistar rats on normal and restricted diets were studied in adulthood.

Contribution of endothelin-1 to renal activator protein-1 activation and macrophage infiltration in aldosterone-induced hypertension.

Aldosterone-induced hypertension is associated with renal damage that may be mediated by endothelin-1 (ET-1). We evaluated whether inflammatory cell infiltration and DNA-binding activity of the transcription factors nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) were increased in kidneys from aldosterone-infused rats. The role of ET-1 in these processes was evaluated by treating rats with the ET(A)-receptor blocker, BMS 182874.

Endothelin A receptor blockade decreases expression of growth factors and collagen and improves matrix metalloproteinase-2 activity in kidneys from stroke-prone spontaneously hypertensive rats.

This study hypothesizes that endothelin-1 induces renal damage by increasing expression of growth/inflammatory factors, important in renal fibrosis. Male stroke-prone spontaneously hypertensive rats (SHRSPs) (8-weeks, n = 24) were randomized into three groups: control group, high-salt group (4% NaCl), and salt plus an endothelin A receptor antagonist, BMS 182874 (40 mg/kg/d). After 20 weeks treatment, rats were killed.

In vivo evidence for antioxidant potential of estrogen in microvessels of female spontaneously hypertensive rats.

In studies conducted in vitro, it has been demonstrated that estrogen has an antioxidant potential that may contribute to its protective effects on the cardiovascular system. However, the antioxidant effect of estrogen in vivo has not been demonstrated. To address this issue, in this study the effects of estrogen on oxidative stress were evaluated in microvessels studied in vivo.