María A. Sevilla

Vav3 proto-oncogene deficiency leads to sympathetic hyperactivity and cardiovascular dysfunction

Although much is known about environmental factors that predispose individuals to hypertension and cardiovascular disease, little information is available regarding the genetic and signaling events involved. Indeed, few genes associated with the progression of these pathologies have been discovered despite intensive research in animal models and human populations. Here we identify Vav3, a GDP-GTP exchange factor that stimulates Rho and Rac GTPases, as an essential factor regulating the homeostasis of the cardiovascular system. Vav3-deficient mice exhibited tachycardia, systemic arterial hypertension and extensive cardiovascular remodeling. These mice also showed hyperactivity of sympathetic neurons from the time of birth. The high catecholamine levels associated with this condition led to the activation of the renin-angiotensin system, increased levels of kidney-related hormones and the progressive loss of cardiovascular and renal homeostasis. Pharmacological studies with drugs targeting sympathetic and renin-angiotensin responses confirmed the causative role and hierarchy of these events in the development of the Vav3-null mouse phenotype. These observations uncover the crucial role of Vav3 in the regulation of the sympathetic nervous system (SNS) and cardiovascular physiology, and reveal a signaling pathway that could be involved in the pathophysiology of human disease states involving tachycardia and sympathetic hyperactivity with unknown etiologies.

Gastric antisecretory and antiulcer activities of an ethanolic extract of Bidens pilosa L. var. radiata Schult. Bip.

Bidens pilosa var. radiata Schult. Bip. is used in folk medicine to treat stomach disorders including peptic ulcers. The ethanolic extract (0.5-2 g/kg) decreased the gastric juice volume, acid secretion, as well as pepsin secretion in pylorus ligated rats. B. pilosa extract showed antiulcer activity against indomethacin-induced gastric lesions. The extract effectively inhibited gastric haemorrhagic lesions induced by ethanol, and with an effective dose of 2 g/kg being more potent than sucralfate (400 mg/kg). In contrast, ranitidine (50 mg/kg) failed to reduce these lesions. These results indicate that B. pilosa ethanolic extract exerts a cytoprotective effect in addition to its gastric antisecretory activity that could be due, partly at least, to the presence of flavonoids of which quercetin was identified by HPLC.

Transcriptional Factor Aryl Hydrocarbon Receptor (Ahr) Controls Cardiovascular and Respiratory Functions by Regulating the Expression of the Vav3 Proto-oncogene

Aryl hydrocarbon receptor (Ahr) is a transcriptional factor involved in detoxification responses to pollutants and in intrinsic biological processes of multicellular organisms. We recently described that Vav3, an activator of Rho/Rac GTPases, is an Ahr transcriptional target in embryonic fibroblasts. These results prompted us to compare the Ahr−/− and Vav3−/− mouse phenotypes to investigate the implications of this functional interaction in vivo. Here, we show that Ahr is important for Vav3 expression in kidney, lung, heart, liver, and brainstem regions. This process is not affected by the administration of potent Ahr ligands such as benzo[a]pyrene. We also report that Ahr- and Vav3-deficient mice display hypertension, tachypnea, and sympathoexcitation. The Ahr gene deficiency also induces the GABAergic transmission defects present in the Vav3−/− ventrolateral medulla, a main cardiorespiratory brainstem center. However, Ahr−/− mice, unlike Vav3-deficient animals, display additional defects in fertility, perinatal growth, liver size and function, closure, spleen size, and peripheral lymphocytes. These results demonstrate that Vav3 is a bona fide Ahr target that is in charge of a limited subset of the developmental and physiological functions controlled by this transcriptional factor. Our data also reveal the presence of sympathoexcitation and new cardiorespiratory defects in Ahr−/− mice.

Long-term treatment with nebivolol improves arterial reactivity and reduces ventricular hypertrophy in spontaneously hypertensive rats.

&NA; The aim of this study was to assess the effects of long‐term nebivolol therapy on high blood pressure, impaired endothelial function in aorta, and damage observed in heart and conductance arteries in spontaneously hypertensive rats (SHR). For this purpose, SHR were treated for 9 weeks with nebivolol (8 mg/kg per day). Untreated SHR and Wistar Kyoto rats were used as hypertensive and normotensive controls, respectively. The left ventricle/body weight ratio was used as an index of cardiac hypertrophy, and to evaluate vascular function, responses induced by potassium chloride, noradrenaline, acetylcholine, and sodium nitroprusside were tested on aortic rings. Aortic morphometry and fibrosis were determined in parallel by a quantitative technique. Systolic blood pressure, measured by the tail‐cuff method, was lower in treated SHR than in the untreated group (194 ± 3 versus 150 ± 4 mm Hg). The cardiac hypertrophy index was significantly reduced by the treatment. In aortic rings, treatment with nebivolol significantly reduced the maximal response to both KCl and NA in SHR. In vessels precontracted with phenylephrine relaxant, activity due to acetylcholine was higher in normotensive rats than in SHR and the treatment significantly improved this response. The effect of sodium nitroprusside on aortic rings was similar in all groups. Medial thickness and collagen content were significantly reduced in comparison with SHR. In conclusion, the chronic antihypertensive effect of nebivolol in SHR was accompanied by an improvement in vascular structure and function and in the cardiac hypertrophy index.

In vitro antioxidant activity of pravastatin provides vascular protection

The production of reactive oxygen species plays roles during the development of endothelial dysfunction and it represents a significant prognostic factor for evaluating the risk of cardiovascular disease. Although statins target cholesterol biosynthesis, the beneficial effects on cardiovascular disease remain to be fully elucidated. In this work, we explored the in vitro effects of pravastatin on vascular functionality. We studied the effect of the incubation with this statin on acetylcholine relaxation using aorta from spontaneously hypertensive rats (SHR). Consistent with a cholesterol-independent mechanism of action, we show that pravastatin induces a significant improvement of endothelium-dependent relaxation that is not completely reversed by mevalonic acid. Assays with 250microM of lucigenin were carried out to verify whether such action could be mediated by the scavenger properties of pravastatin. Treatment of aortic rings derived from Wistar rats with lucigenin promotes superoxide generation (O(2)(-)) and the subsequent loss of both endothelium-dependent and independent relaxations. The addition of pravastatin reduced the lucigenin-triggered O(2)(-) levels as well as its inhibitory effects on acetylcholine- and sodium nitroprusside-dependent responses. These effects were not counteracted by mevalonic acid, further supporting the idea that the effects of pravastatin do not entail alterations in cholesterol biosynthesis. In conclusion, this study can contribute to elucidate the mechanism responsible for the antioxidant activity of pravastatin, and describes relationship between a scavenger effect of pravastatin and the improvement of vascular reactivity.

Cardiovascular effects of nebivolol in spontaneously hypertensive rats persist after treatment withdrawal

Objectives We observed previously that nebivolol treatment for 2 months reduced cardiovascular lesions in spontaneously hypertensive rats (SHR). Therefore, we investigated whether this beneficial effect is increased with a longer treatment, and its persistence after withdrawal. Methods Male SHR were treated with 8 mg/kg per day of nebivolol (N-SHR) for 6 months. A separate group was also given identical treatment but they were then monitored for a further 3 months after drug withdrawal. SHR and Wistar–Kyoto rats (WKY) receiving vehicle were used as controls. Systolic blood pressure and heart rate were measured using the tail-cuff method. Left ventricular weight/body weight ratio was calculated as the hypertrophy index. Cardiac and vascular fibrosis was evaluated on sections stained with sirious red. Vascular reactivity was evaluated on aortic rings through acetylcholine and sodium nitroprusside responses. The effect of treatment on vascular structure was assessed by lumen diameter, wall thickness and medial cross-sectional area determination. Results Blood pressure was reduced in N-SHR. After withdrawal it increased progressively, without reaching the values of the hypertensive controls. Cardiac hypertrophy and collagen content both in heart and aorta were significantly reduced, and these changes persisted after nebivolol suppression. Acetylcholine-induced relaxant response was improved by nebivolol and maintained after withdrawal. Medial thickness and cross-sectional area were significantly reduced in both conductance and resistance arteries, and these effects persisted after withdrawal. Conclusion The nebivolol antihypertensive effect was accompanied by an important reduction of hypertrophy and collagen deposition in both vascular and left ventricle tissue, which was maintained after a long period of therapy withdrawal.

Analgesic, antipyretic and anti-inflammatory activity of the essential oil of Artemisia caerulescens subsp. gallica

The essential oil of Artemisia caerulescens subsp. gallica was observed to have analgesic, antipyretic and anti-inflammatory actions when administered intraperitoneally to rats and mice at doses one-fourth to one-third that of its LD50 of 1.35 ml/kg. Lysine acetylsalicylate was used as a reference compound.

Antihistaminic activity of pulegone on the guinea-pig ileum

Abstract— Pulegone, a natural monoterpene compound, has an antihistamine effect on guinea‐pig ileum. Its antagonism is of the competitive type (PA2 = 6.35) like that of mepyramine and dexchlorpheniramine, two H1‐antagonists, with PA2 values of 10.15 and 8.74, respectively.

Vav3 Is Involved in GABAergic Axon Guidance Events Important for the Proper Function of Brainstem Neurons Controlling Cardiovascular, Respiratory, and Renal Parameters

Vav3 is a phosphorylation GDP/GTP exchange factor for Rho/Rac GTPases. Recently, it has been described that Vav3 knockout mice develop hypertension and sympathoexcitation. In this work, we report the neurological cause of this phenotype.

Genetic Dissection of the Vav2-Rac1 Signaling Axis in Vascular Smooth Muscle Cells

ABSTRACT Vascular smooth muscle cells (vSMCs) are key in the regulation of blood pressure and the engagement of vascular pathologies, such as hypertension, arterial remodeling, and neointima formation. The role of the Rac1 GTPase in these cells remains poorly characterized. To clarify this issue, we have utilized genetically engineered mice to manipulate the signaling output of Rac1 in these cells at will using inducible, Cre-loxP-mediated DNA recombination techniques. Here, we show that the expression of an active version of the Rac1 activator Vav2 exclusively in vSMCs leads to hypotension as well as the elimination of the hypertension induced by the systemic loss of wild-type Vav2. Conversely, the specific depletion of Rac1 in vSMCs causes defective nitric oxide vasodilation responses and hypertension. Rac1, but not Vav2, also is important for neointima formation but not for hypertension-driven vascular remodeling. These animals also have allowed us to dismiss etiological connections between hypertension and metabolic disease and, most importantly, identify pathophysiological programs that cooperate in the development and consolidation of hypertensive states caused by local vascular tone dysfunctions. Finally, our results suggest that the therapeutic inhibition of Rac1 will be associated with extensive cardiovascular system-related side effects and identify pharmacological avenues to circumvent them.