Mechanisms of endothelial dysfunction in obesity-associated hypertension

Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.

Effects of estrogen on the vascular system

The cardiovascular protective actions of estrogen are partially mediated by a direct effect on the vessel wall. Estrogen is active both on vascular smooth muscle and endothelial cells where functionally competent estrogen receptors have been identified. Estrogen administration promotes vasodilation in humans and in experimental animals, in part by stimulating prostacyclin and nitric oxide synthesis, as well as by decreasing the production of vasoconstrictor agents such as cyclooxygenase-derived products, reactive oxygen species, angiotensin II, and endothelin-1. In vitro, estrogen exerts a direct inhibitory effect on smooth muscle by activating potassium efflux and by inhibiting calcium influx. In addition, estrogen inhibits vascular smooth muscle cell proliferation. In vivo, 17ß-estradiol prevents neointimal thickening after balloon injury and also ameliorates the lesions occurring in atherosclerotic conditions. As is the case for other steroids, the effect of estrogen on the vessel wall has a rapid non-genomic component involving membrane phenomena, such as alteration of membrane ionic permeability and activation of membrane-bound enzymes, as well as the classical genomic effect involving estrogen receptor activation and gene expression

Gender differences in vascular expression of endothelin and ET A/ET B receptors, but not in calcium handling mechanisms, in deoxycorticosterone acetate-salt hypertension

We determined if the increased vascular responsiveness to endothelin-1 (ET-1) observed in male, but not in female, DOCA-salt rats is associated with differential vascular mRNA expression of ET-1 and/or ET A/ET B receptors or with functional differences in Ca2+ handling mechanisms by vascular myocytes. Uninephrectomized male and female Wistar rats received DOCA and drinking water containing NaCl/KCl. Control rats received vehicle and tap water. Blood pressure and contractile responses of endothelium-denuded aortic rings to agents which induce Ca2+ influx and/or its release from internal stores were measured using standard procedures. Expression of mRNA for ET-1 and ET A/ET B receptors was evaluated by RT-PCR after isolation of total cell RNA from both aorta and mesenteric arteries. Systolic blood pressure was higher in male than in female DOCA rats. Contractions induced by Bay K8644 (which activates Ca2+ influx through voltage-operated L-type channels), and by caffeine, serotonin or ET-1 in Ca2+-free buffer (which reflect Ca2+ release from internal stores) were significantly increased in aortas from male and female DOCA-salt compared to control aortas. DOCA-salt treatment of male, but not female, rats statistically increased vascular mRNA expression of ET-1 and ET B receptors, but decreased the expression of ET A receptors. Molecular up-regulation of vascular ET B receptors, rather than differential changes in smooth muscle Ca2+ handling mechanisms, seems to account for the increased vascular reactivity to ET-1/ET B receptor agonists and higher blood pressure levels observed in male DOCA-salt rats

The role of endothelium in vascular reactivity

1. This review desribes the role of vascular endothelium in the response induced by different vasoactive agentes. 2. The interaction between endothelium, vascular smooth muscle and platelets is discussed. 3. The hormone control as well as pmhysicochemical alterations that interfere with some endothelium-dependent vascular responses are described

Reactivity of macro-and microvessels of doca-salt hypertensive rats: role of the endothelial cell

The responses to noradrenaline (NA) and acetylcholine (ACh) of aortae and microvessels were cocmpared in control and DOCA-salt hypertensive rats. Macro - and microvessels from hypertensive rats showed an increased response to NA and a decreased response to ACh (an endothelium-dependent vasodilator). Unlike ACh, sodium nitroprusside (an endothelium-independent agent), was equally effective in evoking a vasodilator response from aortae and microvessels of hypertensive rats. These data suggest that the impaired response to ACh and the increased response to NA in DOCA-salt hypertension may result from an alteration of endothelial cell function

Receptores autonômicos centrais / Central autonomic receptors

No presente trabalho säo apresentadas as características principais dos receptores centrais para acetilcolina, noradrenalina, adrenalina e dopamina. Para cada tipo de receptor referido comentam-se a caracterizaçäo farmacológica, a classificaçäo bem como a relaçäo estrutura-atividade de agonistas e antagonistas desses receptores. Refere-se de forma breve, à localizaçäo desses mesmos receptores no SNC. Receptores para Acetilcolina: Säo apresentadas evidências que mostram a existência no SNC de, pelo menos, três tipos de receptores colinérgicos, caracterizados farmacologicamente: os muscarínicos, os nicotínicos e um tipo "híbrido" muscarínico-nicotínico. Receptores Adrenérgicos: Evidências säo apresentadas que apontam a presença de dois tipos de receptores adrenérgicos alfa, caracterizados farmacologicamente como alfa1 e alfa2, mas cuja localizaçäo näo guarda relaçäo com a pós ou pré-sinapse como na periferia. Dois tipos de receptores adrenérgicos ß säo descritos no SNC cuja caracterizaçäo e localizaçäo näo estäo ainda täo bem estabelecidas como no caso dos receptores alfa. Aceitando-se a hipótese de presença de determinaçäo nervosa no SNC que contém adrenalina, postula-se a existência de receptores específicos para esta amina. Entretanto, a inexistência de drogas que interfiram especificamente com estes receptores näo permite ainda aceita er totalmente esta hipótese. A existência de receptores específicos para dopamina no SNC já é bem aceita e apresentam-se evidências de presença de mais de um receptor dopaminérgico central. Um ligado à adenilatociclase e outro näo ligado a esta enzima. A localizaçäo e caracterizaçäo dos receptores dopaminérgicos centrais é bem mais precisa do que aquela dos outros receptores adrenérgicos

Efeito anestesico local do trifluperidol e da atropina. Comparacao com a bupivacaina. / Local anesthetic activity of trifluperidol and antropine.Comparison with bupivacaine

A atividade analgesica do trifluperidol e da atropina foi estudada usando o dolorimetro de Hardy Wolff Goodell. As referidas drogas provocaram aumento do tempo de reacao de ratos a exposicao luminosa somente quando administradas localmente. Por via intraperitoneal, nao houve alteracao do tempo de reacao, descartando-se assim um efeito analgesico sistemico. A atividade anestesica local do trifluperidol e da atropina foi estudada utilizando o metodo de inducao de papulas em cobaias. O efeito do trifluperidol foi considerado bastante semelhante ao da bupivacaina, tendo a atropina sido menos potente.Um efeito sistemico foi descartado pois a reacao normal ao estimulo estava presente ao redor da papula. Os autores concluiram que, semelhantemente a outras butirofenonas, o trifluperitol tambem e capaz de induzir anestesia local. Esta atividade e comparavel a da bupivacaina, sendo a atropina menos potente

Efeito antagonico da atropina sobre a contracao da musculatura lisa intestinal. / Antagonist effect of atropine on the contraction of intestinal smooth muscle

O efeito da atropina sobre a resposta contratil induzida por acetilcolina (Ach), potassio (K), bario (Ba) e calcio (Ca), em ileo isolado de cobaia, foi estudado. As contracoes induzidas por Ach e Ba foram antagonizadas competitivamente, enquanto as contracoes provocadas por K e Ca nao o foram. Concluiu-se que a atropina tem uma relativa especificidade pelo receptor muscarinico mesmo em concentracoes mais elevadas e, desta forma, se comporta diferentemente dos anestesicos locais que sao considerados inibidores inespecificos da contracao do musculo liso