Vasodilation to Bradykinin Is Mediated by an Ouabain-Sensitive Pathway as a Compensatory Mechanism for Impaired Nitric Oxide Availability in Essential Hypertensive Patients

Taddei, Stefano; Ghiadoni, Lorenzo; Virdis, Agostino; Buralli, Simona; Salvetti, Antonio

doi:10.1161/01.cir.100.13.1400

Cited by 112 publications

(109 citation statements)

References 32 publications

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“…In agreement with previous observations, 13,35 the response to bradykinin but not to sodium nitroprusside was found to be reduced in patients with essential hypertension as compared with normotensive control subjects. Moreover, whereas L-NMMA inhibited the vasodilating response to bradykinin in normotensive subjects, it was ineffective in patients with essential hypertension.…”

Section: Discussionsupporting

confidence: 93%

“…12 In the presence of impaired NO availability, endothelium-dependent relaxation seems to be sustained by hyperpolarization, which probably acts as a compensatory mechanism. 13 Since endothelial dysfunction and oxidative stress are promoters of atherosclerosis 14 -16 and are closely related to cardiovascular events, [17][18][19] it is conceivable that an adjunctive target for antihypertensive treatment, in addition to blood pressure lowering, could be represented by restoration of could be represented by prevention of oxidative stress and restoration of NO availability. 20 Although several antihypertensive drugs can increase endothelium-dependent vasodilation in patients with essential hypertension, few results are available concerning the mechanism underlying this effect.…”

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confidence: 99%

“…20 This aspect is crucial, since the widespread concept that treatment-induced augmented response to an endothelial agonist is an index of increased NO production is highly misleading. Thus, given the abovedescribed possibility of compensatory relaxation mechanisms, 13 when no experimental demonstration is given, in several circumstances the mere increase in agonist-induced vasodilation cannot be extrapolated as an increase in NO availability.…”

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Calcium Antagonist Treatment by Lercanidipine Prevents Hyperpolarization in Essential Hypertension

et al. 2003

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Abstract-Essential hypertension is associated with impaired endothelium-dependent vasodilation caused by oxidative stress-induced nitric oxide (NO) breakdown and compensatory production of a hyperpolarizing factor. To test whether calcium antagonist treatment can restore NO availability and prevent hyperpolarization through antioxidant properties, in 15 healthy subjects and 15 patients with essential hypertension, we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial bradykinin (5, 15, 50 ng/100 mL per minute), an endothelium-dependent vasodilator, in basal conditions, during infusion of N G -monomethyl-L-arginine (L-NMMA, 100 g/100 mL per minute), an NO-synthase inhibitor, and ouabain (0.72 g/100 mL per minute), an Na ϩ -K ϩ ATPase inhibitor to prevent hyperpolarization. These infusions were repeated in the presence of the antioxidant vitamin C (8 mg/100 mL/min). The response to sodium nitroprusside was also evaluated. In controls, vasodilation to bradykinin was inhibited by L-NMMA and remained unchanged by ouabain or vitamin C. In hypertensive patients, vasodilation to bradykinin was blunted and resistant to L-NMMA but sensitive to ouabain. Vitamin C increased the response to bradykinin and restored the inhibiting effect of L-NMMA while preventing the effect of ouabain. In hypertensive patients, infusions were repeated after 3-month treatment with lercanidipine (10 to 20 mg daily). Lercanidipine decreased plasma lipoperoxides, isoprostanes, and malondialdehyde and increased plasma antioxidant capacity. Moreover, lercanidipine increased the vasodilation to bradykinin and restored the inhibiting effect of L-NMMA on bradykinin-induced vasodilation while preventing the effect of ouabain. Finally, vitamin C no longer exerted its facilitating activity. These results indicate that in essential hypertension, lercanidipine increases endothelium-dependent vasodilation by restoring NO availability and preventing hyperpolarization, an effect probably determined by antioxidant activity. Key Words: hypertension, essential Ⅲ endothelium Ⅲ nitric oxide Ⅲ endothelium-derived factors Ⅲ free radicals Ⅲ antioxidants Ⅲ calcium antagonists E ndothelium plays a primary role in the modulation of vascular tone 1 by producing and releasing relaxing substances including nitric oxide (NO) 2 and a not-yet identified hyperpolarizing factor (EDHF). 3 In the presence of several cardiovascular risk factors, endothelial cells can also produce contracting factors (EDCFs), which are mainly cyclooxygenase-dependent prostanoids (thromboxane A2 and prostaglandin H2) 4,5 or superoxide anions. 6 Essential hypertension is characterized by impaired endothelium-dependent vasodilation to specific agonists 7-9 as the result of a reduction in NO oxide availability 10,11 caused by production of oxidative stress. 12 In the presence of impaired NO availability, endothelium-dependent relaxation seems to be sustained by hyperpolarization, which probably acts as a compensatory mechanism. 13 Since endothelial dysfunct...

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Section: Discussionsupporting

confidence: 93%

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confidence: 99%

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confidence: 99%

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Calcium Antagonist Treatment by Lercanidipine Prevents Hyperpolarization in Essential Hypertension

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“…Rossoni et al (43) found that nanomolar concentrations of ouabain induce the release of an endothelium-derived relaxing factor that seems to open K Ca channels. In addition, increased EDHF production has been described in different hypertension models, probably to compensate for the vascular tone increase (30,50). The K Ca channel blocker TEA potentiated the response to phenylephrine more strongly in segments of aorta from ouabain-treated than untreated rats.…”

Section: Discussionmentioning

confidence: 99%

Ouabain-induced hypertension is accompanied by increases in endothelial vasodilator factors

Rossoni

Salaíces

Miguel

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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. Ouabain-induced hypertension is accompanied by increases in endothelial vasodilator factors. Am J Physiol Heart Circ Physiol 283: H2110-H2118, 2002. First published July 11, 2002 10.1152/ajpheart.00454.2002The involvement of nitric oxide (NO), prostaglandins, and calcium-dependent potassium channel (K Ca) activators on the negative modulation of phenylephrine-induced contractions was evaluated on the isolated aorta and caudal (CAU) artery obtained from rats treated with ouabain for 5 wk to induce hypertension. In ouabain-treated rats, the reactivity to phenylephrine was reduced in the endothelium-intact aorta but not the CAU segments. Endothelial modulation of phenylephrine contraction, as demonstrated by endothelium removal, NO synthase (NOS) inhibition with N -nitro-L-arginine methyl ester and aminoguanidine, as well as K Ca inhibition with tetraethylammonium, was more pronounced in segments from ouabain-treated animals, and here greater effects were seen in the aorta than in CAU. An increased expression of endothelial NOS and neuronal NOS was seen in the aorta after ouabain treatment. In CAU, only endothelial NOS was detected and ouabain treatment did not alter its expression. These results suggest that ouabain-induced hypertension is accompanied by increased NO release derived from endothelial NOS and neuronal NOS and increased release of an endothelial hyperpolarizing factor that presumably opens K Ca, all of which contribute to the increased negative modulation of the phenylephrine contraction. nitric oxide; endothelial-dependent hyperpolarizing factor; phenylephrine THE PLASMA LEVELS of an endogenous circulating Na ϩ -K ϩ -ATPase inhibitor, characterized as ouabain or a closely related compound (17,36), are increased in several animal models of hypertension (19,39), as well as in human essential hypertension (20). Several studies have shown that chronic administration of ouabain induces hypertension, an effect that seems to be linked to the inhibition of the Na ϩ -K ϩ -ATPase (10,22,23,45,54), although sodium pump inhibition seems not to be the exclusive mechanism of the ouabain-hypertensive effect (26,31,32,52). This enzyme is found in most eukaryotic cells and is the main system involved in the maintenance of sodium homeostasis and the membrane potential, essential factors for controlling vascular tone and blood pressure. It has been suggested that alterations in the activity of the sodium pump might be involved in the genesis or maintenance of hypertensive states (3, 33). Additionally, the hypertension induced by ouabain treatment has been associated with actions in the central nervous system that increase sympathetic activity by activation of the central renin-angiotensin system and impair the arterial baroreceptor reflex (22, 23) and associated with actions in the periphery that produce changes in responsiveness to contractile agents (10,26,45).In some isolated vascular preparations, acutely administered ouabain, at nanomolar concentrations, can enhance the actions of phenylephrine (43). Higher mi...

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“…De plus, ces réponses sont également altérées chez l'animal dans divers modèles d'hypertension, de diabète, d'athérosclérose ou de choc septique [37,[40][41][42][43][44]. À l'inverse, les réponses attribuées à l'EDHF peuvent exercer un rôle compensateur quand la voie de la NO-synthase est altérée chez les patients hypertendus [45] ou dans des modèles animaux de dénudation et de régénération endothéliale [46]. L'amélioration des réponses attribuées à l'EDHF peut contribuer à la restauration de la fonction endothéliale lors de différentes interventions thérapeutiques.…”

Section: Les Réponses Attribuées à L'edhf: éPiphénomène Ou Rôle Physiunclassified

Dialogue entre cellules endothéliales et cellules musculaires lisses

et al. 2003

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Les cellules endothé-liales synthétisent et sécrètent plusieurs substances vasodilatatrices ou vasoconstrictrices en réponse à des stimulus biochimiques (peptides, neuroamines…) ou à des stimulus physiques (force de cisaillement, pression). Au cours des 25 dernières années, deux vasodilatateurs d'origine endothéliale ont été identifiés et caractérisés, la prostacycline synthétisée par la cyclooxygénase à partir de l'acide arachidonique, et le monoxyde d'azote (NO) produit par la NO-synthase à partir de la L-arginine [1]. Cependant, la production de prostacycline ou de NO ne peut expliquer l'ensemble des relaxations (ou vasodilatations) dépendantes de l'endothélium. En présence d'inhibiteurs de cyclo-oxygé-nase et de NO-synthase, un mécanisme additionnel responsable d'une vasorelaxation, toujours dépendante de l'endothélium, est observé dans de nombreuses artères de différentes espèces, y compris chez l'homme ( Figure 1). Ce mécanisme implique l'hyperpolarisation des cellules musculaires lisses et il est particulièrement pré-pondérant dans la circulation coronaire et dans les lits vasculaires périphériques [2]. Calcium et canaux potassiques endothéliaux> Les cellules endothéliales sont des cellules qui jouent, entre autres, un rôle actif et essentiel dans le contrôle du tonus vasculaire, et donc du débit sanguin local, en sécrétant divers agents vasoconstricteurs (endothéline, prostaglandines) ou vasodilatateurs (prostacycline, monoxyde d'azote). Un mécanisme vasodilatateur supplémentaire, associé à une hyperpolarisation des cellules musculaires lisses, est observé principalement dans la circulation coronaire et dans les lits vasculaires périphériques. Ce phéno-mène, attribué à un facteur élusif dénommé facteur hyperpolarisant dépendant de l'endothélium (EDHF, endothelium-derived hyperpolarizing factor), est maintenant partiellement élucidé: il implique une augmentation du calcium intracellulaire, suivie d'une hyperpolarisation de la cellule endothéliale grâce à l'ouverture de canaux potassiques dépendant du calcium. L'hyperpolarisation des cellules endothéliales est alors transmise par diverses voies aux cellules musculaires lisses et se propage le long de l'axe vasculaire non seulement via les cellules musculaires lisses, mais également au travers des cellules endothéliales ellesmêmes. L'endothélium peut donc être considéré comme un tissu conducteur. La découverte d'inhibiteurs spécifiques de l'hyperpolarisation des cellules endothéliales permet de mieux apprécier le rôle des hyperpolarisations de l'endothélium dans la régulation de la motricité vasculaire. < M. Félétou, P.M. Vanhoutte :

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Vasodilation to Bradykinin Is Mediated by an Ouabain-Sensitive Pathway as a Compensatory Mechanism for Impaired Nitric Oxide Availability in Essential Hypertensive Patients

Cited by 112 publications

References 32 publications

Calcium Antagonist Treatment by Lercanidipine Prevents Hyperpolarization in Essential Hypertension

Calcium Antagonist Treatment by Lercanidipine Prevents Hyperpolarization in Essential Hypertension

Ouabain-induced hypertension is accompanied by increases in endothelial vasodilator factors

Dialogue entre cellules endothéliales et cellules musculaires lisses

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