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Acute depletion of heme by succinylacetone alters vascular responses but does not induce hypertension

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Heme plays a critical role in blood pressure regulation because it is required by a number of enzymes that synthesize vascular modulators, including nitric oxide (NO), carbon monoxide (CO), guanosine 3′,5′-cyclic monophosphate (cGMP), endothelium-derived hyperpolarizing factor (EDHF), and prostacyclin. The goal of this study was to examine the vascular effects of a short-term depletion of heme achieved through administration of the heme-synthesis inhibitor succinylacetone (SA), an irreversible inhibitor of aminolevulinic acid dehydratase (ALAD). Rats were depleted of heme by using a 4-day treatment with SA. This treatment impacted hemoenzyme function, decreasing renal nitric oxide synthase (NOS) activity (as indicated by decreased in vitro NOS activity), and increasing kidney microsomal heme oxygenase (HO) activity by 27%. SA treatment also resulted in enhanced reduction in blood pressure after infusions of exogenous NO donor MAHMA NONOate (at high dose) and acetylcholine (at low doses). Nevertheless, this SA treatment was insufficient to produce an overt elevation of basal arterial pressure. This latter lack of effect may be the result of multiple compensatory mechanisms for the regulation of blood pressure.

Le groupe hème joue un rôle essentiel dans la régulation de la pression sanguine étant donné que de nombreuses enzymes s’en servent pour synthétiser des modulateurs vasculaires dont l’oxyde nitrique (NO), le monoxyde de carbone (CO), le guanosine-3′,5′ monophosphate cyclique (cGMP), le facteur hyperpolarisant provenant de l'endothélium (EDHF) et la prostacycline. Le but de cette étude est d’analyser les effets vasculaires d’une déplétion à court terme du groupe hème par quatre jours d’administration de succinylacétone (SA), un inhibiteur de la synthèse du groupe hème qui agit en inhibant de façon irréversible l'acide aminolévulinique déshydratase (ALA-D). On prive des rats de leur groupe hème par l’administration de SA en 4 jours. Ce traitement modifie la fonction enzymatique du groupe hème, car on observe une diminution de l’activité de l’oxyde nitrique synthase (NOS) dans les reins comme le révèle la diminution in vitro de l’activité de la NOS ; l’activité de l’hème oxygénase microsomale (HO) dans les reins augmente de 27 %. Accompagné d’une infusion d’un donneur de NO exogène MAHMA NONOate (à forte dose) et d’acétylcholine (à faible dose), le traitement au SA suscite une plus grande diminution de pression sanguine. Néanmoins, le traitement au SA ne suffit pas à augmenter de façon manifeste la pression artérielle de base et cela est probablement dû aux multiples mécanismes compensatoires de la régulation de la pression sanguine.

Document Type: Research Article

Publication date: 2008-09-01

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