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Shock ; 37(6): 653-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22552019

RESUMO

In clinical practice, prolonged occlusion of main arteries causes accumulation of metabolic waste and lactate. Reperfusion of blood flow is usually accompanied by circulatory shock. This study investigates the molecular mechanisms responsible for acidosis-induced hypotension and proposes therapeutic strategies for improving hemodynamic stability following ischemia-reperfusion acidosis. Vasomotor function of aortic rings was studied after cumulative addition of HCl in organ chambers (pH 7.4-7.0). Cultured vascular smooth muscle cells (VSMCs) were exposed to acidic buffer, and intracellular Ca levels were determined with Fluo3-AM. In an in vivo experiment, rat aorta was cross-clamped for 45 min and followed by declamping. Hemodynamic changes were measured in the presence and absence of an ATP-sensitive K channel (KATP channel) antagonist PNU37883A (3 mg/kg). Acidosis induced vasorelaxation in a dose-dependent manner, which was significantly attenuated by a KATP antagonist glibenclamide. Inhibition of KATP channel increased intracellular Ca load in the cultured VSMCs. Pretreatment with PNU37883A significantly attenuated systemic hypotension following reperfusion. However, systemic antagonism of KATP channel significantly increased the overall mortality. Recording of electrocardiogram showed progressive development of bradyarrhythmia with ST-segment elevation in animals pretreated with PNU37883A before reperfusion. We demonstrate that acidosis-induced vasodilation is, in part, mediated by the activation of KATP channels through reduction of intracellular Ca in VSMCs. However, systemic antagonism of KATP channel significantly increases the overall mortality secondary to the development of cardiac dysrhythmia in animals with profound experimental metabolic acidosis, suggesting that activation of KATP channel is a protective response during reperfusion acidosis.


Assuntos
Acidose/metabolismo , Adamantano/análogos & derivados , Canais KATP/metabolismo , Morfolinas/farmacologia , Traumatismo por Reperfusão/metabolismo , Acidose/fisiopatologia , Adamantano/farmacologia , Animais , Aorta Abdominal/fisiopatologia , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Glibureto/farmacologia , Hemodinâmica , Canais KATP/antagonistas & inibidores , Canais KATP/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/fisiopatologia , Técnicas de Cultura de Tecidos , Vasodilatação
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