SIN-1 Improves Cerebral Blood Flow and Reduces Deviation From Brain Homeostasis During Ischemia and Reperfusion in Rats

Auteurs

Lemale CL, Serna-Higuita LM, Balança B, Simula S, Major S, Martus P, Fredriksson I, Dreier JP

Les auteurs en lien sont membres de l'INS.

Équipes

PhysioNet

Résumé

BACKGROUND: Overall, 75% of patients with acute stroke have elevated mean arterial pressure (MAP). In randomized stroke trials, the indirect NO donor glyceryl trinitrate lowered MAP but improved neither regional cerebral blood flow (rCBF) nor functional outcomes. One probable reason is that the microcirculation cannot bioactivate glyceryl trinitrate. In contrast, the direct NO donor 3-morpholinosydnonimine (SIN-1), not requiring bioactivation, should also release NO in small vessels, where it supports eNOS (endothelial NO synthase)–derived NO in maintaining rCBF in the hypotensive portion of Lassen autoregulatory curve. In a meta-analysis, SIN-1 reduced infarct volume in ischemia models, but the effects of SIN-1 on early pathophysiology are unknown. METHODS: Here, we investigated SIN-1 during a 60-minute bilateral common carotid artery occlusion and reperfusion in forty-eight 12- to 14-week-old Wistar-Kyoto rat (WKY) controls and 48 stroke-prone spontaneously hypertensive rats. We calculated the difference between the median values of each variable in the last 5 minutes of bilateral common carotid artery occlusion and baseline and compared them between treatment (SIN-1/control) and

BACKGROUND: Overall, 75% of patients with acute stroke have elevated mean arterial pressure (MAP). In randomized stroke trials, the indirect NO donor glyceryl trinitrate lowered MAP but improved neither regional cerebral blood flow (rCBF) nor functional outcomes. One probable reason is that the microcirculation cannot bioactivate glyceryl trinitrate. In contrast, the direct NO donor 3-morpholinosydnonimine (SIN-1), not requiring bioactivation, should also release NO in small vessels, where it supports eNOS (endothelial NO synthase)–derived NO in maintaining rCBF in the hypotensive portion of Lassen autoregulatory curve. In a meta-analysis, SIN-1 reduced infarct volume in ischemia models, but the effects of SIN-1 on early pathophysiology are unknown. METHODS: Here, we investigated SIN-1 during a 60-minute bilateral common carotid artery occlusion and reperfusion in forty-eight 12- to 14-week-old Wistar-Kyoto rat (WKY) controls and 48 stroke-prone spontaneously hypertensive rats. We calculated the difference between the median values of each variable in the last 5 minutes of bilateral common carotid artery occlusion and baseline and compared them between treatment (SIN-1/control) and

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