Changes of cerebral blood flow in rats with acute cerebral ischemia and the effect of nitric oxide donor S-nitroso-N-acetyl-penicillamine

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Abstract

BACKGROUND:

Previous studies show that nitric oxide donor can increase cerebral blood flow and improve the function of neurons in cerebral ischemia, but the change does not happen in all the models of cerebral ischemia.

OBJECTIVE:

To observe the effects of nitric oxide donor S-nitroso-N-acetyl-penicillamine (SNAP) on the cerebral blood flow, cyclic guanosine monophosphate (cGMP) content in cerebral cortex, infarct volume and blood pressure in acute ischemic rat brain.

DESIGN:

A randomized and control animal experiment.

SETTING:

Department of Neurosurgery, Aerospace Central Hospital, Peking University.

MATERIALS:

Twenty-eight male Wistar rats of SPF grade, weighing 250–300 g, aged 10–12 weeks were randomly divided into control group (n =14) and SNAP-treated group (n = 14). SNAP (5 mg/bottle) was provided by Beijing Chemical Reagent Company. Laser Doppler Flowmeter (FLO C1; Omegawave Inc., Tokyo, Japan) and immunoassay kit (Amersham Pharmacia Biotech, UK) were applied.

METHODS:

① Model establishment: In the control group, models of cerebral ischemia were induced by ligating right common, internal and external carotid arteries; In the SNAP-treated group, models of cerebral ischemia were induced by ligating right common and external carotid arteries, followed by occluding middle cerebral artery and ligating internal carotid artery. ② Administration: In the SNAP-treated group, SNAP (100 μg/kg) was intravenously infused within 2 minutes, whereas in the control group, phosphate buffered saline (PBS, 1 mL) was intravenously infused (0.5 mL per minute). Six rats were used to measure the volume of cerebral infarction, and the other 8 rats were used to determine other indexes in each group respectively. ③ Determination of indexes: Regional cerebral blood flow (rCBF) was continuously measured by laser-Doppler flowmetry in the ischemic penumbra and contralateral cortex under the continuous monitoring of blood pressure. cGMP concentrations in brain tissue were determined using the enzyme immunoassay 20 minutes after administration. SNAP and PBS were infused in the SNAP-treated group and control group respectively at 10 minutes and 2 hours after ischemia, and the infarct volumes were estimated by 2,3,5-triphenyltetrazolium chloride staining. The differences of the measurement data were compared with the t test.

MAIN OUTCOME MEASURES:

The change of the cGMP and rCBF in acute ischemic rat brain were investigated and recorded after SNAP intravenous infusion.

RESULTS:

All the 28 rats were involved in the final analysis of results. ① rCBF: The rCBF in the ischemic side at the median part of the right frontoparietal cortex decreased to a similar extent between the control group and SNAP-treated group [(58.5±15.5)%, (53.0±11.2)%,t=1.345,P=0.10], which suggested that the severity of ischemia was comparative between the two groups. No significant change was observed in rCBF after the administration of PBS, and there was no obvious difference between the left and right cortices (t =0.896, P > 0.05). The rCBF in cortex of the ischemic side decreased at 15 and 20 minutes after administration of SNAP, and it was significantly different in the ischemic (right) and the contralateral (left) cortices (t=2.298, P=0.01; t=3.499, P< 0.01). ② cGMP levels in bilateral cortices: The cGMP levels in the ischemic and contralateral cortices in the SNAP-treated group were not significantly different [(163.02±40.7) and (162.47±43.98) pmol/g, P> 0.05], but were obviously higher than those in the control group [(105.86±29.4), (112.21±20.64) pmol/g, t=2.977, 2.560, P< 0.01]. ③ Volume of cerebral infarction: The infarction lesions were found mainly focused in the caudate nucleus and cerebral cortices in the right middle cerebral artery distribution field after 4 hours. The infarct volume in the control group was close to that in the SNAP-treated group [(123.35±55.08), (130.25±68.32) mm3, t=1.998, P< 0.05]. ④ Changes of blood pressure: The mean arterial blood pressure in the SNAP-treated group 5 minutes after SNAP infusion was obviously lower than that in the control group (t =1.985, P< 0.05).

CONCLUSION:

The intravenous infusion of SNAP therapy for cerebral ischemia can cause cGMP increase through acting in the upstream of the nitric oxide-cGMP reaction chain. SNAP did not decrease the volume of the cerebral infarction, and it did not protect the brain. However, SNAP can play a role in vasodilation and decompression.

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