Abstract
The aim of the present study was to assess quercetin’s mechanism of action in rat pial microvessels during transient bilateral common carotid artery occlusion (BCCAO) and reperfusion. Rat pial microcirculation was visualized using fluorescence microscopy through a closed cranial window. Pial arterioles were classified in five orders of branchings. In ischemic rats, 30 min BCCAO and 60 min reperfusion caused arteriolar diameter decrease, microvascular leakage, leukocyte adhesion in venules, and reduction of capillary perfusion. Quercetin highest dose determined dilation in all arteriolar orders, by 40 ± 4% of baseline in order 2 vessels, and prevented microvascular permeability [0.15 ± 0.02 normalized gray levels (NGL)], leukocyte adhesion, and capillary failure. Protein kinase C (PKC) inhibition exerted by chelerythrine prior to quercetin attenuated quercetin-induced effects: order 2 arterioles dilated by 19.0 ± 2.4% baseline, while there was an increase in permeability (0.40 ± 0.05 NGL) and leukocyte adhesion with a marked decrease in capillary perfusion. Tyrosine kinase (TK) inhibition by tyrphostin 47 prior to quercetin lessened smaller pial arterioles responses, dilating by 20.7 ± 2.5% of baseline, while leakage increased (0.39 ± 0.04 NGL) sustained by slight leukocyte adhesion and ameliorated capillary perfusion. Inhibition of endothelium nitric oxide synthase (eNOS) by NG-nitro-L-arginine-methyl ester (L-NAME) prior to PKC or TK reduced the quercetin’s effects on pial arteriolar diameter and leakage. eNOS inhibition by L-NAME reduced quercetin effects on pial arteriolar diameter and leakage. Finally, combined inhibition of PKC and TK prior to quercetin abolished quercetin-induced effects, decreasing eNOS expression, while blocking ATP-sensitive potassium (KATP) channels by glibenclamide suppressed arteriolar dilation. In conclusion, the protective effects of quercetin could be due to different mechanisms resulting in NO release throughout PKC and TK intracellular signaling pathway activation.
Highlights
The cerebral transient hypoperfusion induced in rats by bilateral common carotid artery occlusion (BCCAO) and followed by reperfusion has been shown to induce a decrease in pial arteriolar diameter, disruption of the blood–brain barrier, leukocyte adhesion, and a reduction in capillary perfusion
Protein kinase C (PKC) inhibition exerted by chelerythrine prior to quercetin attenuated quercetin-induced effects: order 2 arterioles dilated by 19.0 ± 2.4% baseline, while there was an increase in permeability (0.40 ± 0.05 normalized gray levels (NGL)) and leukocyte adhesion with a marked decrease in capillary perfusion
These protective effects have been observed to be partly reduced by inhibition of nitric oxide release by l-NAME, endothelium nitric oxide synthase (eNOS) inhibitor, able to decrease dilation of arterioles and capillary perfusion, to increase leakage, while there were no significant effect on leukocyte adhesion (Lapi et al, 2012)
Summary
The cerebral transient hypoperfusion induced in rats by bilateral common carotid artery occlusion (BCCAO) and followed by reperfusion has been shown to induce a decrease in pial arteriolar diameter, disruption of the blood–brain barrier, leukocyte adhesion, and a reduction in capillary perfusion. These microvascular responses were significantly affected by quercetin, a natural flavonoid, effective in preventing arteriolar diameter decrease and macromolecular leakage, in reducing leukocyte adhesion, and facilitating capillary perfusion (Lapi et al, 2012).
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