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1 Medical College of Wisconsin
2 University of Texas Southwestern Medical Center
* To whom correspondence should be addressed. E-mail: rroman{at}mcw.edu.
Hypertension is a major risk factor for stroke but the factors that contribute to the increased incidence and severity of ischemic stroke in hypertension remain to be determined. 20-hydroxyeicosatetraenoic acid (20-HETE) has been reported to be a potent constrictor of cerebral arteries and inhibitors of 20-HETE formation reduce infarct size following cerebral ischemia. The present study examined whether elevated production of 20-HETE in the cerebral vasculature could contribute to the larger infarct size previously reported after transient middle cerebral artery occlusion (MCAO) in hypertensive strains of rat (SHR and SHRSP). The synthesis of 20-HETE in the cerebral vasculature of SHRSP measured by LC/MS was about twice that seen in WKY rats. This was associated with elevated expression of CYP4A protein and CYP4A1 and 4A8 mRNA. Infarct volume after transient MCAO was greater in SHRSP (36±4% of hemisphere volume) than in SHR (19±5%) or WKY rats (5±2%). This was associated with a significantly greater reduction in rCBF in SHR and SHRSP rats than in WKY rats during the ischemic period (78% versus 62%). In WKY rats, rCBF returned to 75% of control following reperfusion. In contrast, SHR and SHRSP rats exhibited a large (166+18 % of baseline) and sustained (1 hr) postischemic hyperperfusion. Acute blockade of the synthesis of 20-HETE with HET0016 (1 mg/Kg) reduced infarct size by 59% in SHR and 87% in SHRSP rats. HET0016 had no effect on the fall in rCBF during MCAO, but eliminated the hyperemic response. HET0016 also attenuated vascular O2•- formation and restored endothelium-dependent dilation in cerebral arteries of SHRSP. These results indicate the production of 20-HETE is elevated in the cerebral vasculature of SHRSP, and contributes to oxidative stress, endothelial dysfunction and the enhanced sensitivity to ischemic stroke in this hypertensive model.
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