Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats.

Abstract

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 [spontaneously hypertensive rat (SHR) and spontaneously hypertensive stroke-prone rat (SHRSP)]. The synthesis of 20-HETE in the cerebral vasculature of SHRSP measured by liquid chromatography-tandem mass spectrometry was about twice that seen in Wistar-Kyoto (WKY) rats. This was associated with the elevated expression of cytochrome P-450 (CYP)4A protein and CYP4A1 and CYP4A8 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 regional cerebral blood flow (rCBF) in SHR and SHRSP than in WKY rats during the ischemic period (78% vs. 62%). In WKY rats, rCBF returned to 75% of control following reperfusion. In contrast, SHR and SHRSP exhibited a large (166+/-18% of baseline) and sustained (1 h) postischemic hyperperfusion. Acute blockade of the synthesis of 20-HETE with N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016; 1 mg/kg) reduced infarct size by 59% in SHR and 87% in SHRSP. 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.

• Authors: Kathryn M Dunn, Marija Renic, Averia K Flasch, David R Harder, John Falck, Richard J Roman
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 295 Issue 6 Pg. H2455-65 (Dec 2008) ISSN: 0363-6135 [Print] United States
• PMID: 18952718 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amidines
• Enzyme Inhibitors
• HET0016
• Hydroxyeicosatetraenoic Acids
• Isoenzymes
• Reactive Oxygen Species
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid
• Cytochrome P-450 CYP4A

Topics

• Amidines (pharmacology)
• Animals
• Blood Pressure
• Cerebral Arteries (drug effects, metabolism, pathology, physiopathology)
• Cerebrovascular Circulation (drug effects)
• Cytochrome P-450 CYP4A (metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Hydroxyeicosatetraenoic Acids (metabolism)
• Hypertension (complications, metabolism, pathology, physiopathology)
• Infarction, Middle Cerebral Artery (complications, metabolism, pathology, physiopathology)
• Isoenzymes (metabolism)
• Male
• Oxidative Stress
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Reactive Oxygen Species (metabolism)
• Severity of Illness Index
• Stroke (etiology, metabolism, pathology, physiopathology, prevention & control)
• Time Factors
• Up-Regulation