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1 Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
2 Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
3 Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Saitama, Japan
* To whom correspondence should be addressed. E-mail: rroman{at}mcw.edu.
This study characterized the time course of changes in cerebral blood flow (CBF) and vascular diameter in a dual hemorrhage model of subarachnoid hemorrhage (SAH) in rats and examined whether acute blockade of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) with TS-011, N-(3-Chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide, can reverse delayed vasospasm in this model. Rats received an intracisternal (icv) injection of blood (0.4 ml) on day 0 and a second injection 2 days later. CBF was sequentially measured using laser-Doppler flowmetry and the diameters of the cerebral arteries were determined after filling the cerebral vasculature with a casting compound. CBF fell to 67% of control after the first icv injection of blood but returned to a value near control 24 hrs later. CBF again fell to 63% of control following a second icv injection of blood and remained 30% below control for 5 days. The fall in CBF following the second icv injection of blood was associated with a sustained 30% reduction in the diameters of the middle cerebral, posterior communicating and basilar arteries. Acute blockade of the synthesis of 20-HETE with TS-011 (0.1 mg/kg, iv), 5 days following the second SAH, increased the diameters of the cerebral arteries and CBF returned to control. These results indicate that the rats develop delayed vasospasm following induction of the dual hemorrhage model of SAH and that acute blockade of the synthesis of 20-HETE with TS-011 reverses cerebral vasospasm in this model. They also implicate 20-HETE in the development and maintenance of delayed cerebral vasospasm.
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