¹Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA

Correspondence: Dr Jin Zhou, Section on Pharmacology, Department of Health and Human Services, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, MSC 1514, Bldg. 10, Room 2D57, Bethesda, MD 20892, USA. E-mail: ZhouJ@intra.nimh.nih.gov

Received 14 October 2004; Revised 7 December 2004; Accepted 9 December 2004; Published online 23 February 2005.

Abstract

Endothelial dysfunction and inflammation enhance vulnerability to hypertensive brain damage. To explore the participation of Angiotensin II (Ang II) in the mechanism of vulnerability to cerebral ischemia during hypertension, we examined the expression of inflammatory factors and the heat shock protein (HSP) response in cerebral microvessels from spontaneously hypertensive rats and their normotensive controls, Wistar Kyoto rats. We treated animals with vehicle or the Ang II AT₁ receptor antagonist candesartan, 0.3 mg/kg/day, via subcutaneously implanted osmotic minipumps for 4 weeks. Spontaneously hypertensive rats expressed higher Angiotensin II AT₁ receptor protein and mRNA than normotensive controls. Candesartan decreased the macrophage infiltration and reversed the enhanced tumor necrosis factor- and interleukin-1 mRNA and nuclear factor-B in microvessels in hypertensive rats. The transcription of many HSP family genes, including HSP60, HSP70 and HSP90, and heat shock factor-1 was higher in hypertensive rats and was downregulated by AT₁ receptor blockade. Our results suggest a proinflammatory action of Ang II through AT₁ receptor stimulation in cerebral microvessels during hypertension, and very potent antiinflammatory effects of the Ang II AT₁ receptor antagonist. These compounds might be considered as potential therapeutic agents against ischemic and inflammatory diseases of the brain.