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Pre-treatment with candesartan protects from cerebral ischaemia

Section on Pharmacology, NIMH, NIH, Bethesda MD 20892, USA

Yasuaki Nishimura

Section on Pharmacology, NIMH, NIH, Bethesda MD 20892, USA

Juan Saavedra

Section on Pharmacology, NIMH, NIH, Bethesda MD 20892, USA, Saavedrj{at}irp.nimh.nih.gov

Angiotensin II (Ang II) regulates cerebral blood flow by stimulating cerebral vasoconstriction via AT₁receptors. In adult spontaneously hypertensive rats (SHR), the cerebrovascular autoregulatory curve is shifted to the right, in the direction of higher blood pressures, an indication of excessive cerebrovascular vasoconstriction. A restricted capacity to dilate cerebral blood vessels may be responsible for the enhanced vulnerability to cerebrovascular ischaemia during hypertension. We found that chronic treatment with the AT₁-receptor antagonist, candesartan, (0.5 mg/kg/day for 14 days, via osmotic minipumps implanted in the subcutaneous tissue) blocked Ang II binding to AT₁ -receptors in cerebral blood vessels and in brain areas involved in the regulation of cerebrovascular flow, and increased the ratio of lumen-wall area in the middle cerebral artery. Candesartan treatment normalised the lower part of the autoregulatory curve in SHR, and markedly decreased cerebral ischaemia as a consequence of middle cerebral artery occlusion with reperfusion. Protection from ischaemia is related to arterial remodelling, enhanced compensatory vasodilatation in the peripheral area of ischaemia, decreased reduction in cerebral blood flow following the occlusion of a major cerebral blood vessel, and protection from injury in the periphery of the lesion. Our results indicate that pre-treatment with AT₁-antagonists such as candesartan could be of benefit in the prevention and treatment of brain ischaemia.

Key Words: renin angiotensin system • angiotensin receptors • genetic hypertension • stroke • brain injury

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Journal of Renin-Angiotensin-Aldosterone System, Vol. 2, No. 3, 174-179 (2001)
DOI: 10.3317/jraas.2001.024


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