Angiotensin II AT(1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats.
OBJECTIVE
Angiotensin II, through stimulation of AT(1) receptors, not only controls blood pressure but also modulates cerebrovascular flow. We sought to determine whether selective AT(1) antagonists could be therapeutically advantageous in brain ischemia during chronic hypertension.


METHODS
We pretreated spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto controls with the AT(1) antagonist candesartan (CV-11974), 0.5 mg/kg per day, for 3 to 14 days, via subcutaneously implanted osmotic minipumps. We analyzed cerebral blood flow by laser-Doppler flowmetry, cerebral stroke in SHR after occlusion of the middle cerebral artery with reperfusion, and brain AT(1) receptors by quantitative autoradiography.


RESULTS
Candesartan treatment normalized blood pressure and the shift toward higher blood pressures at both the upper and lower limits of cerebrovascular autoregulation in SHR. Candesartan pretreatment of SHR for 14 days partially prevented the decrease in blood flow in the marginal zone of ischemia and significantly reduced the volume of total and cortical infarcts after either 1 or 2 hours of middle cerebral artery occlusion with reperfusion, relative to untreated SHR, respectively. This treatment also significantly reduced brain edema after 2 hours of middle cerebral artery occlusion with reperfusion. In SHR, candesartan markedly decreased AT(1) binding in areas inside (nucleus of the solitary tract) and outside (area postrema) the blood-brain barrier and in the middle cerebral artery.


CONCLUSIONS
Pretreatment with an AT(1) antagonist protected hypertensive rats from brain ischemia by normalizing the cerebral blood flow response, probably through AT(1) receptor blockade in cerebral vessels and in brain areas controlling cerebrovascular flow during stroke.
Nishimura
Y
Y
Section on Pharmacology, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA.
Ito
T
T
Saavedra
J M
JM
D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001562:Benzimidazoles / Q000008:administration & dosage*; D001667:Binding, Competitive / Q000187:drug effects; D001713:Biphenyl Compounds; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001929:Brain Edema / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C081643:candesartan