Protection against ischemia and improvement of cerebral blood flow in genetically hypertensive rats by chronic pretreatment with an angiotensin II AT1 antagonist.
OBJECTIVE
Pretreatment with angiotensin II AT(1) receptor antagonists protects against cerebral ischemia. We studied whether modulation of cerebral blood flow (CBF) and morphometric changes in brain arteries participated in this protective mechanism.


METHODS
We pretreated adult spontaneously hypertensive rats with equally antihypertensive doses of candesartan (0.1 or 0.3 mg/kg per day), nicardipine (0.1 mg/kg per day), or captopril (3.0 mg/kg per day) for 3 or 28 days via subcutaneous osmotic minipumps followed by permanent left middle cerebral artery (MCA) occlusion distal to the origin of the lenticulostriate arteries. We measured CBF by autoradiography with 4-iodo-[N-methyl-(14)C]antipyrine 3 hours after operation and the areas of infarct and tissue swelling 24 hours after operation. Morphometric changes in the MCA were studied after antihypertensive treatment.


RESULTS
Twenty-eight days of candesartan pretreatment decreased the infarct area by 31%; reduced the CBF decrease at the peripheral area of ischemia and the cortical volume of severe ischemic lesion, where CBF was <0.50 mL/g per minute; increased the MCA external diameter by 16%; and reduced the media thickness of the MCA by 23%. Captopril pretreatment for 28 days decreased the infarct area by 25%. Pretreatment with candesartan for 3 days or nicardipine for 28 days was ineffective.


CONCLUSIONS
Angiotensin II system inhibition protects against neuronal injury more effectively than calcium channel blockade. Protection after AT(1) receptor blockade is not directly correlated with blood pressure reduction but with normalization of MCA media thickness, leading to increased arterial compliance and reduced CBF decrease during ischemia at the periphery of the lesion.
Ito
Takeshi
T
Section on Pharmacology, Intramural Research Program, National Institute of Mental Health, Bethesda, Md 20892, USA.
Yamakawa
Haruki
H
Bregonzio
Claudia
C
Terrón
José A
JA
Falcón-Neri
Alicia
A
Saavedra
Juan M
JM
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009529:Nicardipine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D002216:Captopril; D009529:Nicardipine; C081643:candesartan