Intracisternal administration of Angiotensin II AT1 receptor antisense oligodeoxynucleotides protects against cerebral ischemia in spontaneously hypertensive rats.
Pharmacological blockade of peripheral and brain Angiotensin II (Ang II) AT(1) receptors protects against brain ischemia. To clarify the protective role of brain AT(1) receptors, we examined the effects of specific antisense oligodeoxynucleotides (AS-ODN) targeted to AT(1) receptor mRNA administered intracisternally to spontaneously hypertensive rats (SHRs), 4 and 7 days before middle cerebral artery (MCA) occlusion, and we determined the infarct size and tissue swelling 24 h after surgery. A single intracisternal injection of AT(1) mRNA receptor antisense oligodeoxynucleotides reduced systemic blood pressure for 5 days and AT(1) receptor binding for at least 4 days in the area postrema and the nucleus of the solitary tract. A similar injection of scrambled oligodeoxynucleotides (SC-ODN) was without effect. Both blood pressure and AT(1) receptor binding returned to normal 7 days after antisense receptor mRNA administration. Both the infarction size and the tissue swelling after middle cerebral artery occlusion were reduced when the antisense oligodeoxynucleotide was administered 7 days, but not 4 days, before the operation. We conclude that 4 to 5 days of decrease in brain AT(1) receptor binding by a single administration of an AT(1) receptor mRNA oligodeoxynucleotide are sufficient to significantly protect the brain against ischemia resulting from total occlusion of a major cerebral vessel.
Yamakawa
Haruki
H
Section on Pharmacology, IRP, NIMH, NIH, DHHS, 10 Center Drive, Bldg 10, Room 2D-57, Bethesda, MD 20892, USA.
Phillips
M Ian
MI
Saavedra
Juan M
JM
D000803:Angiotensin I / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001345:Autoradiography; D001794:Blood Pressure / Q000187:drug effects; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002946:Cisterna Magna; D004195:Disease Models, Animal; D006973:Hypertension / Q000235:genetics / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D008845:Microinjections; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics*; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000803:Angiotensin I