Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition.
Inhibition of angiotensin II AT1 receptors protects against stroke, reducing the cerebral blood flow decrease in the periphery of the ischemic lesion. To clarify the mechanism, spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were pretreated with the AT1 receptor antagonist candesartan (0.3 mg. kg.(-1) d(-1)) for 28 days, a treatment identical to that which protected SHR from brain ischemia, and the authors studied middle cerebral artery (MCA) and common carotid morphology, endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), and protein expression in cerebral microvessels, principal arteries of the Willis polygon, and common carotid artery. The MCA and common carotid artery of SHR exhibited inward eutrophic remodeling, with decreased lumen diameter and increased media thickness when compared with WKY rats. In addition, there was decreased eNOS and increased iNOS protein and mRNA in common carotid artery, circle of Willis, and brain microvessels of SHR when compared with WKY rats. Both remodeling and alterations in eNOS and iNOS expression in SHR were completely reversed by long-term AT1 receptor inhibition. The hemodynamic, morphologic, and biochemical alterations in hypertension associated with increased vulnerability to brain ischemia are fully reversed by AT1 receptor blockade, indicating that AT1 receptor activation is crucial for the maintenance of the pathologic alterations in cerebrovascular circulation during hypertension, and that their blockade may be of therapeutic advantage.
Yamakawa
Haruki
H
Section on Pharmacology, Division of Intramural Health Programs, National Institute of Mental Health/NIH/DHHS, 10 Center Drive, Building 10, Room 2D-57 Bethesda, MD 20892, USA.
Jezova
Miroslava
M
Ando
Hiromichi
H
Saavedra
Juan M
JM
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001157:Arterial Occlusive Diseases / Q000473:pathology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D001929:Brain Edema / Q000473:pathology; D017536:Carotid Artery, Common / Q000473:pathology; D002536:Cerebral Arteries / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D006973:Hypertension / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D008833:Microcirculation / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR / Q000378:metabolism*; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D012016:Reference Values; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; C081643:candesartan