title: Chronic At1 receptor blockade alters the mechanisms mediating hypoxic dilation in middle cerebral arteries.
abstract: The purpose of this study was to determine whether chronic blockade of the angiotensin II (ANG II) AT1 receptor under normal physiological conditions impairs vascular relaxation mechanisms in isolated middle cerebral arteries (MCA). Male Sprague-Dawley rats on a standard diet were given losartan (1 mg/mL) in the drinking water or normal water ad libitum for 7 days. Vessel diameters were measured by television microscopy before and during exposure to various vasodilator agonists and reductions in PO2 from 140 mm Hg to 35-45 mm Hg. Dilations to acetylcholine (1 microM), the stable prostacyclin analogue iloprost (10 pg/mL), and the Gs protein activator cholera toxin (1 ng/mL) were completely eliminated in vessels from losartan-treated animals. However, middle cerebral arteries from control and losartan-treated rats still demonstrated significant dilations in response to reduced PO2. Hypoxic dilation of middle cerebral arteries from control rats was eliminated by indomethacin (1 microM) and unaffected by the NOS inhibitor L-NAME (100 microM) whereas dilation in response to reduced PO2 in middle cerebral arteries from losartan-treated rats was eliminated by L-NAME and unaffected by indomethacin. Middle cerebral arteries from control and losartan-treated animals exhibited similar dilations in response to the NO-donor sodium nitroprusside (1 microM). These data suggest that AT1 receptor activation is important in maintaining normal vascular relaxation mechanisms in cerebral resistance arteries during normal physiological conditions, and that AT1 receptor blockade causes a shift in the mechanisms of hypoxic dilation of middle cerebral arteries from cyclooxygenase metabolites to NO.
authors.affiliation: Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Phillips
authors.forename: Julian H
authors.initials: JH
authors.lastname: Lombard
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010100:Oxygen / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D019808:Losartan; D010100:Oxygen