Document Detail

2,3',4,5'-Tetramethoxystilbene prevents deoxycorticosterone-salt-induced hypertension: contribution of cytochrome P-450 1B1.
MedLine Citation:
PMID:  20852048     Owner:  NLM     Status:  MEDLINE    
Reactive oxygen species (ROS) contribute to various models of hypertension, including deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Recently, we have shown that ROS, generated by cytochrome P-450 1B1 (CYP1B1) from arachidonic acid, mediate vascular smooth muscle cell growth caused by angiotensin II. This study was conducted to determine the contribution of CYP1B1 to hypertension and associated pathophysiological changes produced by DOCA (30 mg/kg) given subcutaneously per week with 1% NaCl + 0.1% KCl in drinking water to uninephrectomized rats for 6 wk. DOCA-salt treatment increased systolic blood pressure (SBP). Injections of the selective inhibitor of CYP1B1, 2,3',4,5'-tetramethoxystilbene (TMS; 300 μg/kg ip every 3rd day) initiated at the 4th week of DOCA-salt treatment normalized SBP and decreased CYP1B1 activity but not its expression in the aorta, heart, and kidney. TMS also inhibited cardiovascular and kidney hypertrophy, prevented the increase in vascular reactivity and endothelial dysfunction, and minimized the increase in urinary protein and K(+) output and the decrease in urine osmolality, Na(+) output, and creatinine clearance associated with DOCA-salt treatment. These pathophysiological changes caused by DOCA-salt treatment and associated increase in vascular superoxide production, NADPH oxidase activity, and expression of NOX-1, and ERK1/2 and p38 MAPK activities in the aorta, heart, and kidney were inhibited by TMS. These data suggest that CYP1B1 contributes to DOCA-salt-induced hypertension and associated pathophysiological changes, most likely as a result of increased ROS production and ERK1/2 and p38 MAPK activity, and could serve as a novel target for the development of agents like TMS to treat hypertension.
Seyhan Sahan-Firat; Brett L Jennings; Fariborz A Yaghini; Chi Young Song; Anne M Estes; Xiao R Fang; Nasreen Farjana; Amir I Khan; Kafait U Malik
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-09-17
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  299     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-03     Completed Date:  2011-01-13     Revised Date:  2014-01-08    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1891-901     Citation Subset:  IM    
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MeSH Terms
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / blood
Antihypertensive Agents / pharmacology*
Aorta / drug effects,  enzymology
Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*,  metabolism
Blood Pressure / drug effects*
Cardiomegaly / enzymology,  physiopathology,  prevention & control
Disease Models, Animal
Diuresis / drug effects
Endothelium, Vascular / drug effects,  enzymology
Enzyme Inhibitors / pharmacology*
Hydroxyeicosatetraenoic Acids / blood
Hypertension / enzymology,  etiology,  pathology,  physiopathology,  prevention & control*
Kidney / drug effects,  enzymology,  pathology,  physiopathology
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Muscle, Smooth, Vascular / drug effects,  enzymology,  physiopathology
Myocardium / enzymology,  pathology
NADH, NADPH Oxidoreductases / metabolism
Proteinuria / enzymology,  physiopathology,  prevention & control
Rats, Sprague-Dawley
Sodium Chloride, Dietary*
Stilbenes / pharmacology*
Superoxides / metabolism
Time Factors
Vasoconstriction / drug effects
Vasodilation / drug effects
p38 Mitogen-Activated Protein Kinases / metabolism
Grant Support
Reg. No./Substance:
0/2,4,3',5'-tetramethoxystilbene; 0/Antihypertensive Agents; 0/Enzyme Inhibitors; 0/Hydroxyeicosatetraenoic Acids; 0/Sodium Chloride, Dietary; 0/Stilbenes; 11062-77-4/Superoxides; 40GP35YQ49/Desoxycorticosterone; 59985-28-3/12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 79551-86-3/20-hydroxy-5,8,11,14-eicosatetraenoic acid; EC Hydrocarbon Hydroxylases; EC P-450 CYP1B1; EC 1.6.-/NADH, NADPH Oxidoreductases; EC 1.6.99.-/NADPH oxidase 1; EC Protein Kinase 1; EC Protein Kinase 3; EC Mitogen-Activated Protein Kinases

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