2,3',4,5'-Tetramethoxystilbene prevents deoxycorticosterone-salt-induced hypertension: contribution of cytochrome P-450 1B1.
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.
Sahan-Firat
Seyhan
S
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Jennings
Brett L
BL
Yaghini
Fariborz A
FA
Song
Chi Young
CY
Estes
Anne M
AM
Fang
Xiao R
XR
Farjana
Nasreen
N
Khan
Amir I
AI
Malik
Kafait U
KU
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000097:blood; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D006332:Cardiomegaly / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D065633:Cytochrome P-450 CYP1B1; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D004231:Diuresis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D006973:Hypertension / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D011507:Proteinuria / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary; D013267:Stilbenes / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C440850:2,4,3',5'-tetramethoxystilbene; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D017673:Sodium Chloride, Dietary; D013267:Stilbenes; D013481:Superoxides; D003900:Desoxycorticosterone; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D001189:Aryl Hydrocarbon Hydroxylases; C585499:Cyp1b1 protein, rat; D065633:Cytochrome P-450 CYP1B1; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases