Cytochrome P450 1B1 contributes to angiotensin II-induced hypertension and associated pathophysiology.
Hypertension is the leading cause of cardiovascular diseases, and angiotensin II is one of the major components of the mechanisms that contribute to the development of hypertension. However, the precise mechanisms for the development of hypertension are unknown. Our recent study showing that angiotensin II-induced vascular smooth muscle cell growth depends on cytochrome P450 1B1 led us to investigate its contribution to hypertension caused by this peptide. Angiotensin II was infused via miniosmotic pump into rats (150 ng/kg per minute) or mice (1000 μg/kg per day) for 13 days resulting in increased blood pressure, increased cardiac and vascular hypertrophy, increased vascular reactivity to vasoconstrictor agents, increased vascular reactive oxygen species production, and endothelial dysfunction in both species. The increase in blood pressure and associated pathophysiological changes were minimized by the cytochrome P450 1B1 inhibitor 2,3',4,5'-tetramethoxystilbene in both species and was markedly reduced in Cyp1b1(-/-) mice. These data suggest that cytochrome P450 1B1 contributes to angiotensin II-induced hypertension and associated pathophysiological changes. Moreover, 2,3',4,5'-tetramethoxystilbene, which prevents both cytochrome P450 1B1-dependent and -independent components of angiotensin II-induced hypertension and inhibits associated pathophysiological changes could be clinically useful in the treatment of hypertension and associated cardiovascular and inflammatory diseases.
Jennings
Brett L
BL
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tenn 38163, USA.
Sahan-Firat
Seyhan
S
Estes
Anne M
AM
Das
Kanak
K
Farjana
Nasreen
N
Fang
Xiao R
XR
Gonzalez
Frank J
FJ
Malik
Kafait U
KU
D000804:Angiotensin II / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D006332:Cardiomegaly / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D065633:Cytochrome P-450 CYP1B1; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology / Q000633:toxicity
C440850:2,4,3',5'-tetramethoxystilbene; D017382:Reactive Oxygen Species; D013267:Stilbenes; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D001189:Aryl Hydrocarbon Hydroxylases; C585498:Cyp1b1 protein, mouse; C585499:Cyp1b1 protein, rat; D065633:Cytochrome P-450 CYP1B1; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases
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