Cytochrome P450 1B1 contributes to increased blood pressure and cardiovascular and renal dysfunction in spontaneously hypertensive rats.
OBJECTIVE
We investigated the contribution of cytochrome P450 (CYP) 1B1 to hypertension and its pathogenesis by examining the effect of its selective inhibitor, 2,4,3',5'-tetramethoxystilbene (TMS), in spontaneously hypertensive rats (SHR).


METHODS
Blood pressure (BP) was measured bi-weekly. Starting at 8 weeks, TMS (600 μg/kg, i.p.) or its vehicle was injected daily. At 14 weeks, samples were collected for measurement.


RESULTS
TMS reversed increased BP in SHR (207 ± 7 vs. 129 ± 2 mmHg) without altering BP in Wistar-Kyoto rats. Increased CYP1B1 activity in SHR was inhibited by TMS (RLU: aorta, 5.4 ± 0.7 vs. 3.7 ± 0.7; heart, 6.0 ± 0.8 vs. 3.4 ± 0.4; kidney, 411 ± 45 vs. 246 ± 10). Increased vascular reactivity, cardiovascular hypertrophy, endothelial and renal dysfunction, cardiac and renal fibrosis in SHR were minimized by TMS. Increased production of reactive oxygen species and NADPH oxidase activity in SHR, were diminished by TMS. In SHR, TMS reduced increased plasma levels of nitrite/nitrate (46.4 ± 5.0 vs. 28.1 ± 4.1 μM), hydrogen-peroxide (36.0 ± 3.7 vs. 14.1 ± 3.8 μM), and thiobarbituric acid reactive substances (6.9 ± 1.0 vs. 3.4 ± 1.5 μM). Increased plasma levels of pro-inflammatory cytokines and catecholamines, and cardiac activity of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, c-Src tyrosine kinase, and protein kinase B in SHR were also inhibited by TMS.


CONCLUSIONS
These data suggests that increased oxidative stress generated by CYP1B1 contributes to hypertension, increased cytokine production and sympathetic activity, and associated pathophysiological changes in SHR. CYP1B1 could be a novel target for developing drugs to treat hypertension and its pathogenesis.
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN, 38163, USA.
Brett L
BL
Jennings
David E
DE
Montanez
Michael E
ME
May
Anne M
AM
Estes
Xiao R
XR
Fang
Fariborz A
FA
Yaghini
Alie
A
Kanu
Kafait U
KU
Malik
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002395:Catecholamines / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D016391:Genes, src / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology*; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR / Q000378:metabolism* / Q000502:physiology; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
C440850:2,4,3',5'-tetramethoxystilbene; D002395:Catecholamines; D016207:Cytokines; D017382:Reactive Oxygen Species; D013267:Stilbenes; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; D006861:Hydrogen Peroxide; D001189:Aryl Hydrocarbon Hydroxylases; C585499:Cyp1b1 protein, rat; D065633:Cytochrome P-450 CYP1B1; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases