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Contribution of Cytochrome (CYP) P450 1B1 in Various Models of Hypertension in Rats and Mice: A Novel Target for the Development of Anti‐Hypertensive Agents
Author(s) -
Jennings Brett Lawrence,
SahanFirat Seyhan,
Estes Anne M,
Malik Kafait U
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.786.21
Subject(s) - cyp1b1 , endocrinology , medicine , blood pressure , angiotensin ii , cytochrome p450 , chemistry , pharmacology , metabolism
Previously, we reported that inhibition of CYP1B1 with 2, 4, 3′, 5′‐tetramethoxystilbene (TMS) in rats prevented the development and maintenance of angiotensin II (Ang II)‐induced hypertension. We have found that TMS (300 μg/kg, i.p. every 3 rd day) also reduces mean arterial pressure (MAP) in DOCA/Salt‐hypertensive rats (154 ± 1 mmHg to 96 ± 1 mmHg, P < 0.05) and in spontaneously hypertensive rats (163 ± 14 mmHg to 116 ± 4 mmHg, P < 0.05). To further elucidate the role of CYP1B1 in hypertension, studies were conducted in CYP1B1 knockout (CYP1B1 −/− ) and wild‐type (CYP1B1 +/+ ) mice. Ang II infused by mini osmotic pumps (1mg/kg/min sc.) for 13 days produced a significantly smaller increase in MAP (P < 0.05) in CYP1B1 −/− mice (112 ± 1 to 128 ± 2 mmHg) than in CYP1B1 +/+ mice (113 ± 3 mmHg to 158 ±3 mmHg). In Ang II‐treated CYP1B1 +/+ mice, responses of the mesenteric artery to phenylephrine and endothelin‐1, media to lumen ratio and aortic ROS production were significantly increased compared to Ang II‐treated CY1B1 −/− mice. Administration of DOCA (35 mg/kg/week im. + 1% NaCl in drinking water) increased MAP from 102 ± 1 to 153 ± 4 mmHg in CYP1B1 +/+ but not in CYP1B1 −/− mice. These data suggest that CYP1B1 contributes to the development of hypertension, most likely via increased ROS generation and vascular reactivity and hypertrophy, and could serve as a novel target for the development of agents like TMS for the treatment of hypertension.