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Departments of 1 Pharmacology, 2 Comparative Medicine, and 3 Pediatrics, New York Medical College, Valhalla, New York 10595
Inhibition
of cytochrome P-450 (CYP450) enzymes
with cobalt chloride (CoCl2)
prevented hypertension, organ hypertrophy, and renal injury induced by
DOCA and salt (1% NaCl) in uninephrectomized (UNx) rats. Systolic
blood pressure (SBP) rose to 193 ± 6 mmHg by
day
21 from control levels of 150 ± 7 mmHg in response to DOCA-salt treatment, a rise that was prevented by
CoCl2 (24 mg · kg
1 · 24 h1). The effects of
DOCA-salt treatment, which increased protein excretion to 88.3 ± 6.9 mg/24 h on day
21 from 9.0 ± 1.1 mg/24 h on
day
3, were prevented by
CoCl2.
CoCl2 also attenuated the renal
and left ventricular hypertrophy and the increase in media-to-lumen ratio in hypertensive rats. DOCA-salt treatment increased excretion of
endothelin (ET)-1 from 81 ± 17 to 277 ± 104 pg · 100 g body wt1 · 24 h1 associated with a
fourfold increase in 20-hydroxyeicosatetraenoic acid (20-HETE)
excretion from 3.0 ± 1.1 to 12.2 ± 1.9 ng · 100 g body
wt1 · 24 h1
(days
3 vs.
21).
CoCl2 blunted these increases by
58 and 72%, respectively. In aortic rings pulsed with
[3H]thymidine, ET-1
increased its incorporation. Dibromododec-11-enoic acid, an inhibitor
of 20-HETE synthesis, attenuated ET-1-induced increases in
[3H]thymidine
incorporation. We distinguished effects of
CoCl2 acting via CO generation vs.
suppression of CYP450-arachidonic acid metabolism by treating
UNx-salt-DOCA rats with 1-aminobenzotriazole (ABT), which suppresses
CYP450 enzyme activity, and compared these results to those produced by
CoCl2. ABT reduced hypertension,
as did CoCl2. Unlike
CoCl2, ABT did not prevent organ
hypertrophy and proteinuria, suggesting that these effects were
partially related to CO formation. Blockade of the
ETA receptor with BMS-182874
reduced SBP, organ hypertrophy, and proteinuria, indicating the
importance of ET-initiated abnormalities to the progression of lesions
in UNx-salt-DOCA.
cobalt chloride; 20-hydroxyeicosatetraenoic acid; cardiovascular hypertrophy; cytochrome P-450
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