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-hydroxylase activity
with ABT reduces blood pressure in the SHR
1 Departments of
Biopharmaceutical Sciences and Pharmaceutical Chemistry,
The
mechanism-based cytochrome P-450 (CYP) inhibitor
1-aminobenzotriazole (ABT) was characterized as an inhibitor of renal arachidonic acid metabolism and administered to spontaneously hypertensive rats (SHRs) to determine the effect of reduced eicosanoid production on mean arterial pressure (MAP). A single intraperitoneal dose of ABT to Sprague-Dawley rats caused a dose-dependent loss of
renal CYP content, arachidonic acid metabolism, and CYP4A protein. In
the cortex and outer medulla, ABT showed a high degree of selectivity for the CYP4A enzymes, reflected by the potent inhibition of 19- and
20-hydroxyeicosatetraenoic acid (19- and 20-HETE) formation. A 50 mg/kg
dose of ABT reduced cortical 20-HETE formation to 16.1 ± 0.82% of
control and outer medullary 20-HETE formation to 23.8 ± 0.45% of
control. In contrast, there was no inhibition of renal epoxygenase activity at this dose. Renal CYP content, arachidonic acid
- and (-1)-hydroxylase activity, and CYP4A protein levels gradually return to control levels by 72 h after a single dose of ABT.
Cortical 20-HETE formation recovered from 17.9 ± 3.15% of control
at 6 h to 84.8 ± 4.67% of control at 72 h after ABT administration. A single injection of ABT to 7-wk-old SHRs caused an
acute reduction in MAP, which remained suppressed for at least 12 h.
The effect was maximal within 4 h and averaged 17-23 mmHg during
the 4- to 12-h period after administration. 20-HETE formation was
inhibited 85% in the cortex and 70-80% in the outer medulla during the period when MAP was reduced. A structurally related ABT
analog 1-hydroxybenzotriazole had no effect on blood pressure or renal
arachidonic acid metabolism. These results identify ABT as a selective
inhibitor of renal CYP4A activity and provide further support for a
role for 20-HETE in the regulation of blood pressure.
cytochrome P-450 4A; 20-hydroxyeicosatetraenoic acid; renal eicosanoids
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