Endothelin-1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension

Inhibition of cytochrome P-450 (CYP450) enzymes with cobalt chloride (CoCl2 ) prevented hypertension, organ hypertrophy, and renal injury induced by DO CA and salt (1% NaCl) in uninephrectomized (UNx) rats. Systolic blood press ure (SBP) rose to 193 +/- 6 mmHg by clay 21 from control levels of 150 +/- 7 mmHg in response to DOCA-salt treatment, a rise that was prevented by CoC l2 (24 mg.kg(-1).24 h(-1)). The effects of DOCA-salt treatment, which incre ased protein excretion to 88.3 +/- 6.9 mg/24 h on day 21 from 9.0 +/- 1.1 m g/24 h on day 3, were prevented by CoCl2. CoCl2 also attenuated the renal a nd 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 wt(-1).24 h(-1) associate d with a fourfold increase in 20-hydroxyeicosatetraenoic acid (20-HETE) exc retion from 3.0 +/- 1.1 to 12.2 +/- 1.9 ng 100 g body wt(-1).24 h(-1) (days 3 vs. 21). CoCl2 blunted these increases by 58 and 72%, respectively. In a ortic rings pulsed with [H-3]thymidine, ET-1 increased its incorporation. D ibromododec-11-enoic acid, an inhibitor of 20-HETE synthesis, attenuated ET -1-induced increases in [H-3]thymidine incorporation. We distinguished effe cts 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 t o those produced by CoCl2. ABT reduced hypertension, as did CoCl2. Unlike C oCl2, ABT did not prevent organ hypertrophy and proteinuria, suggesting tha t these effects were partially related to CO formation. Blockade of the ETA receptor with BMS-182874 reduced SEP, organ hypertrophy, and proteinuria, indicating the importance of ET-initiated abnormalities to the progression of lesions in UNx-salt-DOCA.