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

Abstract

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 h−1). 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 wt−1 ⋅ 24 h−1 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 wt−1 ⋅ 24 h−1( 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.

Inhibition of the formation of EETs and 20-HETE with 1-aminobenzotriazole attenuates pressure natriuresis

“…20-HETE then may contribute to pressure natriuresis by inhibiting both Na ϩ -K ϩ -ATPase activity and Na ϩ /H ϩ exchange, whereas EETs would be expected to act by inhibiting the Na ϩ /H ϩ exchanger alone. The view that 20-HETE and/or EETs contribute to pressure natriuresis is consistent with the large body of evidence indicating that the formation of these compounds is altered in genetic and experimental animal models of hypertension (1,26,29,47,50,51,63,(67)(68)(69)71). It also fits with previous findings that inhibitors of the renal formation of 20-HETE and/or EETs promote the development of salt-sensitive hypertension in normotensive strains of rats (25,67), that increasing the renal formation of 20-HETE with clofibrate or tempol lowers blood pressure in Dahl S rats (26,63,71), and that increasing renal levels of EETs with soluble epoxide hydrolase inhibitors lowers blood pressure in spontaneously hypertensive (77) and ANG II-hypertensive rats (27).…”

“…Recent studies have suggested that ANG II stimulates the renal formation of EETs (64) and 20-HETE (1,3,24,46) and that 20-HETE mediates some of the inhibitory actions of ANG II (3,11,65) and endothelin (24,46,47) on tubular transport of Na ϩ . These results may provide a possible link between the synthesis of EETs and 20-HETE and the recent observation (35) that clamping the renal levels of ANG II with captopril and an intrarenal infusion of ANG II blunts pressure natriuresis.…”

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

“…This fall in MAP is consistent with previous findings in the SHR, in which inhibition of the renal formation of 20-HETE with ABT, 13 sodium 10-undecynyl sulfate (10-SUYS), 11 or antisense oligonucleotides 16 have been reported to reduce blood pressure in this strain. ABT has also been reported to lower blood pressure in deoxycorticosterone acetate (DOCA) salt-hypertensive rats 17,18 and in rats with angiotensin II-induced hypertension. 10,19 In contrast, HET0016 (10 mg/kg per day) had no effect on blood pressure in the SD rats fed a low salt diet, despite the fact that HET0016 is a more potent and selective inhibitor of the formation of 20-HETE than ABT.…”

Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase

“…Between the second and third week, urinary excretion of ET-1 and HETE had increased by three to four fold. Blockade of the ET A receptor could lower blood pressure and attenuate organ hypertrophy and proteinuria while decreasing the excretion of 20-HETE [37].…”