Abstract P426: Suppression of Intrarenal Ras With a 20-hydroxyeicosatetraenoic Acid Antagonist Attenuates Ang II-dependent Malignant Hypertension and Reverses Established Ang-II-dependent Hypertension in Cyp1a1-ren-2 Transgenic Rats

Abstract

Rationale and Objective: Interplay of 20-HETE and ANG II might be a factor in pathophysiology of many forms of experimental hypertension. We hypothesized that intrarenal 20-HETE potentiates prohypertensive actions of ANG II in Cyp1a1-Ren-2 transgenic rats (TGR), a model of ANG II-dependent malignant hypertension. Therefore, we evaluated the antihypertensive effectiveness of a new, orally active 20-HETE antagonist (SOLA) in this model. Methods: Treatment with SOLA (10 mg.kg -1 .day - 1 in drinking water) was started either simultaneously with induction of hypertension (early treatment) by indol-3-carbinol or 10 days later, during established hypertension (late treatment). Systolic blood pressure (SBP, measured by radiotelemetry) was monitored continuously and indices of renal and cardiac injury, and kidney 20-HETE and ANG II levels were determined at the end of experiments. Results: In TGR with induced hypertension, early SOLA treatment reduced SBP elevation (to 161±3 vs. 199±3 mmHg in induced TGR, p<0.001), reduced albuminuria (16±2 vs. 35±3 mg/24 h, p<0.002), glomerulosclerosis index (0.12±0.01 vs. 0.32±0.02, p<0.001) and cardiac hypertrophy (left ventricle weight (mg)/tibial length ratio: 16.9±0.4 vs 20.6±0.5, p<0.02). TGR with induced hypertension exhibited elevated intrarenal 20-HETE levels (15.2±0.03 vs. 9.2±0.02 μg/g in noninduced rats, p<0.01); however, the elevation was not altered by SOLA treatment. Hypertensive TGR showed also augmented kidney ANG II levels (405±30 vs. 51±2 fmol/g in noninduced rats, p<0.001). SOLA treatment significantly lowered kidney ANG II (95±19). Remarkably, in TGR with established hypertension, late SOLA treatment also decreased SBP (from 187±4 to 158±4 mmHg, p<0.002) and exhibited cardio- and renoprotective effects in addition to a marked suppression of kidney ANG II levels (72±12 fmol/g). Conclusion: In hypertensive TGR the new orally active 20-HETE antagonist attenuated the development and largely reversed the established ANG II-dependent experimental malignant hypertension, likely via suppression of intrarenal ANG II levels. This suggests that intrarenal RAS activation by 20-HETE is important in pathophysiology of this hypertension form