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Abstract: TH-OR080

Malignant Hypertension Can Be Partially Attenuated and Reversed by a 20-Hydroxyeicosatetraenoic Acid Antagonist

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Certikova chabova, Vera, 1st Faculty of medicine, Charles University, Praha 2, Czechia
  • Sedláková, Lenka, Institute for Clinical and Experimental Medicine, Praha 4, Czechia
  • Cervenka, Ludek, Institute of Clinical and Experimental Medicine, Praha 4, Czechia
Background

20-hydroxyeicosatetraenoic acid (20-HETE), the product of cytochrome P450-dependent ω-hydroxylase might potentiate prohypertensive actions of angiotensin II (ANG II) in Cyp1a1-Ren-2 transgenic rats, a model of ANG II-dependent malignant hypertension. Therefore, we evaluated the antihypertensive effectiveness of a 20- HETE receptor antagonist (AAA) in this model.

Methods

Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. Treatment with AAA (N-disodium succinate-20-hydroxyeicosa-6(Z),15(Z)-diencarboxamide) was started either simultaneously with induction of hypertension or 10 days later, during established hypertension. Systolic blood pressure (SBP) was monitored by radiotelemetry, indices of renal and cardiac injury, and kidney ANG II levels were determined.

Results

In I3C-induced hypertensive rats, early AAA treatment reduced SBP elevation (to 161±3 vs. 199±3 mmHg in untreated I3C-induced rats), reduced albuminuria, glomerulosclerosis index and cardiac hypertrophy (p<0.05 in all cases). Untreated I3C-induced rats showed augmented kidney ANG II (405±14 vs. 52±3 fmol/g in noninduced rats, p<0.05). AAA treatment lowered it to levels not significantly different from that in noninduced rats (72±6 fmol/g). Remarkably, in TGR with established hypertension, AAA also decreased SBP (from 187±4 to 158±4 mmHg, p<0.05) and exhibited organoprotective effects in addition to a marked suppression of kidney ANG II levels. In conclusion, 20-HETE antagonist attenuated the development and largely reversed the established ANG II dependent malignant hypertension, likely via suppression of intrarenal ANG II levels.

Conclusion

Intrarenal ANG II activation by 20-HETE is important in the pathophysiology of this model of ANG II -dependent hypertension. 20-HETE antagonists can partially reverse both developing and established hypertension and target organ damage.

Funding

  • Government Support - Non-U.S.