TY - JOUR
T1 - 20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established
T2 - A study in Cyp1a1-Ren-2 transgenic rats
AU - Sedláková, Lenka
AU - Kikerlová, Soňa
AU - Husková, Zuzana
AU - Červenková, Lenka
AU - Chábová, Věra Čertíková
AU - Zicha, Josef
AU - Falck, J R
AU - Imig, John D.
AU - Kompanowska-Jezierska, Elzbieta
AU - Sadowski, Janusz
AU - Krátký, Vojtěch
AU - Červenka, Luděk
AU - Kopkan, Libor
N1 - Funding Information:
This work was supported by the Ministry of Health of the Czech Republic [grant number 15-25396A (to J.Z.)]; the Ministry of Health, Czech Republic – conceptual development of research organization (‘Institute for Clinical and Experimental Medicine – IKEM’), [grant number IN 00023001 (to L.S.)]; the Robert A. Welch Foundation [grant number I-0011 (to J.R.F.)]; and the National Institute of Health [grant number DK103616 (to J.D.I.)].
Publisher Copyright:
© 2018 Portland Press Ltd. All Rights Reserved.
PY - 2018/9/12
Y1 - 2018/9/12
N2 - We hypothesized that vascular actions of 20-hydroxyeicosatetraenoic acid (20-HETE), the product of cytochrome P450 (CYP450)-dependent ω-hydroxylase, 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 20-HETE receptor antagonist (AAA) in this model. 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 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. In I3C-induced hypertensive rats, early AAA treatment reduced SBP elevation (to 161 +− 3 compared with 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 compared with 52 +− 3 fmol/g in non-induced rats, P<0.05) which was markedly lowered by AAA treatment (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 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. This suggests that intrarenal ANG II activation by 20-HETE is important in the pathophysiology of this hypertension form.
AB - We hypothesized that vascular actions of 20-hydroxyeicosatetraenoic acid (20-HETE), the product of cytochrome P450 (CYP450)-dependent ω-hydroxylase, 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 20-HETE receptor antagonist (AAA) in this model. 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 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. In I3C-induced hypertensive rats, early AAA treatment reduced SBP elevation (to 161 +− 3 compared with 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 compared with 52 +− 3 fmol/g in non-induced rats, P<0.05) which was markedly lowered by AAA treatment (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 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. This suggests that intrarenal ANG II activation by 20-HETE is important in the pathophysiology of this hypertension form.
UR - http://www.scopus.com/inward/record.url?scp=85053116578&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053116578&partnerID=8YFLogxK
U2 - 10.1042/BSR20171496
DO - 10.1042/BSR20171496
M3 - Article
C2 - 30054426
AN - SCOPUS:85053116578
SN - 0144-8463
VL - 38
JO - Bioscience reports
JF - Bioscience reports
IS - 5
M1 - BSR20171496
ER -