Abstract
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.
Highlights
Hypertension is the major independent risk factor of myocardial infarction, stroke, and progression of chronic kidney disease, and the most important single contributor to the global disease burden and to global mortality [1,2]
I3C-induction resulted in severe hypertension. 20-hydroxyeicosatetraenoic acid (20-HETE) receptor antagonist significantly attenuated the development of hypertension across the whole treatment time (SBP was reduced by approximately 30 mmHg)
These rats displayed hunched posture, piloerection, and polydipsia, the typical features accompanying malignant hypertension [13,14,15,16,17,18,19]; notably, these phenotype characteristics were absent from I3C-induced rats treated with 20-HETE antagonist or angiotensin II (ANG II) type 1 (AT1) receptor antagonist
Summary
Hypertension is the major independent risk factor of myocardial infarction, stroke, and progression of chronic kidney disease, and the most important single contributor to the global disease burden and to global mortality [1,2]. Malignant hypertension is the most severe and, if untreated, a fatal form c 2018 The Author(s). Its hallmark is acute extreme elevation of blood pressure (BP), which is associated with severe end-organ damage, especially the kidney [3,4,5,6,7]. There is a great need for new therapies to combat severe hypertension and the associated organ damage. The prerequisite for the development of new pharmacological measures is a more detailed understanding of the pathophysiology of malignant hypertension, which is still to come
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