20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats

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.

Increased Endogenous Activity of the Renin-Angiotensin System Reduces Infarct Size in the Rats with Early Angiotensin II-dependent Hypertension which Survive the Acute Ischemia/Reperfusion Injury

“…The infarct size was normalized to the area at risk. This approach has been validated in many experimental studies and is currently accepted as the "gold standard" for measurement of myocardial infarct size in small animals (Sanada et al, 2011). The incidence and severity of ventricular arrhythmias during the 20-min ischemia and first 3 min of reperfusion were assessed according to the Lambeth Conventions (Walker et al, 1988).…”

“…This therapy has become a "golden standard" in the treatment since the 1970s (Ginks et al, 1972;Maroko et al, 1972). On the other hand, restoration of coronary artery blood flow may cause cardiomyocyte death and microvascular dysfunction and worsen tissue damage; this phenomenon is termed "myocardial ischemia/reperfusion (I/R) injury" (Sanada et al, 2011;Jennings, 2013). The exact mechanisms of I/R injury are not fully understood but it may paradoxically diminish the beneficial effects of myocardial reperfusion.…”

Epoxyeicosatrienoic Acid Analog and 20-HETE Antagonist Combination Prevent Hypertension Development in Spontaneously Hypertensive Rats

“…EET-A [disodium (Z)-(13-(3-pentylureido) tridec-8-enoyl)- l -aspartate], a 14,15-EET analog, was given in drinking water, and its concentration was adjusted in such a way that the daily dose was either 10 mg/kg/day (EET-A) or a high dose of 40 mg/day/kg (EET-A HD). 20-HETE receptor antagonist {disodium [(6Z,15Z)-20-hydroxyeicosa-6,15-dienoyl]- l -aspartate; AAA} was also given in drinking water at a concentration adjusted to yield a daily dose of 10 mg/kg/day, based on our recent studies ( Gangadhariah et al, 2014 ; Sedláková et al, 2018 ; Gawrys et al, 2020a ). The EET-A and AAA were designed and synthesized in the laboratory of JRF.…”

“…20-HETE is a very unique AA metabolite with both pro- and antihypertensive activities ( Nowicki et al, 1997 ; Ward et al, 2004 ; Wu et al, 2014 ). Interestingly, both the stimulation of its production ( Jíchová Š et al, 2016 ) and the inhibition of its action ( Sedláková et al, 2018 ) can cause beneficial effects. Moreover, we have recently shown that, after acute infusion of both compounds, a significant improvement in renal hemodynamics is observed, with a subsequent reduction in blood pressure ( Walkowska et al, 2021 ).…”

Early Renal Vasodilator and Hypotensive Action of Epoxyeicosatrienoic Acid Analog (EET-A) and 20-HETE Receptor Blocker (AAA) in Spontaneously Hypertensive Rats

“…Thereafter, 14,15-EET analog, disodium (S)-2-(13-(3-pentyl)ureido)-tridec-8(Z)-enamido)succinate (EET-A; 5 mg/kg) or N-disodium succinate-20-hydroxyeicosa-6(Z),15(Z)-diencarboxamide (AAA;10 mg/kg) were given, alone or combined. The dose of EET-A was determined in preliminary experiments and the AAA dose was validated earlier ( Sedláková et al, 2018 ).…”