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

Iwona Baranowska,John R Falck,Agnieszka Walkowska,Olga Gawrys,John D Imig,Adeniyi M Adebesin,Krzysztof H Olszynski,Elżbieta Kompanowska-Jezierska,Luděk Červenka

doi:10.3389/fphar.2021.798642

Abstract

Numerous studies indicate a significant role for cytochrome P-450-dependent arachidonic acid metabolites in blood pressure regulation, vascular tone, and control of renal function. Epoxyeicosatrienoic acids (EETs) exhibit a spectrum of beneficial effects, such as vasodilatory activity and anti-inflammatory, anti-fibrotic, and anti-apoptotic properties. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that inhibits sodium reabsorption in the kidney. In the present study, the efficiency of EET-A (a stable analog of 14,15-EET) alone and combined with AAA, a novel receptor antagonist of 20-HETE, was tested in spontaneously hypertensive rats (SHR). Adult SHR (16 weeks old) were treated with two doses of EET-A (10 or 40 mg/kg/day). In the following experiments, we also tested selected substances in the prevention of hypertension development in young SHR (6 weeks old). Young rats were treated with EET-A or the combination of EET-A and AAA (both at 10 mg/kg/day). The substances were administered in drinking water for 4 weeks. Blood pressure was measured by telemetry. Once-a-week observation in metabolic cages was performed; urine, blood, and tissue samples were collected for further analysis. The combined treatment with AAA + EET-A exhibited antihypertensive efficiency in young SHR, which remained normotensive until the end of the observation in comparison to a control group (systolic blood pressure, 134 ± 2 versus 156 ± 5 mmHg, respectively; p < 0.05). Moreover the combined treatment also increased the nitric oxide metabolite excretion. Considering the beneficial impact of the combined treatment with EET-A and AAA in young rats and our previous positive results in adult SHR, we suggest that it is a promising therapeutic strategy not only for the treatment but also for the prevention of hypertension.

Highlights

According to WHO, hypertension is one of the most significant risk factor for all-cause morbidity and mortality worldwide, and it is responsible for approximately 10 million deaths globally every year (World Health Organization, 2013; Stanaway et al, 2018)
We confirmed our previous finding that the antihypertensive treatment unaccompanied by the 14,15-epoxyeicosatrienoic acids (EETs) analog
We hypothesize that the hypertensive activity of EET-A

Summary

Introduction

According to WHO, hypertension is one of the most significant risk factor for all-cause morbidity and mortality worldwide, and it is responsible for approximately 10 million deaths globally every year (World Health Organization, 2013; Stanaway et al, 2018). This multifactorial disease is a result of the complex interplay between environmental and pathophysiological factors involving multiple systems as well as genetic predispositions (Oparil et al, 2018). Since morbidity and mortality related to hypertension increase continuously each year, a deeper understanding of the underlying mechanisms responsible for blood pressure elevation and novel antihypertensive therapies are still in great demand. An excellent review summarizing the role of EETs in blood pressure regulation (Imig, 2019) was published recently, which clearly points that EET deficiency can lead to hypertension and renal dysfunction, giving a rationale to EET supplementation as a novel therapeutic option

Methods

Results

Conclusion