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

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

doi:10.3389/fphar.2021.798642

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

Front Pharmacol. 2022 Jan 17:12:798642. doi: 10.3389/fphar.2021.798642. eCollection 2021.

Authors

Affiliations

¹ Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Institute, Polish Academy of Science, Warsaw, Poland.
² Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
³ Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia.
⁴ Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
⁵ Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States.
⁶ Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, United States.

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.

Keywords: 20-HETE antagonist; EET analog; epoxyeicosatrienoic acids; primary hypertension; spontaneously hypertensive rats.

Abstract

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