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

Agnieszka Walkowska,Janusz Sadowski,John R Falck,John D Imig,Luděk Červenka,Elżbieta Kompanowska-Jezierska

doi:10.3389/fphys.2021.622882

Abstract

Cytochrome P450 (CYP-450) metabolites of arachidonic acid: epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) have established role in regulation of blood pressure (BP) and kidney function. EETs deficiency and increased renal formation of 20-HETE contribute to hypertension in spontaneously hypertensive rats (SHR). We explored the effects of 14,15-EET analog (EET-A) and of 20-HETE receptor blocker (AAA) on BP and kidney function in this model. In anesthetized SHR the responses were determined of mean arterial blood pressure (MABP), total renal (RBF), and cortical (CBF) and inner-medullary blood flows, glomerular filtration rate and renal excretion, to EET-A, 5 mg/kg, infused i.v. for 1 h to rats untreated or after blockade of endogenous EETs degradation with an inhibitor (c-AUCB) of soluble epoxide hydrolase. Also examined were the responses to AAA (10 mg/kg/h), given alone or together with EET-A. EET-A significantly increased RBF and CBF (+30% and 26%, respectively), seen already within first 30 min of infusion. The greatest increases in RBF and CBF (by about 40%) were seen after AAA, similar when given alone or combined with EET-A. MABP decreased after EET-A or AAA but not significantly after the combination thereof. In all groups, RBF, and CBF increases preceded the decrease in MABP. We found that in SHR both EET-A and AAA induced renal vasodilation but, unexpectedly, no additive effect was seen. We suggest that both agents have a definite therapeutic potential and deserve further experimental and clinical testing aimed at introduction of novel antihypertensive therapy.

Highlights

Cytochrome P450 (CYP-450) metabolites of arachidonic acid, generated mostly by the vascular endothelium and smooth muscle cells, display distinct vasoactivity and have established role in the control of blood pressure (BP) and kidney function
In preliminary studies we examined the effect of administering different doses of epoxyeicosatrienoic acids (EETs) analog (EET-A) (2.5, 5, and 10 mg/kg for 1 h) on mean arterial blood pressure (MABP), renal hemodynamics and excretion in normotensive rats
An expected c-AUCB induced increase in renal perfusion could have been offset by a decrease in renal blood flow (RBF) and cortical blood flow (CBF) following a decrease in BP, which would result in zero net effect

Summary

Introduction

Cytochrome P450 (CYP-450) metabolites of arachidonic acid, generated mostly by the vascular endothelium and smooth muscle cells, display distinct vasoactivity and have established role in the control of blood pressure (BP) and kidney function. The major metabolite group, epoxyeicosatrienoic acids (EETs), exhibit anti-hypertensive properties that depend on their vasodilator and on the natriuretic potency (Imig, 2013, 2019). SEH inhibitors effectively increased tissue EETs, decreased BP and provided organ protection only under conditions of EETs deficiency, e.g., resulting from increased conversion of EETs to DHETEs dependent on enhanced activity of sEH (Honetschlägerová et al, 2011; Neckár et al, 2012) Another approach to increase EET activity is to apply agonistic analogs that were designed to reduce EETs degradation and improve their solubility (Imig et al, 2010)

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