Acute hypotensive effect of EET‐A, a stable analog of epoxyeicosatrienic acid (EET), in spontaneously hypertensive rats: dependence on endogenous EETs activity

Abstract

IntroductionArterial hypertension and related disorders are one of the main mortality causes world‐wide. Recent evidence points to epoxyeicosatrienoic acids (EETs) as significant factors in blood pressure regulation. These cytochrome P‐450 dependent metabolites of arachidonic acid, exhibit vasodilator and natriuretic activity. Therefore EETs might contribute to reduction of elevated blood pressure and have therapeutic potential. In our spontaneously hypertensive rats (SHR), potential hypotensive efficiency was examined of EET‐A (disodium (S)‐2‐(13‐(3‐entyl)ureido)‐tridec‐8(Z)‐enamido) succinate), a stable 14,15‐EET analog. EET‐A effects were studied in animals that were or were not pretreated with c‐AUCB (cis‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)‐ cyclohexyloxy]‐benzoic acid), an inhibitor of soluble epoxide hydrolase (sEH) which prevents degradation of EETs. Inhibition of sEH increases endogenous EETs levels.MethodsAnesthetized SHR aged 16 weeks (established hypertension) received 1‐hour infusion of EET‐A (5 mg/kg BW iv) or its solvent. These acute experiments were performed in rats pretreated for 14 days with oral c‐AUCB (8.5 mg/kg/24 h, in drinking water) or in untreated rats receiving c‐AUCB solvent. Throughout experiments mean arterial blood pressure (MABP) and left kidney total blood flow (RBF, renal artery probe) and perfusion of the cortex, outer‐ and inner medulla (CBF, OMBF, IMBF; laser‐Doppler fluxes) were measured, along with renal excretion of water (V), total solute (UosmV), and sodium (UNaV).ResultsBasal MABP measured after chronic treatments tended to be lower after c‐AUCB compared to solvent‐treated group; otherwise no meaningful between‐group differences in renal hemodynamics and excretion parameters were seen. In control group pretreated with c‐AUCB‐solvent, EET‐A administration was followed by a delayed significant progressive decrease in MABP, down to a value 6% below control (p=0.01). In AUCB‐pretreated group no significant post‐EET‐A change in MABP was seen. During EET‐A infusion RBF and CBF significantly and fairly rapidly increased, to 130% and 124% of the control levels, respectively, comparably in untreated and c‐AUCB pretreated group and became almost always significant within the first 30 minutes of EET‐A infusion.SummaryIn acute experiments with anesthetized SHR, administration of EET analog (EET‐A) caused a significant delayed reduction of MABP. Not unexpectedly, previous enhancement of endogenous EETs activity after sEH blockade tended to reduce baseline MABP and virtually abolished the pressure reduction in response to exogenous EET analog. Irrespective of the baseline endogenous EET activity, EET‐A invariably induced renal vasodilation. The data indicate that in adult SHR a hypotensive effect can be obtained both by administration of EET analog and by enhancing endogenous EETs activity. On the other hand, only EET‐A treatment was found to improve renal hemodynamics.Support or Funding InformationNational Science Centre 2017/26/M/NZ5/00367