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

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.

Lipid Mediators Metabolic Chaos of Asthmatic Mice Reversed by Rosmarinic Acid

“…As shown in Figure 4A, the 14,15-DHET levels increased significantly in the RosA group (p < 0.05) and also increased in the SXCF group, which proved the anti-inflammatory effect of SXCF and RosA. Furthermore, 14,15-EET has been shown to have a hypotensive impact [52], while elevated EETs and DHETs levels are associated with ischemic stroke [53]. As shown in Figure 5, 14,15-DHET was overregulated in the RosA group.…”

Blockade of 20-hydroxyeicosatetraenoic acid receptor lowers blood pressure and alters vascular function in mice with smooth muscle-specific overexpression of CYP4A12-20-HETE synthase

“…Both male and female mice were used in this study as they exhibited similar phenotypic changes with respect to Cyp4a12 overexpression, blood pressure and vascular function and remodeling. A water-soluble 20-HETE receptor antagonist, N-disodium succinate-20-hydroxyeicosa-6(Z),15(Z)-diencarboxamide (AAA), was used to assess the contribution of 20-HETE to the phenotype of these mice [4,38,39]. AAA was administered to the mice, via the drinking water (vehicle), at a dose of 10 mg/kg/day.…”

“…AAA was administered to the mice, via the drinking water (vehicle), at a dose of 10 mg/kg/day. This dose was used as it was sufficient to lower SBP in previous reports [39,40]. Mice were divided into three groups: WT; Myh11-4a12; and Myh11-4a12 þ AAA treatment.…”

Effects of Epoxyeicosatrienoic Acid-Enhancing Therapy on the Course of Congestive Heart Failure in Angiotensin II-Dependent Rat Hypertension: From mRNA Analysis towards Functional In Vivo Evaluation

“…Therefore, an alternative approach, which circumvents this limitation, consists of applying EETs-agonistic analogs designed to resist degradation. This new approach has not yet been adequately explored: the obtained results were not entirely consistent and not yet comprehensively evaluated in HF [20][21][22][23][24][25].…”