TY - JOUR
T1 - Combined treatment with epoxyeicosatrienoic acid analog and 20-hydroxyeicosatetraenoic acid antagonist provides substantial hypotensive effect in spontaneously hypertensive rats
AU - Gawrys, Olga
AU - Husková, Zuzana
AU - Baranowska, Iwona
AU - Walkowska, Agnieszka
AU - Sadowski, Janusz
AU - Kikerlová, Soňa
AU - Vaňourková, Zdeňka
AU - Honetschlägerová, Zuzana
AU - Škaroupková, Petra
AU - Červenka, Luděk
AU - Falck, John R.
AU - Imig, John D.
AU - Kompanowska-Jezierska, Elzbieta
N1 - Publisher Copyright:
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Objectives: The global morbidity and mortality related to hypertension and associated disorders increases continuously and novel therapeutic strategies are still in high demand. Increasing evidence suggests the important role in blood pressure regulation of cytochrome P-450dependent metabolites of arachidonic acid. Epoxyeicosatrienoic acids (EETs) induce vasodilation and natriuresis, and have renoprotective and anti-inflammatory properties. 20-HETE is an arachidonic acid metabolite with both prohypertensive and antihypertensive activities. To explore the pathophysiological role of arachidonic acid metabolites in more detail, we examined the antihypertensive efficiency of EET-A, a stable analog of 14,15-EET, and of AAA, a novel antagonist of the 20-HETE receptors. Methods: Male spontaneously hypertensive rats (SHR) were treated for 5 weeks with EET-A, AAA or the combination; age-matched untreated SHR and normotensive Wistar–Kyoto rats served as controls. EET-A and AAA were administered in drinking water at 10mg/kg/day each. SBP was measured by telemetry and urine, blood, and tissue samples were collected for relevant analyses. Results: EET-A or AAA given alone had no significant effect on SHR blood pressure. In contrast, combined treatment with AAA and EET-A was significantly antihypertensive, causing a decrease in SBP from 180±3 to 160±5mmHg (P<0.05). Additionally, the combined treatment attenuated cardiac hypertrophy, decreased kidney ANG II level, increased natriuresis, and increased the excretion of nitric oxide metabolites. Conclusion: Considering the beneficial impact of the combined treatment with EET-A and AAA on SHR blood pressure and cardiovascular and renal function, we suggest that the treatment is a promising therapeutic strategy for human hypertension.
AB - Objectives: The global morbidity and mortality related to hypertension and associated disorders increases continuously and novel therapeutic strategies are still in high demand. Increasing evidence suggests the important role in blood pressure regulation of cytochrome P-450dependent metabolites of arachidonic acid. Epoxyeicosatrienoic acids (EETs) induce vasodilation and natriuresis, and have renoprotective and anti-inflammatory properties. 20-HETE is an arachidonic acid metabolite with both prohypertensive and antihypertensive activities. To explore the pathophysiological role of arachidonic acid metabolites in more detail, we examined the antihypertensive efficiency of EET-A, a stable analog of 14,15-EET, and of AAA, a novel antagonist of the 20-HETE receptors. Methods: Male spontaneously hypertensive rats (SHR) were treated for 5 weeks with EET-A, AAA or the combination; age-matched untreated SHR and normotensive Wistar–Kyoto rats served as controls. EET-A and AAA were administered in drinking water at 10mg/kg/day each. SBP was measured by telemetry and urine, blood, and tissue samples were collected for relevant analyses. Results: EET-A or AAA given alone had no significant effect on SHR blood pressure. In contrast, combined treatment with AAA and EET-A was significantly antihypertensive, causing a decrease in SBP from 180±3 to 160±5mmHg (P<0.05). Additionally, the combined treatment attenuated cardiac hypertrophy, decreased kidney ANG II level, increased natriuresis, and increased the excretion of nitric oxide metabolites. Conclusion: Considering the beneficial impact of the combined treatment with EET-A and AAA on SHR blood pressure and cardiovascular and renal function, we suggest that the treatment is a promising therapeutic strategy for human hypertension.
KW - 20-hydroxyeicosatetraenoic acid antagonist
KW - epoxyeicosatrienoic acid analog
KW - epoxyeicosatrienoic acids
KW - primary hypertension
KW - spontaneously hypertensive rats
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U2 - 10.1097/HJH.0000000000002462
DO - 10.1097/HJH.0000000000002462
M3 - Article
C2 - 32384390
AN - SCOPUS:85089302292
SN - 0263-6352
VL - 38
SP - 1802
EP - 1810
JO - Journal of hypertension
JF - Journal of hypertension
IS - 9
ER -