Effective Antihypertensive Treatment with Epoxyeicosatrienoic Acid Analog (EET‐A) and 20‐HETE Antagonist (AAA) of Spontaneously Hypertensive Rats (SHR)

Abstract

IntroductionDespite decades of research the death toll of hypertension and associated disorders increases significantly each year. This impose the need to further determine the mechanisms underlying the development of hypertension and to implement more efficient therapeutic strategies. Growing number of research suggest the important role of cytochrome P‐450 dependent metabolites of arachidonic acid (AA) in blood pressure regulation. The epoxyeicosatrienoic acids (EETs) exhibit vasodilatory activity, they decrease sodium reabsorption and possess renoprotective and anti‐inflammatory properties. Considering the beneficial effects of EETs, we decided to test the efficiency of stable analog of 14,15‐EET [disodium (S)‐2‐(13‐(3‐entyl)ureido)‐tridec‐8(Z)‐enamido) succinate] called EET‐A, together with AAA [N‐disodium succinate‐20‐hydroxyeicosa‐6(Z),15(Z)‐diencarboxamide], a novel receptor antagonist of 20‐HETE which is another potent AA metabolite with both pro‐ and antihypertensive activity. To test the antihypertensive potential of both substances we employed spontaneously hypertensive rats (SHR), which are currently considered the best model to study human essential hypertension.MethodsMale SHR in the established stage of hypertension (16 week old) were treated for four weeks with EET‐A (n=8), AAA (n=6), as well as the combination of EET‐A and AAA (n=7) and compared to age‐matched untreated SHR (n=10) and WKY (n=5). Both tested substances were administered in drinking water in the dose of 10 mg/kg/day each. Systolic blood pressure (SBP) was measured by telemetry. Once a week observations in metabolic cages (food and water intake, feces, diuresis) were performed; urine, blood and tissue samples were collected for further analysis.ResultsEET‐A or AAA given alone had no significant effect on blood pressure of SHR. However, the combined treatment with AAA + EET‐A was significantly antihypertensive (161±5 vs 180±3 mmHg, p<0.05). Additionally, combined AAA and EET‐A attenuated cardiac hypertrophy expressed as left ventricle weight to tibia length (22.95±0.61 vs 24.75±0.35 mg/mm in untreated SHR, p<0.05), decreased kidney ANG II level, increased natriuresis and increased the excretion of nitric oxide metabolites (7.6±1.4 vs 4.8±0.7 μmol/24h in untreated SHR, p<0.05).SummaryTaking into account all the beneficial impact of the combined treatment with EET‐A and AAA on cardiovascular and renal function of adult SHR we suggest that it constitute a very promising novel antihypertensive strategy.Support or Funding InformationSupported by National Science Centre Poland (grant no 2017/26/M/NZ5/00367)and MH CZ ‐ DRO („Institute for Clinical and Experimental Medicine – IKEM, IN 00023001“)