14,15-epoxyeicosatrienoic acid analog augments hypotensive effect of an endothelin-A receptor blocker antrasentan and prevents oedema and organ hypertrophy in spontaneously hypertensive rats.

Abstract

Endothelin-1 (ET-1) contributes to control of blood pressure (BP) and body fluid homeostasis. Blocking prohypertensive ET-1 receptors appeared promising treatment but the critical disturbing side-effect was oedema. Epoxyeicosatrienoic acids (EETs) have natriuretic and vasodilatory activity, hence they could find some therapeutical potential for patients with hypertension and end organ damage. We evaluated the effectiveness of atrasentan (ATR) combined with 14,15-EET analog, EET-A, on BP, kidney function and heart morphology, and ATR-dependent oedema in conscious spontaneously hypertensive rats (SHR). Systolic (SBP), mean and diastolic BP were measured by telemetry in SHR receiving in drinking water: ATR (5 mg/kg/day; n=6), EET-A (10 mg/kg/day; n=6), ATR+EET-A (n=6) or control solvent (C; n=5) for two weeks. Urine and blood sampling, and 24-h observations in metabolic cages were performed weekly. At the end animals were euthanized and organs were harvested. In the second protocol effectiveness of single intragastric drug application on renal electrolyte and water transport was tested. After two weeks of ATR+EET-A treatment SBP decreased significantly more (-13±2 mmHg; p<0.05) than after ATR alone (-3±1 mmHg). Decreases in plasma sodium (-9 mmol/l) and osmolality (-3 mosm/l) were significant in ATR group only, associated with the greatest increase in body weight. In ATR+EET-A and EET-A alone groups organ weights were significantly lower than with ATR alone. Our results suggest that addition of EET-A prolongs the hypotensive effect of ATR and prevents post-ATR water retention. Importantly, EET-A given orally, alone or combined with ATR, shows strong cardio- and renoprotective activity.