Abstract 047: 20-SOLA, A Novel Water-soluble 20-HETE Antagonist, Elicits Natriuresis And Abrogates Hypertension In Cyp4a14 Knockout Mice.

Abstract

20-HETE (20-hydroxyeicosatetraenoic acid) is a cytochrome P450 (CYP) 4A-derived arachidonate metabolite. In the vasculature, 20-HETE increases smooth muscle contraction, endothelial dysfunction/activation and sensitivity to constrictor stimuli; all of which contribute to hypertension. In renal tubules, 20-HETE inhibits ion transport and has pro-natriuretic functions in salt-sensitive models of hypertension. The pro-natriuretic effect of 20-HETE has not been reported in mouse models of 20-HETE-dependent hypertension. The CYP4a14 knockout (KO) male mice exhibit androgen-dependent upregulation of Cyp4a12, the sole 20-HETE synthase in mice, and display 20-HETE-dependent hypertension; female KO mice show no increase in Cyp412-20-HETE and are normotensive. We examined the effect of 20-SOLA (2,5,8,11,14,17-hexaoxanonadecan-19-yl-20-hydroxyeicosa-6(Z),15(Z)-dienoate), a water-soluble 20-HETE antagonist, and determined its effect on blood pressure (BP) and natriuresis in the KO mice. Administration of 20-SOLA (10mg/kg/day in drinking water) normalized BP in male KO mice; a significant reduction was observed on day 4 (146±1 vs153±2 mmHg in untreated littermates) reaching BP of the normotensive female KO mice (124±1 and 126±1 mmHg for treated and untreated, respectively) at day 10 of treatment (124±1 vs. 153±2 mmHg in untreated male KO; p<0.05). 20-SOLA decreased vascular reactivity to phenylephrine in male KO renal microvessels by 7-fold (EC50: 1.58±0.23 vs 0.22±0.03 μM). Moreover, treatment with 20-SOLA increased urine output in KO male mice as compared to untreated littermates (1.25±0.04 vs. 1.06±0.04 mL; p<0.05). The urine output to water intake ratio was significantly elevated in 20-SOLA-treated KO vs. untreated (0.25±0.01 vs. 0.19±0.01, p<0.05). Importantly, treatment with 20-SOLA increased urinary sodium excretion in the KO male mice (12.33±0.44 vs. 8.33±0.63 μmol/gr BW/24Hrs; p<0.05). These results suggest that 20-HETE has an anti-natriuretic effect in the kidneys of KO mice and that antagonism of 20-HETE’s action using 20-SOLA elicited natriuresis concurrent with reduction in blood pressure. The potential vascular and tubular mechanisms underlying 20-HETE anti-natriuretic action are being currently explored.