Cytochrome P4504A inhibitors attenuate the exaggerated natriuretic response to volume expansion in thyroidectomized rats.

Cecilia Colombero,Susana Nowicki,Marcela Venara,Richard J Roman,Daniel Gonzalez

doi:10.14814/phy2.12040

Abstract

Thyroidectomy augments the natriuretic response to volume expansion; however, the mechanism remains unknown. This study assessed the role of 20‐hydroxyeicosatetraenoic acid (20‐HETE) in the natriuretic response to an acute volume expansion in hypothyroid rats. Urine flow (1.9‐fold), sodium excretion (2.4‐fold), fractional sodium excretion (3.8‐fold), and distal delivery of sodium (4.1‐fold) increased to a greater extent in thyroidectomized rats (TX) than in sham‐operated controls (SHAM) following i.v. infusion of isotonic saline (5% body weight) over 60 min. This was associated with inhibition of both proximal and distal tubular reabsorption of sodium. Administration of two mechanistic and chemical dissimilar inhibitors of the synthesis of 20‐HETE, 1‐aminobenzotriazole (ABT), and N‐hydroxy‐N’‐(‐4‐butyl‐2‐methylphenyl)formamidine (HET0016) decreased the natriuretic response in TX rats. Glomerular filtration rate was lower in TX than in SHAM rats and was not altered by the CYP4A inhibitors. The expression, intrarenal distribution, and the formation of 20‐HETE and expoxygenase metabolites of arachidonic acid were similar in the cortex and medulla of SHAM and TX rats. These results suggest that CYP4A‐derived metabolites of arachidonic acid play an important role in the enhanced natriuretic response to volume expansion in hypothyroid rats even though TX did not alter the expression or activity of these enzymes.

Highlights

The excretion of sodium and water under basal conditions (Bradley et al 1974) and the natriuretic response to volume expansion (Holmes and DiScala 1970; Singleton et al 1999) is markedly elevated in thyroidectomized rats
TX + T3, thyroidectomized rats replaced with triiodothyronine. The results of this investigation suggest that CYP4A metabolites of arachidonic acid play an important role in the enhanced natriuretic response to volume expansion in hypothyroid rats
This conclusion is based on the observation that administration of two chemically and mechanistically different inhibitors of the renal formation of 20-hydroxyeicosatetraenoic acid (20-HETE) reduced the diuretic and natriuretic response to an acute volume expansion in TX rats

Summary

Introduction

The excretion of sodium and water under basal conditions (Bradley et al 1974) and the natriuretic response to volume expansion (Holmes and DiScala 1970; Singleton et al 1999) is markedly elevated in thyroidectomized rats. Cytochrome P450 (CYP) metabolites of arachidonic acid (AA) in the kidney play an important role in the renal tubular handling of salt and water (Webb et al.1996; Capdevila et al 2007; Fernandez et al 2012). EETs inhibit sodium transport in the proximal tubule and collecting duct (Pavlov et al 2011) while 20-HETE inhibits Na+/H+ exchange in the proximal tubule, Na+,K+-2Cl- transport in the thick ascending limb of Henle’s loop, and Na+, K+-ATPase activity in both nephron segments (Webb et al 1996; Nowicki et al 1997; Yu et al 2007).

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