(845.3) Effects of Fumarate on Blood Pressure and Renal Hemodynamics in Normotensive Rats: Possible Contribution of Sodium Potassium Co-transporter (NKCC)

Poster Board Number: B176

Osaze Edosuyi (University of Benin, Texas Southern University), Myung Choi (Texas Southern University), Ighodaro Igbe (University of Benin), Adebayo Oyekan (Texas Southern University)

The tricarboxylic acid cycle product, fumarate, and its related products, have been implicated in the etiology of genetic and non-genetic models of hypertension. Fumarate showed a mechanistic link to nitric oxide (NO) production and thus impacted blood pressure and renal hemodynamics in both models. This study evaluated the possibility of a role of fumarate in regulation of blood pressure and renal hemodynamics in normotensive rats and elucidate possible mechanisms involved. Animals were anaesthetized with Thiobutabarbital (100 mg/kg, ip). The carotid artery was cannulated for mean arterial blood pressure (MABP) measurement and the left kidney was exposed to measure cortical blood flow (CBF) and medullary blood flow (MBF). Blood and urine were collected to determine glomerular filtration rate (GFR), urine volume (Uv) and sodium excretion (UNaV). The fumarase inhibitor, pyromellitic acid (PMA) (0.1 mg/kg/h), or fumarate (0.1 mg/kg/h) were infused in these animals. To determine renal sodium excretory mechanisms involved with fumarate, fumarate (1 mg/kg, po) was administered to normotensive rats treated with hydrochlorothiazide (HCTZ) (10 mg/kg, po) or furosemide (10 mg/kg, po), urine was collected hourly for five (5) hours and assayed for sodium. Fumarate elicited a hypotensive effect, with peak effect at the 45th minute (126 ± 6.2 vs 93 ±2.6 mmHg, plt;0.05). Similarly, inhibition of fumarase caused a time-dependent decrease in MABP (plt;0.05). There was a consistent drop in CBF in fumarate-infused rats and although PMA caused an initial rise in CBF at 15 mins, there was a 10-fold increase in CBF at 60 min when compared to fumarate-infused rats (plt;0.05). MBF also decreased in a time-dependent fashion in rats infused with fumarate. Consistent with the drop in MABP and CBF, GFR reduced (0.89 ± 0.26 vs 0.39 ± 0.11 mL/min, plt;0.05) at 30 mins before to returning to baseline levels at 60 mins in fumarate-infused rats. Uv was unchanged in rats infused with fumarate but there was a 1-fold reduction in UNaV at 30 mins (plt;0.05). Also, PMA, tended to increase UNaV at 30 mins, compared to baseline. However, there was an exacerbation in UNaV in PMA-infused rats (24.2 ± 3.8 µmol/L) compared to fumarate-infused rats at 30 mins (4.56 ±1.4 µmol/L, plt;0.05). Fumarate increased UNaV compared to control (plt;0.05), however, there was no significant difference in UNaV between furosemide-treated and furosemide-treated fumarate rats. These data indicate that fumarate and its products elicited vasodilatory effects that reduced blood pressure and exerted vascular and tubular effects on renal hemodynamics. Also, the tubular effects, possibly involves inhibition of sodium potassium co-transporter (NKCC).

Key words: Tricarboxylic acid cycle, fumarate, blood pressure, renal hemodynamics, NKCC

This work was supported by the National Institutes of health (NIH) grant, HL 03674 and 5 G12 MD007605





Fig 1: Effect of continuous infusion of fumarate (0.1 mg/kg/h, iv) or pyromellitic acid (PMA) (0.1 mg/kg/h, iv) on mean arterial blood pressure (MABP) (A), cortical blood flow (CBF) (B) and medullary blood flow (MBF) (C) in normotensive rats. *p < 0.05, **p < 0.05 vs baseline.; Fig 2: Glomerular filtration rate (GFR) (A), urine volume (B) and urinary sodium excretion (C) in rats infused with fumarate (0.1 mg/kg/h, iv) or pyromellitic acid (PMA) (0.1 mg/kg/h, iv). Sodium excretion in rats treated with fumarate (1 mg/kg, po) or frusemide (10 mg/kg).*p < 0.05 vs baseline.