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

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 (UNa V). 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, p<0.05). Similarly, inhibition of fumarase caused a time-dependent decrease in MABP (p<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 (p<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, p<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 UNa V at 30 mins (p<0.05). Also, PMA, tended to increase UNa V at 30 mins, compared to baseline. However, there was an exacerbation in UNa V in PMA-infused rats (24.2 ± 3.8 µmol/L) compared to fumarate-infused rats at 30 mins (4.56 ±1.4 µmol/L, p<0.05). Fumarate increased UNa V compared to control (p<0.05), however, there was no significant difference in UNa V 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). © FASEB.