Intracerebroventricular Administration of Fibroblast Growth Factor Receptor Inhibitor Attenuates High‐Phosphate Diet‐Induced Exercise Pressor Reflex Overactivation in Rats

Abstract

Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. As a result, dietary Pi intake in the US far exceeds the recommended daily allowance. A previous study from our laboratory has demonstrated that dietary Pi excess induces an exaggerated rise in blood pressure and renal sympathetic nerve activity (RSNA) in response to muscle contraction. This augmented pressor response was further shown to be mediated by an exaggerated skeletal muscle exercise pressor reflex (EPR). However, the underlying mechanism responsible for the EPR overactivity observed remains unknown. Fibroblast growth factor (FGF) 23 is one of the principle hormones involved in Pi homeostasis. It can cross the blood brain barrier and activate FGF receptors in the brainstem. The purpose of this study was to test the hypothesis that Pi‐induced EPR overactivity is mediated by brain FGF receptor stimulation. Sprague‐Dawley rats were fed a normal Pi (NP) diet containing 0.6% Pi (n=13) or a high Pi (HP) diet containing 1.2% Pi (n=13) for three months. Subsequently, mean arterial pressure (MAP) and RSNA responses to EPR activation were measured in decerebrate NP and HP animals. MAP and RSNA measures were obtained before and after intracerebroventricular (ICV) administration of the FGF receptor inhibitor PD173074. ICV PD173074 administration significantly reduced the exaggerated MAP (Δ=35±4 vs. 9±2 mmHg, P<0.01) and RSNA responses (Δ=84±16 vs. 32±7 %, P<0.01) to electrically induced hindlimb muscle contraction via ventral root stimulation (i.e. EPR activation) in the HP group, but did not significantly affect the responses in the NP group (ΔMAP =18±3 vs. 13±2 mmHg, ΔRSNA=40±10 vs. 30±7 %). MAP and RSNA responses to intra‐arterial infusion of capsaicin in the hindlimb (designed to assess the metabolically‐sensitive component of the EPR) were also attenuated by PD173074 in HP rats (ΔMAP=43±4 vs. 24±5 mmHg, ΔRSNA=98±25 vs. 48±9 %, P≤ 0.02) but remained unchanged in NP animals (ΔMAP=32±4 vs. 34±4 mmHg, ΔRSNA=61±12 vs. 66±18 %). The findings suggest that stimulation of FGF receptors in the brain contributes significantly to the generation of exaggerated EPR activity after excess Pi consumption. Moreover, the data demonstrate a novel action of central FGF receptor inhibition by reversing the EPR overactivity manifest in animals fed a high Pi diet. Importantly, the results implicate dietary Pi as a potential therapeutic target for the prevention and/or treatment of abnormally large sympathetic and blood pressure responses to exercise.Support or Funding InformationNIH 5RO1HL133179‐02This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.