Preventing Hypertension and Sympathetic Overactivation by Targeting Phosphate
Preventing Hypertension and Sympathetic Overactivation by Targeting Phosphate
An increasing number of studies have indicated that most fast food and common grocery items,
 contain large amount of inorganic phosphate-based food additives , which are highly
 absorbable. The long-term cardiovascular consequences of a high phosphate diet are unknown
 but the existing database implicates phosphate excess as an independent risk factor for
 cardiovascular events in individuals with and without chronic kidney diseases (CKD). High
 phosphate consumption clearly induces BP elevation in rats with normal kidneys. However, the
 mechanisms underlying phosphate-induced hypertension and the relevance of these rodent
 studies to human hypertension have not been determined. We seek to investigate the role of
 high phosphate diet in human hypertension and assess the effect of high phosphate diet on
 muscle sympathetic nerve activity and the exercise pressor reflex.
Animal studies suggest that high phosphate diet raises blood pressure but the mechanism
 underlying this phenomenon is not known. To study the effect of high phosphorus diet on blood
 pressure in humans, we will perform randomized crossover studies in stage 1 prehypertensive
 subjects. To ensure stable Pi intake prior to randomization, Pi consumption will be estimated
 by food recall during a run-in and washout phase for 2 consecutive days, using the Automated
 Self-Administered 24-Hour (ASA24®) Dietary Assessment Tool
 (https://epi.grants.cancer.gov/asa24/). After the run-in period, all subjects will be
 maintained on a low Pi diet (700 mg/d) and a low Na diet of approximately 1,930 mg/d
 throughout the study for 8 weeks. Subjects will also be randomized to receive Sodium
 Phosphate 2 capsules daily (containing a total of 500 mg of Pi, 372mg of sodium) for 4 weeks
 during the high Pi phase (total Pi intake 1,200 mg/d) vs 2 capsules of Sodium Chloride (NaCl,
 containing a total of 372mg of sodium) to match Na content to Sodium Phosphate without extra
 Pi daily for 4 weeks during the low Pi phase (total Pi intake = 700 mg/d).

 The total Na intake during the entire study will be at recommended level of 2,300 mg/d.
 Investigational drug service at UT Southwestern will dispense Sodium Phosphate vs. NaCl
 tablets tablets and the study subjects will be blinded to the type of supplement they
 receive.

 During the periods of high and low Pi phases, we will monitor 24-hr UPiV to ensure adherence.
 Since approximately 70% of ingested Pi is absorbed and excreted in the urine, we expect 24-hr
 UPiV excretion to be approximately 840 mg during the high Pi phase and 490 mg during the low
 Pi phase. If 24-hr UPiV is < 800 mg during the high Pi diet or > 500 mg during the low Pi
 diet, the research dietitian will provide additional counseling to improve adherence to the
 menu plan. If needed, the research diet will be altered to be more compatible with subject
 preference. 24-hr UPiV will be reassessed within 1 week in these individuals. If the levels
 remain below goal, subjects will be excluded from the study.

 24-hr urinary Pi, Na, K, Cr, and Ca excretion will be assessed after weeks 2 and 4 of the low
 and high Pi phases. Serum electrolytes and Pi will be monitored every 2 weeks. Serum FGF23,
 PTH, and soluble Klotho levels and 24-h ambulatory BP will be obtained after 4 weeks on the
 study diet. Then, on a separate day, we will assess muscle SNA and BP at rest and during
 rhythmic handgrip of 30% and 45% each for 3 minutes. Additionally, we will test the role of
 dietary Pi on the response to isometric exercise by assessing SNA and BP during static
 handgrip at 30% MVC for 2 minutes followed by post exercise circulatory arrest (PECA). The
 latter maneuver will maximally activate the metaboreflex. Each exercise intervention will be
 separated by at least 30 minutes. The order of exercise intervention will be randomized.
 Subsequently, subjects will stop the first study supplement and undergo washout for 2 weeks.
 After 2 weeks of washout, they will receive the 2nd study supplement. Measurement of 24-h
 ambulatory BP, SNA at rest and during handgrip exercise will be repeated in the same fashion.
Inclusion Criteria: (answer must be yes to all to enter trial; check yes or no)

 º ≥ 18 years of age

 º Stage 1 Prehypertension (office BP 120-129/80-84 mmHg and normal ABPM <130/80)

 Exclusion Criteria: (answer must be no to all to enter trial)

 º Diabetes mellitus or other systemic disease

 º Cardiopulmonary disease

 º Treatment with antihypertensive medications

 º eGFR< 60 ml/min/1.73m2

 º Pregnancy

 º Hypersensitivity to nitroprusside or phenylephrine

 º Psychiatric illness

 º H/o substance abuse or current smoker

 º H/o malignancy

 º Serum Phos <2.4 mg/dL or >4.5 mg/dL