Kynurenine Infusion Disrupts Normal Blood Pressure Circadian Rhythms

Abstract

Kynurenine is the first stable product of tryptophan metabolism, and its level increases with age. Elevated kynurenine/tryptophan ratios have been implicated in many aging‐related diseases including chronic kidney disease (CKD). We hypothesized that chronic infusion of kynurenine would induce alterations in renal‐related parameters, such as blood pressure, sodium excretion and glomerular filtration rate (GFR), that could contribute to development of age‐related CKD. In an IACUC‐approved study, three‐month‐old male Sprague Dawley rats were instrumented with aortic and venous catheters, as well as telemeters for blood pressure monitoring, and then housed in metabolic cages for urine collection. Following a five‐day control period, rats received continuous kynurenine infusion (5 mg/kg, 10 mg/kg, 50 mg/kg) or vehicle for 4 weeks. We found that GFR decreased after 2 weeks of KYN treatment [1.29 (n=5) vs. 1.51 (control, n=16) or 1.50 (vehicle, n=3) mL/min p=0.04]. The normal circadian rhythm for blood pressure was disrupted by all doses of kynurenine while heart rate maintained its normal diurnal pattern. Mean arterial pressure in kynurenine‐treated rats tended to increase over time compared to vehicle‐treated. Kynurenine infusion also induced increased water consumption. These data suggest that kynurenine treatment impacts renal function and may contribute to the development of CKD. Non‐dipping blood pressure is a significant risk factor for cardiovascular disease, even in the context of normotension. Further studies will be needed to determine the mechanism of this effect.