Reduced blood flow increases the in vivo ammonium ion concentration in the RIF-1 tumor

Abstract

Previous studies from our laboratory have suggested that pooling of ammonium in tumor tissues may be caused by its inefficient removal due to the poor vasculature commonly found in tumors. The purpose of these experiments was to validate the relationship between tumor ammonium ion concentration and tumor blood flow, and to determine whether large concentrations of ammonium ion detected by Nuclear Magnetic Resonance (NMR) spectroscopy are either produced within the tumor or simply imported into the tumor through the blood stream. To test this hypothesis, we reduced blood flow in subcutaneously grown Radiation Induced Fibrosarcoma-1 (RIF-1) tumors, either by creating partial ischemia with a bolus injection of hydralazine or by occlusion with surgical sutures. 14N and 31P NMR spectroscopy were used to detect the presence of ammonium, and to assess the bioenergetic status of the tumors, respectively. A correlation between ammonium ion concentration and PCr/Pi ratio was established for untreated tumors. An increase in the in vivo tumor ammonium ion concentration was observed for every tumor that experienced a reduction in blood flow caused by either hydralazine injection or suture ligation. Changes in ammonium ion concentration paralleled changes in the bioenergetics of hydralazine-treated tumors. Our results support the hypothesis that a reduction in tumor blood flow is responsible for the accumulation of ammonium in tumors, and that detected ammonium originated from within the tumor.