Vestibular neurons in the rat contain imidazoleacetic acid-ribotide, a putative neurotransmitter involved in blood pressure regulation.

A substantial body of research has led to the recognition that the vestibular system participates in blood pressure modulation during active movements and changes in posture, and that this modulation is effected at least partly by the caudal vestibular nuclei. The I-4 isomer of imidazoleacetic acid-ribotide (IAA-RP) is a putative neurotransmitter/modulator that is thought to be an endogenous regulator of general sympathetic drive, particularly systemic blood pressure. The present study employed immunofluorescence and light and electron microscopic immunocytochemistry to visualize IAA-RP in the vestibular nuclei of adult male rats. The results demonstrate IAA-RP immunolabeling of subpopulations of vestibular neurons in the descending nucleus and the caudal half of the medial nucleus, with scattered immunostained vestibular neurons also present more rostrally. On the basis of double immunofluorescence staining for IAA-RP and calbindin, many of these ribotide-immunoreactive neurons appear to be innervated by cerebellar Purkinje cell afferents. Ultrastructural observations in the caudal vestibular nuclei confirm the IAA-RP immunolocalization in cell bodies and dendritic processes, and in some myelinated axons and presynaptic boutons. The regional distribution of IAA-RP immunoreactivity corresponds to the location of vestibular neurons involved in autonomic functions. The presence of IAA-RP in those neurons suggests that they participate specifically in vestibulo-autonomic regulation of blood pressure. The localization of immunostain in processes and terminals suggests that vestibulo-autonomic activity is subject to local feedback control. Overall, the observations offer a chemoanatomic basis for understanding the vestibular side effects commonly experienced by patients treated with clonidine and other imidazoline-related drugs.

Role of platelet derived endothelial cell growth factor/thymidine phosphorylase in fluoropyrimidine sensitivity and potential role of deoxyribose-1-phosphate.

Thymidine phosphorylase (TP) catalyzes the phosphorolytic cleavage of thymidine (TdR) to thymine and deoxyribose-1-phosphate (dR-1-P). TP, which is overexpressed in a wide variety of solid tumors, is involved in the activation and inactivation of fluoropyrimidines. We investigated the role of TP in 5'-deoxy-5-fluorouridine (5'DFUR), 5-fluorouracil (5FU) and trifluorothymidine (TFT) sensitivity. TP had no effect on TFT while it activated 5'DFUR and to a lesser extent 5FU. In order to provide an explanation for this difference in activation of 5'DFUR and 5FU, we studied the role of the 5FU co-substrate, dR-1-P, needed for its activation.

Role of cellular ribose-5-phosphate content in the regulation of 5-phosphoribosyl-1-pyrophosphate and de novo purine synthesis in a human hepatoma cell line.

5-Phosphoribosyl-1-pyrophosphate (PRPP) is an important regulator of de novo purine synthesis. However, the role of ribose-5-phosphate (R5P), the precursor for PRPP, in the regulation of PRPP and de novo purine synthesis has not yet been clarified conclusively. This study was designed to clarify interrelationships between R5P content, PRPP availability, and the rate of de novo purine synthesis in the cultured human hepatoma cell line (HepG2), a plausible model for normal human hepatocytes. Increasing glucose concentration in the culture media from 0 to 10 mmol/L resulted in a 2.9-fold elevation of cellular R5P content (from 107 +/- 31 to 311 +/- 57 nmol/g protein), associated with a correlated increase of 7.14-fold in cellular PRPP availability (from 4.76 +/- 3.4 to 34 +/- 8.4 pmol/mg protein/min) and of 149-fold in the rate of de novo purine synthesis (from 55 to 8,204 dpm/mg protein/h). Plotting the rate of de novo purine synthesis versus R5P content indicates that at a wide range of R5P content, including that prevailing in hepatocytes under physiological conditions, the rate of purine synthesis depends on R5P content. A similar dependence was also demonstrated for PRPP availability. The rate of de novo purine synthesis exhibited a sigmoidal dependence on PRPP availability. The demonstration in human hepatocytes of dependence of the rate of purine synthesis on R5P content has implications concerning the pathogenesis of purine overproduction associated with several inborn and acquired conditions in man.