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Injection (iv) of human urine into rabbits results in a fall in body temperature accompanied by peripheral vasodilation in a thermoneutral ambient temperature and suppression of shivering metabolism in the cold. There were no consistent changes in mean arterial pressure in response to the injection of urine. If the production of urine is prevented by occlusion of the ureters of rabbits, body temperature falls. Injection of endogenous pyrogen (iv) into rabbits, which have had their ureters occluded, results in a significant attenuation in the magnitude of the fever as compared to controls. These observations suggest that there is an endogenously produced cryogenic substance ("endogenous cryogen") normally excreted in an active form by the kidneys and which when either injected, or prevented from being excreted (by clamping the ureters), results in a regulated fall in body temperature. In addition, in human patients on regular dialysis treatment who still had residual renal function, the oral temperature was slightly below normal before hemodialysis and slightly above normal after hemodialysis, a difference averaging 0.39 degrees C (P less than 0.001). These data are in agreement with the hypothesis that endogenous cryogen is a dialyzable substance, and that its concentration is reduced (and therefore the patient's body temperature rises) during hemodialysis.

We studied the mechanism of transepithelial zinc (Zn) transport using monolayers of Caco-2 cells grown on permeable filter supports. 65Zn transport could be fitted to a modified Michaelis-Menten equation, which includes a nonsaturable [linear diffusion constant of nonsaturable component (Kd) = 0.08%.cm-2.90 min-1] and a saturable component [upper well Zn concentration at half Jmax (Kt) = 226 microM and maximal rate of saturable Zn transport (Jmax) = 1.06 nmol.cm-2.90 min-1]. Caco-2 cells contained metal-inducible metallothionein (MT) protein and mRNA as well as mRNA for cysteine-rich intestinal protein (CRIP). Cells pretreated with 10 nM 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] for 3 days transported more Zn (159%) than controls (0.48 +/- 0.02 nmol.cm-2.90 min-1) when each was incubated with 100 microM Zn for 90 min. This effect was significant after 24 h of 1 alpha,25-(OH)2D3 pretreatment and continued to increase up to 72 h, with concomitant increases in MT mRNA levels being observed (4-fold by 24 h, 10-fold by 72 h). MT protein levels were only modestly elevated by 72 h 1 alpha,25(OH)2D3 treatment (from 0.32 +/- 0.04 to 0.45 +/- 0.03 nmol MT/mg protein). CRIP mRNA levels were reduced by 1 alpha,25(OH)2D3 treatment. The lysosome-disrupting agent quinacrine (0.5 mM) inhibited basal Zn transport by 68%, suggesting the possible presence of a lysosome-mediated component for transepithelial Zn transport in Caco-2 cells. 1 alpha,25(OH)2D3-stimulated Zn transport was not affected by quinacrine, suggesting that 1 alpha,25(OH)2D3-induced Zn transport is distinct from the putative lysosome-mediated Zn transport pathway.

Intestinal brush-border-membrane vesicles were prepared from the porcine small bowel by magnesium precipitation and differential centrifugation, and were functionally intact. The influence of dietary ligands on 65Zn uptake was determined using a 65Zn concentration of 5 PM, an incubation time of 1 min and a reaction temperature of 27", with a rapid filtration technique. At this low Zn concentration the addition of an excess of folate, histidine or glucose had no effect on Zn uptake. Addition of picolinate, citrate and phytate to the incubation medium significantly reduced Zn uptake at all concentrations of ligand examined. Any inhibitory effects of folk acid in vivo may thus be due to a mucosal rather than lumen interaction. Those ligands inhibiting absorption may have done so through the formation of Zn-ligand complexes, which are either insoluble, or which reduce the binding of Zn to its mucosal receptor. This in vitro model of Zn absorption is useful for comparing the effects of potential Zn-binding ligands in the diet.

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