Human cells acquire vitamin C using two different transporter systems, the sodium-ascorbic acid co-transporters with specificity for ascorbic acid, and the facilitative glucose transporters with specificity for dehydroascorbic acid. There is no information on the mechanism of vitamin C transport across the intestinal barrier, a step that determines the bioavailability of vitamin C in humans. We used the colon carcinoma cell line CaCo-2 as an in vitro model for vitamin C transport in enterocyte-like cells. The results of transport kinetics, sodium dependence, inhibition studies, and reverse transcriptase-PCR analysis indicated that CaCo-2 cells express the sodium-ascorbate co-transporters SVCT1 and SVCT2, the dehydroascorbic acid transporters GLUT1 and GLUT3, and a third dehydroascorbic acid transporter with properties expected for GLUT2. Analysis by real time quantitative PCR revealed that the post-confluent differentiation of CaCo-2 cells was accompanied by a marked increase (4-fold) in the steadystate level of SVCT1 mRNA, without changes in SVCT2 mRNA levels. Functional studies revealed that the differentiated cells expressed only one functional ascorbic acid transporter having properties expected for SVCT1, and transported ascorbic acid with a V max that was increased at least 2-fold compared with pre-confluent cells. Moreover, post-confluent Caco-2 cells growing as monolayers in permeable filter inserts showed selective sorting of SVCT1 to the apical membrane compartment, without functional evidence for the expression of SVCT2. The identification of SVCT1 as the transporter that allows vectorial uptake of ascorbic acid in differentiated CaCo-2 cells has a direct impact on our understanding of the mechanism for vitamin C transport across the intestinal barrier.

Thirteen healthy subjects (11 men and 2 women; 30.2 +/- 5.4 yr; 73.5 +/- 10.3 kg; 178.9 +/- 10.4 cm; body mass index, 22.9 +/- 1.6 kg/m2) participated at the 62-day expedition to the Broad Peak (8,047 m), Pakistan. Weight, body water, and water turnover (deuterium dilution and elimination) were measured eight times to assess long-term changes. Body weight fell during the ascent to the base camp [from 73.2 +/- 9.8 (baseline) to 71.7 +/- 9.7 kg; P < 0.05] and decreased until the end of the base camp stay (66.7 +/- 7.2 kg; P < 0.0001). Body compartments changed at different rates. Total body water decreased during the ascent (from 43.1 +/- 7.3 to 41.0 +/- 7.7 liters; P < 0.05) and remained unchanged until the base camp was reached (41.2 +/- 6.9 liters; P < 0.01) but decreased further during the base camp stay (40.6 +/- 5.2 liters). Water content of the body (total body water-to-body weight ratio) fell during the ascent (from 58.6 +/- 3.4 to 55.8 +/- 4.4%; P < 0.01), approached the baseline value during the base camp (57.4 +/- 4.0 and 58.3 +/- 5.1%), and increased again until the end of the base camp (60.6 +/- 3.4 and 60.9 +/- 4.3%). The compartment of the solids increased during the ascent (from 30.2 +/- 3.4 to 32.2 +/- 4.9 kg; P < 0.01) and approached the baseline value on arrival at the base camp (30.5 +/- 4.7 kg). Until the end of the base camp, the compartment of the solids fell (26.9 +/- 2.6 and 26.1 +/- 4.0 kg), indicating that weight loss was due to a loss of body solids, presumably mostly fat mass. Water turnover during the pretest period (sea level) was 45 +/- 7 ml.kg-1.day-1; it increased during the ascent (56 +/- 11 and 60 +/- 10 ml.kg-1.day-1) but remained constant during the base camp stay (63 +/- 12, 58 +/- 9, and 56 +/- 10 ml.kg-1.day-1). It increased during the ascent to Broad Peak (73 +/- 20 ml.kg-1.day-1; P < 0.05) and even more during the descent to civilization (83 +/- 17 ml.kg-1.day-1; P < 0.05).

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These data suggest that the endothelin production is markedly increased in smooth muscle cells of coronary atherosclerotic plaques. The enhanced endothelin release may stimulate smooth muscle cell proliferation in a paracrine or autocrine manner and thus may contribute to the development or progression of coronary artery disease.

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