Diurnal rhythms of bile acid synthesis were studied in Sprague-Dawley rats maintained in 12 h of illumination and 12 h of darkness each day. Synthesis, measured as output from a chronic bile fistula, underwent a consistent diurnal change with an amplitude of about 20% around mean daily synthesis and a peak in the dark period. The peak in cholate synthesis preceded the peak in chenodeoxycholate synthesis which preceded the peak in alpha-muricholate synthesis which preceded the peak in beta-muricholate synthesis. Fasting, intravenous infusion of dexamethasone (100 microgram/kg . h), adrenalectomy, and ocular enucleation all failed to abolish the diurnal rhythm in synthesis. In one rat studied 30 days after ocular enucleation the diurnal rhythm in synthesis persisted; however, relative to 4 days after enucleation the phase of the rhythm shifted about 90 degrees suggesting that light deprivation caused the rhythm to become free-running with a period slightly different from 24 h.
A B S T R A C T Bile salts disrupt a functional "gastric mucosal barrier" increasing net forward-diffusion (+) of Na+ and back-diffusion (-) of H+. Studying canine Heidenhain pouches, we attempted to distinguish between two possible mechanisms for this effect: (a) mucosal uptake ofbile salt with subsequent cellular injury or (b ) dissolution ofmucosal lipids by intralumenal bile salt. A 10 mM mixture of six conjugated bile salts simulating the proportions found in human bile induced net Na+ flux of 15.5+3.2 and net H+ flux of -9.9±3.3 ,ueq/min. This change was accompanied by an increase in phospholipid efflux out ofgastric mucosa from a base-line value of 13.2+2.7 to 54.8+2.8 nmol/min (P < 0.001) and an increase in cholesterol efflux from 11.7+3.8 to 36.3+3.2 nmol/min (P< 0.001). Saturation with lecithin (25 mM) and cholesterol (50 mM) blocked disruption of the gastric mucosal barrier by bile salt (Na+ flux -1.2+±0.9, H+ flux 0.6±1.8 ,ueq/min). A 10 mM solution of taurodehydrocholate, a bile salt that does not form micelles, induced no net Na+ (-0.3 +0.8) or H+ flux (-0.7+1.4) and did not increase efflux of phospholipid (11.3+1.7) or cholesterol (10.4+2.0) over base line. Bile salt was absorbed from the mixture of six conjugates at 752±+85 nmol/min. Addition of subsaturation amounts of lecithin (4 mM) reduced bile salt absorption threefold to 252±+57 (P < 0.001), but abnormal Na+ flux (14.1+3.4) and H+ flux (-15.6±3.5) persisted. Taurodehydrocholate was absorbed to an intermediate extent (467 + 116). Dissolution ofmucosal lipids is apparently the mechanism by which bile salt disrupts the gastric mucosal barrier, and presumably at least one mechanism by which bile salt can injure the gastric mucosa.
The present study was undertaken to assess the mechanism by which protonated taurocholic acid disrupts the gastric mucosal barrier. By the criterion of lecithin solubilization, the critical micellar concentration of taurocholic acid (pH 1) was 4.5 mM, as opposed to 3.0 mM for sodium taurocholate (pH 7). In canine Heidenhain pouches, taurocholic acid significantly increased net forward diffusion of Na+ and backdiffusion of H+ at concentrations of 9, 4.5, and 3.5 mM, indicating that micelle formation was not required for disruption of the gastric mucosal barrier by this bile acid. Saturation of the 9 mM taurocholic acid solution with lecithin (and cholesterol) did not prevent disruption of the gastric mucosal barrier. At 9 mM, taurocholic acid was absorbed from the pouches at a mean rate of 1,150 +/- 115 nmol/min in contrast to an absorption rate of 225 +/- 10 nmol/min for sodium taurocholate at the same concentration. These findings indicate that, unlike ionized bile salts, disruption of the gastric mucosal barrier by taurocholic acid is mediated largely by uptake of bile acid by the gastric mucosa rather than dissolution of mucosal membrane lipids.
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