Abstract: Treatment with carbamazepine (CBZ) affects cholesterol concentrations, but little is known about the precise nature and underlying mechanisms of changes in lipoprotein metabolism. We investigated prospectively the effects of CBZ on lipid metabolism in normolipemic adults. In 21 healthy males, lipoprotein and noncholesterol sterol concentrations were measured before and during treatment with CBZ for 70 +/- 18 days. Thirteen subjects underwent kinetic studies of apolipoprotein-B (ApoB) metabolism with the use of endogenous stable isotope labeling. Lipoprotein kinetic parameters were calculated by multicompartmental modeling. Significant increases in total cholesterol, in ApoB-containing lipoproteins [very-low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low-density lipoprotein (LDL)], and in triglycerides, but not in high-density lipoprotein (HDL), were observed. Lipoprotein particle composition remained unchanged. Mean fractional catabolic and production rates of ApoB-containing lipoproteins were not significantly different, although mean production rates of VLDL and IDL were substantially increased (+46 +/- 139% and +30 +/- 97%, respectively), whereas mean production of LDL remained unchanged (+2.1 +/- 45.6%). Cholestanol in serum increased significantly but not the concentrations of plant sterols (campesterol, sitosterol) and the cholesterol precursors (lathosterol, mevalonic acid). There was a significant correlation between the decrease in free thyroxine and the increase in IDL cholesterol. Treatment with CBZ increases mainly ApoB-containing lipoproteins. CBZ seems not to influence endogenous cholesterol synthesis or intestinal absorption directly. The increase is neither related to increased ApoB production nor to decreased catabolism but is rather due to changes in the conversion cascade of IDL particles, most likely as an indirect effect through a decrease in thyroid hormones.
Abstract: BACKGROUND: Application of pyruvate was shown to improve contractile function in isolated animal myocardium and hemodynamics in patients with congestive heart failure. We assessed the influence of pyruvate on systolic and diastolic myocardial function and its subcellular mode of action in isolated myocardium from end-stage failing human hearts. METHODS AND RESULTS: In muscle strip preparations, concentration-dependent effects of pyruvate on developed and diastolic force (n=6), aequorin light emission reflecting intracellular Ca(2+) transients (n=6), and rapid cooling contractures reflecting sarcoplasmic reticulum (SR) Ca(2+) content (n=11) were measured. Pyruvate resulted in a concentration-dependent increase in developed force and a decrease in diastolic force, with a maximum effect of 155% and 21%, respectively, at 20 mmol/L pyruvate (P<0.05). This was associated with a dose-dependent prolongation of time to peak tension and relaxation time. Pyruvate increased rapid cooling contractures by 51% and aequorin light signals by 85% (at 15 and 20 mmol/L; P<0.05). This indicates increased SR Ca(2+) content and increased intracellular Ca(2+) transients. The inotropic effect of pyruvate was still present after elimination of SR Ca(2+) storage function with 10 micromol/L cyclopiazonic acid and 1 micromol/L ryanodine (n=8). Pyruvate significantly increased intracellular pH from 7.31+/-0.03 to 7.40+/-0.04 by BCECF fluorescence (n=6). CONCLUSIONS: The present findings indicate that pyruvate improves contractile performance of failing human myocardium by increasing intracellular Ca(2+) transients as well as myofilament Ca(2+) sensitivity. The former seem to result from increased SR Ca(2+) accumulation and release, the latter from increased intracellular pH.
Abstract: BACKGROUND: Recently identified ABCG5/8 transporters are responsible in part for the different absorption rates of campesterol, sitosterol, and cholesterol. These transporters are also expressed in the liver and might regulate biliary sterol secretion. AIMS: This study was therefore conducted to determine the biliary secretion rates and hepatic clearances of campesterol, sitosterol, and cholesterol. SUBJECTS: Six healthy, male volunteers. METHODS: Deuterium labelled sitosterol and campesterol, and unlabelled sitostanol were constantly infused together with a liquid formula using a duodenal perfusion technique. Biliary secretion and hepatic clearance rates were calculated from hourly bile and plasma samples. RESULTS: Plasma concentrations of cholesterol, campesterol, and sitosterol averaged 167.5 (50) mg/dl (SD), 0.50 (0.22) mg/dl, and 0.30 (0.10) mg/dl, respectively. Sitosterol showed a significantly higher biliary secretion rate (1.23 (0.87) mg/h) than campesterol (0.76 (0.54) mg/h, p=0.0321), but both plant sterols had significantly lower biliary secretion rates compared with cholesterol (47.7 (17.5) mg/h; p=0.001 for both). Hepatic clearance of cholesterol (0.31 (0.18) dl/h) was significantly lower compared with campesterol (2.11 (2.51) dl/h) and sitosterol (4.97 (4.70) dl/h; p=0.028 for both), and the clearance of campesterol was significant lower compared with sitosterol (p=0.028). CONCLUSION: The observed inverse relation between hepatic clearance and known intestinal absorption of cholesterol, campesterol, and sitosterol supports the hypothesis that the ABCG5/8 transporters regulating intestinal sterol absorption might also be involved in biliary sterol excretion.
Abstract: OBJECTIVE: The gastrointestinal peptides neuropeptide Y (NPY), peptide YY (PYY), pancreatic polypeptide (PP), substance P (SP), cholecystokinin (CCK) and gastric inhibitory polypeptide (GIP) are released into the portal vein mainly during the absorptive phase. Their direct actions and their hormone modulatory effects on liver carbohydrate metabolism were investigated. METHODS: Isolated rat liver, single-pass-perfused via both the hepatic artery (120 cm H2O, 30% flow) and the portal vein (20 cm H2O, 70% flow) with a Krebs-Henseleit buffer containing 5 mM glucose, 2 mM lactate and 0.2 mM pyruvate, NPY (5 nM), PYY (5 nM), PP (5 nM), SP (100 nM), CCK (100 nM) and GIP (10 nM) was infused for 10 min via either vessel. In additional experiments, insulin (100 nM), glucagon (1 nM) or noradrenaline (1 microM) were applied for 5 min via the portal vein during a 20 min portovenous infusion of one of the peptides. RESULTS: Under basal conditions, neither arterial nor portal NPY, PYY, PP, SP, CCK or GIP modified hepatic glucose and lactate metabolism. Also, none of the peptides enabled an action of portal insulin in the normally insulin-insensitive isolated perfused rat liver. NPY and PYY, but not PP, SP, CCK or GIP, inhibited the increase in glucose release by glucagon and noradrenaline. Under basal conditions, none of the peptides altered hepatic flow. Only portal NPY and PYY enhanced slightly the noradrenaline-dependent reduction of portal flow. CONCLUSIONS: NPY, PYY, PP, SP, CCK and GIP do not act directly as regulators of basal hepatic carbohydrate metabolism. NPY and PYY act as signal factors of the absorptive phase function as antagonists of the postabsorptive glucose regulatory hormones glucagon and noradrenaline.
Abstract: The hepatic metabolism of lidocaine (1 mg/kg intravenously) to its metabolite monoethylglycinexylidide (MEG-X) is the basis of the standard MEG-X test. To reduce the lidocaine-induced side effects, we evaluated the MEG-X formation after 0.5 and 1 mg/kg lidocaine intravenously in subjects with normal (n = 5) and severely impaired liver function (n = 7) (study I). From this study, a low-dose test (MEG-X concentration 30 minutes after 50 mg lidocaine intravenously [MEG-X30min] normalized to standard MEG-X test results) was developed. Sensory side effects from this low dose and from the standard MEG-X test were compared in a double-blind, randomized, cross-over study (study II) comprising 15 individuals with normal liver function and 45 patients with cirrhosis (15 Child A, 15 Child B, and 15 Child C). In study I, MEG-X formation rate was dose-independent in patients with severely impaired liver function. In study II, normalized MEG-X test results (ranging from < or = 4 to 120 microg/L) were virtually identical to the standard test results (mean difference: -1.9 microg/L; 95% confidence interval [CI]: -5.3; 1.5 microg/L). Fewer individuals experienced side effects (30% vs. 53%) with the low-dose test (P = .0013). In a multivariate analysis, the Child-Pugh score was inversely related to the occurrence of side effects. The low-dose MEG-X test gives almost identical results to the standard MEG-X test and is associated with fewer side effects, which occur less often in individuals with more severely compromised liver function.
