SK&F 97426-A: a novel bile acid sequestrant with higher affinities and slower dissociation rates for bile acids in vitro than cholestyramine.

SK&F 97426-A is a novel bile acid sequestrant that is threefold more potent than cholestyramine at increasing bile acid excretion in the hamster. SK&F 97426-A is a quaternary alkylammonium polymethacrylate that was selected for comparison with cholestyramine in vivo because of its superior in vitro bile acid binding properties. Association, dissociation, affinity, and capacity experiments were performed under physiologically relevant conditions with the most abundant bile acids found in human bile. The bile acids came to equilibrium with SK&F 97426-A and cholestyramine within approximately 30 min and 6 min, respectively. SK&F 97426-A and cholestyramine had similar capacities for all the bile acids (between 2.5 and 4 mmol/g) and both had similar, very high affinities and slow dissociation rates for the dihydroxy bile acids. However, SK&F 97426-A had much higher affinities for the trihydroxy bile acids glycocholic acid and taurocholic acid than did cholestyramine. Dissociation of glycocholic acid and taurocholic acid from SK&F 97426-A was also much slower (27 and 25%, respectively, dissociated after 60 min) than from cholestyramine (89 and 84%, respectively, dissociated after 60 min). The higher affinities and slower dissociation rates of the trihydroxy bile acids for and from SK&F 97426-A probably account for the increased potency of SK&F 97426-A over cholestyramine in vivo.

Postprandial lipoprotein metabolism in normolipidemic men with and without coronary artery disease.

A delayed clearance of postprandial lipoproteins from the plasma may play a role in the etiology of premature coronary atherosclerosis. To address this hypothesis, we studied chylomicron (remnant) metabolism in two groups of 20 selected normolipidemic men aged 35-65 years, a group of coronary artery disease (CAD) patients, and a matched control group with documented minimal coronary atherosclerosis. Subjects received an oral fat load supplemented with cholesterol and retinyl palmitate. Plasma samples obtained during the next 24-hour period were analyzed for total as well as d less than 1.019 g/ml and d greater than 1.019 g/ml triacylglycerol, cholesterol, and retinyl ester concentrations. Although both groups of patients responded identically in terms of the appearance of gut-derived lipids in the plasma, CAD patients showed a marked delay in the clearance of retinyl esters as well as in the normalization of plasma triacylglycerol concentrations. Postheparin plasma hepatic lipase activity was significantly lower in the CAD group. Apolipoprotein E phenotype measurements did not reveal marked differences in frequency between both groups. The frequency distribution was not unusual in comparison with the normal Dutch population. The magnitude of the postprandial responses of triacylglycerol and retinyl esters was correlated positively with the fasting levels of plasma triacylglycerol and negatively with high density lipoprotein subfraction 2 cholesterol concentrations. These data indicate that the clearance of postprandial lipoproteins in normolipidemic CAD patients as selected in the present study is delayed as compared with that of controls without coronary atherosclerosis and suggest that postprandial lipoproteins may play a role in the etiology of their disease.

Cholesterol content and heat sensitivity of nine mammalian cell lines.

The cholesterol, phospholipid and protein contents of nine mammalian cell lines, three lymphoid and six attached cell lines, were measured, along with the sensitivity of the cells to hyperthermia at 42 degrees and 44 degrees C. The free cholesterol content and the protein content per cell correlated positively with the time required to kill 99 per cent of the cells at 44 degrees C. The phospholipid content showed a less significant positive correlation whilst the cholesterol ester content and the cholesterol:phospholipid molar ratio did not correlate with heat sensitivity. There were no correlations observed when the levels of these cell components were compared to heat survival at 42 degrees C. As the three lymphoid lines are small, very heat sensitive cells, the six monolayer lines were analysed separately. In this case, only the protein and the free cholesterol content maintained a significant correlation (at the 5 per cent level). It is concluded that the levels of cholesterol or phospholipid cannot be used as reliable indicators of the heat sensitivity of a cell.

Heat-induced thermotolerance expressed in the energy metabolism of mammalian cells.

Measurements were made of the effect of heat treatment on ATP levels in control and thermotolerant populations of murine lymphoma (L5178YS) and Ehrlich ascites cells to investigate whether the development of thermotolerance is associated with an increased ability of cells to maintain energy metabolism when challenged with heat treatment. For the L5178YS cells a single heat treatment produced a rapid reduction in ATP levels. However, previously heat treated L5178YS cells showed an increased ability to maintain ATP levels when challenged with a second heat treatment, and this ability to maintain ATP levels varied in a manner which correlated with the appearance and decay of thermotolerance seen in the parallel cell survival studies. In contrast both single and fractionated heat treatments did not reduce ATP levels in Ehrlich ascites cells.