T. Krause

Meperidine exerts agonist activity at the α2B-adrenoceptor subtype

Background The opioid agonist meperidine has actions, such as antishivering, that are more pronounced than those of other opioid agonists and that are not blocked with nonselective opioid antagonists. Agonists at the &agr;2 adrenoceptors, such as clonidine, are very effective antishivering drugs. Preliminary evidence also indicates that meperidine interacts with &agr;2 adrenoceptors. The authors therefore studied the ability of meperidine to bind and activate each of the &agr;2-adrenoceptor subtypes in a transfected cell system. Methods The ability of meperidine to bind to and inhibit forskolin-stimulated cyclic adenosine monophosphate formation as mediated by the three &agr;2-adrenoceptor subtypes transiently transfected into COS-7 cells has been tested. The ability of the opioid antagonist naloxone and the &agr;2-adrenoceptor antagonists yohimbine and RX821002 to block the analgesic action of meperidine in the hot-plate test was also assessed. The ability of meperidine to fit into the &agr;2B adrenoceptor was assessed using molecular modeling techniques. Results Meperidine bound to all &agr;2-adrenoceptor subtypes, with &agr;2B having the highest affinity (&agr;2B, 8.6 ± 0.3 &mgr;m; &agr;2C, 13.6 ± 1.5 &mgr;m, P < 0.05; &agr;2A, 38.6 ± 0.7 &mgr;m). Morphine was ineffective at binding to any of the receptor subtypes. Meperidine inhibited the production of forskolin-stimulated cyclic adenosine monophosphate mediated by all receptor subtypes but was most effective at the &agr;2B adrenoceptor (&agr;2B, 0.6 &mgr;m; &agr;2A, 1.3 mm; &agr;2C, 0.3 mm), reaching the same level of inhibition (approximately 70%) as achieved with the &agr;2-adrenoceptor agonist dexmedetomidine. The analgesic action of meperidine was blocked by naloxone but not by the &agr;2-adrenoceptor antagonists yohimbine and RX821002. The modeling studies demonstrated that meperidine can fit into the &agr;2B-adrenoceptor subtype. Conclusion Meperidine is a potent agonist at the &agr;2 adrenoceptors at its clinically relevant concentrations, especially at the &agr;2B-adrenoceptor subtype. Activation of the &agr;2B receptor does not contribute significantly to the analgesic action of meperidine. This raises the possibility that some of its actions, such as antishivering, are transduced by this mechanism.

Hydroxyethyl Starch (HES 130/0.4) Impairs Intestinal Barrier Integrity and Metabolic Function: Findings from a Mouse Model of the Isolated Perfused Small Intestine

Background The application of hydroxyethyl starch (HES) for volume resuscitation is controversially discussed and clinical studies have suggested adverse effects of HES substitution, leading to increased patient mortality. Although, the intestine is of high clinical relevance and plays a crucial role in sepsis and inflammation, information about the effects of HES on intestinal function and barrier integrity is very scarce. We therefore evaluated the effects of clinically relevant concentrations of HES on intestinal function and barrier integrity employing an isolated perfused model of the mouse small intestine. Methods An isolated perfused model of the mouse small intestine was established and intestines were vascularly perfused with a modified Krebs-Henseleit buffer containing 3% Albumin (N=7) or 3% HES (130/0.4; N=7). Intestinal metabolic function (galactose uptake, lactate-to-pyruvate ratio), edema formation (wet-to-dry weight ratio), morphology (histological and electron microscopical analysis), fluid shifts within the vascular, lymphatic and luminal compartments, as well as endothelial and epithelial barrier permeability (FITC-dextran translocation) were evaluated in both groups. Results Compared to the Albumin group, HES perfusion did not significantly change the wet-to-dry weight ratio and lactate-to-pyruvate ratio. However, perfusing the small intestine with 3% HES resulted in a significant loss of vascular fluid (p<0.01), an increased fluid accumulation in the intestinal lumen (p<0.001), an enhanced translocation of FITC-dextran from the vascular to the luminal compartment (p<0.001) and a significantly impaired intestinal galactose uptake (p<0.001). Morphologically, these findings were associated with an aggregation of intracellular vacuoles within the intestinal epithelial cells and enlarged intercellular spaces. Conclusion A vascular perfusion with 3% HES impairs the endothelial and epithelial barrier integrity as well as metabolic function of the small intestine.