British journal of pharmacology
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Comparative Study
Interactions of metoclopramide and ergotamine with human 5-HT(3A) receptors and human 5-HT reuptake carriers.
The actions of metoclopramide and ergotamine, drugs which are used as a combined migraine medication, on human (h)5-HT3A receptors and 5-HT reuptake carriers, stably expressed in HEK-293 cells, were studied with patch-clamp- and ([3H]5-HT)-uptake techniques. At clinical concentrations, metoclopramide inhibited peak and integrated currents through h5-HT3A receptors concentration-dependently (IC50 = 0.064 and 0.076 microM, respectively) when it was applied in equilibrium (60 s before and during 5-HT (30 microM) exposure). The onset and offset time constants of metoclopramide action were 1.3 and 2.1 s, respectively. ⋯ Above clinical concentrations, ergotamine (>3 microM) inhibited them. When both drugs were applied together (0.10 microM metoclopramide +0.001 to 0.01 microM ergotamine), an inhibition of both, peak and integrated current responses was observed. Neither metoclopramide (< or =30 microM) nor ergotamine (< or =30 microM) had an effect on the 5-HT reuptake carrier as they did not alter the citalopram-sensitive [3H]5-HT uptake.
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Hydrogen sulfide (H2S) is a naturally occurring gaseous transmitter, which may play important roles in normal physiology and disease. Here, we investigated the role of H2S in the organ injury caused by severe endotoxemia in the rat. Male Wistar rats were subjected to acute endotoxemia (Escherichia coli lipopolysaccharide (LPS) 6 mg kg(-1) intravenously (i.v.) for 6 h) and treated with vehicle (saline, 1 ml kg(-1) i.v.) or DL-propargylglycine (PAG, 10-100 mg kg(-1) i.v.), an inhibitor of the H2S-synthesizing enzyme cystathionine-gamma-lyase (CSE). ⋯ Pretreatment of rats with PAG abolished the LPS-induced increase in the MPO activity and in the formation of H2S and in the liver. These findings support the view that an enhanced formation of H2S contributes to the pathophysiology of the organ injury in endotoxemia. We propose that inhibition of H2S synthesis may be a useful therapeutic strategy against the organ injury associated with sepsis and shock.