Brain monoamine output alterations after a single venlafaxine challenge in experimental hepatic encephalopathy

Venlafaxine (VEN) pharmacokinetics and effects on the brain monoamine output were investigated in the context of experimental hepatic encephalopathy (HE). Systemic VEN (10 mg/kg; subcutaneous) was administered to chronic portacaval shunted (PCS) and sham-operated rats. Their neocortical extracellular levels of 5-HT, 5-HIAA, NA, and DA were then assessed using microdialysis. Serum, brain extracellular, and brain tissue levels of racemic VEN and its main metabolites were also investigated. In a dose-equipotent manner, the VEN challenge increased the 5-HT levels in PCS rats compared with VEN-treated controls, whereas the 5-HIAA levels decreased similarly with time after the challenge in PCS and controls. Brain extracellular NA levels increased similarly in PCS and controls after VEN, but DA increased predominantly in controls. A similar single dose challenge resulted in clearly higher VEN levels in serum, brain extracellular fluid, and brain tissue in the PCS rats compared with controls. However, the VEN brain tissue/serum ratios were in the same order of magnitude for the two groups. Of the main VEN metabolites, only O-desmethylvenlafaxine (ODV) could be detected in pharmacologically significant amounts. The ODV concentration was also elevated in all three investigated biomatrices of the PCS rats versus control rats. The authors concluded that a typical novel brain monoamine-acting drug, such as VEN, exhibits both pharmacokinetic and pharmacodynamic alterations in experimental HE. Accordingly, the results of this study suggest that this frequently used type of drug should be further studied for its potential combined kinetic/dynamic actions in compromised patients with liver impairment.     

Pasteurella multocida toxin is a mitogen for bone cells in primary culture

The effect of recombinant Pasteurella multocida toxin (PMT) on primary cultures of embryonic chick bone-derived osteoblastic cells was investigated. It was found that PMT was a potent mitogen for primary derived chicken osteoblasts. The toxin stimulated DNA synthesis and cell proliferation in quiescent osteoblasts at the first passage and accelerated cell growth in subconfluent cultures. Cell viability was not affected by PMT, even at relatively high concentrations. Osteoblast numbers increased in a dose-dependent manner in response to PMT. Intracellular inositol phosphates were elevated in response to PMT, but no elevation in cyclic AMP (cAMP) levels was evident. Indeed, PMT inhibited cAMP elevation in osteoblasts in response to cholera toxin at a stage before other PMT-mediated events take place. In addition to increased cell turnover, PMT down-regulated the expression of several markers of osteoblast differentiation. Both alkaline phosphatase and type I collagen were reduced, but osteonectin was not affected. The in vitro deposition of mineral in cultures of primary osteoblasts and osteoblast-like osteosarcoma cells was also inhibited by the presence of PMT. This suggests that PMT interferes with differentiation at a preosteoblastic stage.     

Differential effects of nerve impulses on adrenergic storage vesicles in rat heart

The effects of increasing and decreasing activity in sympathetic neurons on light (D420 = 1.05) and heavy (D420 = 1.15) populations of adrenergic vesicles have been determined. Norepinephrine (NE) was used as a marker for the soluble contents of the vesicles, and dopamine beta-hydroxylase was used as a marker for the vesicle membranes. Cold exposure was used to increase activity in the sympathetic nervous system. A 40% decrease in the NE content of the rat heart with no change in the activity of dopamine beta-hydroxylase was observed after 70 minutes at 5 degrees C. The fall in NE content was completely blocked by pretreating the animals with chlorisondamine. Separation of light and heavy populations of vesicles was achieved with linear sucrose density gradients. Cold stress of 70 minutes duration led to a marked decrease in the NE content of the light vesicles. Blocking adrenergic nerve impulses with chlorisondamine resulted in an increase in total NE in the heart but had no effect on dopamine beta-hydroxylase activity. The initial effect of chlorisondamine was to increase the NE content of the light vesicles. The administration of alpha-methyl-p-tyrosine for 6 hours caused an approximately equal loss of NE from both vesicle populations. The decrease in total heart NE was about 25% and could be prevented by pretreating the animals with chlorisondamine. These results suggest that the light vesicle fraction is involved in the rapid or short-term responses to changes in nerve impulse frequency. Changes in the NE content of the heavy vesicles in rat heart were seen only after longer times, suggesting that these particles may function only as auxiliary storage sites for the neurotransmitter.