The electro-mechanical window in anaesthetized guinea pigs: a new marker in screening for Torsade de Pointes risk.

BACKGROUND AND PURPOSE: QT prolongation is commonly used as a surrogate marker for Torsade de Pointes (TdP) risk of non-cardiovascular drugs. However, use of this indirect marker often leads to misinterpretation of the realistic TdP risk, as tested compounds may cause QT prolongation without evoking TdP in humans. A negative electro-mechanical (E-M) window has recently been proposed as an alternative risk marker for TdP in a canine LQT1 model. Here, we evaluated the E-M window in anaesthetized guinea pigs as a screening marker for TdP in humans. EXPERIMENTAL APPROACH: The effects of various reference drugs and changes in body temperature on the E-M window were assessed in instrumented guinea pigs. The E-M window was defined as the delay between the duration of the electrical (QT interval) and mechanical (QLVP(end) ) systole. KEY RESULTS: Drugs with known TdP liability (quinidine, haloperidol, domperidone, terfenadine, thioridazine and dofetilide), but not those with no TdP risk in humans (salbutamol and diltiazem) consistently decreased the E-M window. Interestingly, drugs with known clinical QT prolongation, but with low risk for TdP (amiodarone, moxifloxacin and ciprofloxacin) did not decrease the E-M window. Furthermore, the E-M window was minimally affected by changes in heart rate or body temperature. CONCLUSIONS AND IMPLICATIONS: A decreased E-M window was consistently observed with drugs already known to have high TdP risk, but not with drugs with low or no TdP risk. These results suggest that the E-M window in anaesthetized guinea pigs is a risk marker for TdP in humans.

Distribution and expression levels of somatostatin and somatostatin receptors in the ileum of normal and acutely Schistosoma mansoni-infected SSTR2 knockout/lacZ knockin mice.

We recently described the widespread expression of somatostatin (SOM) receptors (SSTRs) in the non-inflamed and inflamed murine ileum. Surprisingly, no significant changes were observed in the SSTR2 expression during intestinal inflammation. These data, combined with several recent independent lines of investigation, raised some question about the long presumed central role of SSTR2 in the SOM-mediated effects in the physiological and pathological activity of the gastrointestinal (GI) tract. To further unravel the role of SSTR2 in GI physiology, we studied the expression of SOM and SSTRs in the normal and inflamed SSTR2 knockout/lacZ knockin (SSTR2(-/-)) ileum. The SSTR2(-/-) ileum was characterized by a widespread distribution of multiple SSTR subtypes in non-inflamed and inflamed conditions. Moreover, the absence of SSTR2 did not induce any compensatory effect in the distribution pattern or expression level of any of the other SSTR subtypes. In contrast, the amount of SOM mRNA was significantly lower in SSTR2(-/-) ileum than that in wild type animals. Quantitative analysis revealed a decreased number of SOM-expressing neurons in both enteric plexuses of the knockout animals, implying a possible link between the number of SOM-expressing enteric neurons and the expression of SSTR2 in the enteric nervous system. In conclusion, these data show that a reconsideration of the role of SSTR2 in the GI somatostatinergic effects is in order and further corroborate recent data on the role of other SSTR subtypes in the inflammatory effects of SOM during intestinal inflammation.

Effect of intestinal inflammation on the cell-specific expression of somatostatin receptor subtypes in the murine ileum.

Despite our knowledge of somatostatin (SOM) in gastrointestinal functions, little information is available on the SOM receptors (SSTRs) mediating these effects. This study focussed on the expression of SSTRs in non-inflamed and Schistosoma mansoni-infected murine ileum using immunocytochemistry, reverse transcriptase (RT)-PCR and quantitative real time RT-PCR (qPCR). In the non-inflamed ileum, SSTRs showed a widespread, cell-type specific expression pattern. For instance, SSTR2A immunoreactivity was detected in a minor population of submucous but not myenteric glial cells. In the inflamed ileum, significant changes in the expression pattern of SSTRs occurred, with SSTR1 and SSTR3 expression on mucosal mast cells (MMCs) and mucosal nerve fibres. SSTR4-immunoreactive nerve fibres were detected in granulomas and the lamina propria. qPCR experiments indicated significantly increased mRNA levels for SOM, SSTR1 and SSTR3 in inflamed ileum. This study reveals that SSTRs are expressed in specific cell types in murine ileum. Expression of SSTR1 and SSTR3 on MMCs and increased density of SOM-expressing nerve fibres in the lamina propria during inflammation, support the hypothesis that SOM is implicated in the physiological control of MMCs during intestinal inflammation. Evidence is provided that in mouse mainly SSTR1, SSTR3 and SSTR4 are involved in the somatostatinergic inflammatory effects during intestinal schistosomiasis.