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After RYGB, fasting insulin decreases to levels like those of lean control subjects and diabetes is reversed (fasting blood glucose < 125 mg/dl). This leads us to propose that 1) exclusion of food from the foregut corrects hyperinsulinemia and 2) fasting insulin is dissociated from the influence of fasting glucose, insulin resistance, and BMI. The mechanisms for reversal of diabetes in the face of reduced insulin remain a paradox.

The hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) enzymes represent novel targets for the treatment of anemia, ulcerative colitis, and ischemic and metabolic disease inter alia. We have identified a novel small-molecule inhibitor of PHD, 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), through structurebased drug design methods. The pharmacology of JNJ-42041935 was investigated in enzyme, cellular, and wholeanimal systems and was compared with other compounds described in the literature as PHD inhibitors. JNJ-42041935, was a potent (pK I ϭ 7.3-7.9), 2-oxoglutarate competitive, reversible, and selective inhibitor of PHD enzymes. In addition, JNJ-42041935 was used to compare the effect of selective inhibition of PHD to intermittent, high doses (50 g/kg i.p.) of an exogenous erythropoietin receptor agonist in an inflammationinduced anemia model in rats. JNJ-42041935 (100 mol/kg, once a day for 14 days) was effective in reversing inflammationinduced anemia, whereas erythropoietin had no effect. The results demonstrate that JNJ-42041935 is a new pharmacological tool, which can be used to investigate PHD inhibition and demonstrate that PHD inhibitors offer great promise for the treatment of inflammation-induced anemia.

1 Asthma research is arguably limited by an absence of appropriate animal models to study the pharmacology of in¯ammatory mediators that a ect airway hyperresponsiveness and remodelling. Here we assessed an assay based on mouse tracheal segments cultured for 1 ± 32 days, and investigated contractile responses mediated by muscarinic and 5-hydroxytryptamine (5-HT) receptors following long-term exposure to tumour necrosis factor-alpha (TNFa). 2 Following culture, in the absence of TNFa, maximum contractile responses to KCl and carbachol were similar, with an increase in response up to day two and a decrease to a stable level after 8 days. Maximal relaxations to isoprenaline were not a ected by the culture procedure. The potency of KCl and isoprenaline increased throughout the study. DNA microarray data revealed that global gene expression changes were greater when tissues were introduced to culture than when they were maintained in culture. The morphology of smooth muscle cells was maintained throughout the culture period. 3 5-HT induced a weak contraction in both fresh and cultured (up to 8 days) segments. Culture with TNFa produced a time-and concentration-dependent increase in the maximal contraction to 5-HT, evidently mediated by 5-HT 2A receptors, whereas, the potency for carbachol was reduced. 4 In conclusion, the phenotype of airway smooth muscle remained largely intact during the culture period, even though minor changes were obtained during the ®rst days of culture. The timedependent e ect of TNFa indicates the importance of studying the long-term e ect of cytokines on the smooth muscle cells in relation to airway hyperresponsiveness and remodelling.

4 The pKB values estimated on the gastric assay were lower than those on the atrial assay. However, the difference between the values on the gastric and atrial assays was not constant. The difference between the two assays for famotidine was not significant. 5 We conclude that the apparent varying selectivity ofthe antagonists for gastric and atrial histamine H2-receptors may be explained by the differential loss of antagonists into the gastric secretion from the receptor compartment and that there is no need to postulate heterogeneity of histamine H2-receptors.

HIF prolyl 4-hydroxylases (PHD) are a family of enzymes that mediate key physiological responses to hypoxia by modulating the levels of hypoxia inducible factor 1-R (HIF1R). Certain benzimidazole-2-pyrazole carboxylates were discovered to be PHD2 inhibitors using ligand-and structure-based methods and found to be potent, orally efficacious stimulators of erythropoietin secretion in vivo.

Although oxyntic cell secretion can be studied at many organisation levels between isolated cell suspensions and non‐invasive techniques in animals, the isolated, lumen‐perfused, stomach preparation of the mouse represents a hierarchical level which eliminates extrinsic regulatory influences but retains all the cellular architecture known to be necessary for physiological responses and so can be defined as the physiological unit of acid secretion. The feeding pattern before and the distending pressure during an experiment have been identified as the main determinants of basal secretion: the combination of an intragastric pressure of 12 cmH2O and the fasted state generated a stable basal secretion over 2 h providing a satisfactory basis for bioassays. Basal acid secretion was lowered by treatment with omeprazole and sodium thiocyanate but not with tetrodotoxin, N‐methylatropine or tiotidine, suggesting that basal secretion does not involve nervous stimulation or the local release of histamine under these experimental conditions. The improved assay permitted the full characterization of cumulative agonist concentration‐effect curves in single stomach preparations to histamine, 5‐methylfurmethide, pentagastrin and isobutylmethylxanthine. Interestingly, pentagastrin produced sustained stimulation of gastric acid secretion under conditions when there was no pharmacological evidence that histamine secretion was taking place. This finding is discussed in relation to the role of histamine in the control of gastric acid secretion.

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