Thermal sensitivity and activation energy of intrinsic intestinal motility in small vertebrates

1. 1.|In vitro thermal sensitivity (t.s.) of mammalian small intestine is significantly greater than t.s. of the gut of ectothermic vertebrates. In vitro contraction frequency (c.f.) of endothermic gut is an order of magnitude greater than ectothermic gut at equivalent temperatures.2. 2.|Gut contraction t.s. is generally consistent within a given order of mammals and differs between orders. Differences in gut contraction t.s. found in the ectothermic vertebrates do not relate to taxonomic grouping.3. 3.|An inverse relationship exists between gut c.f. and body weight in ectotherms and also probably in mammals. This relationship is seen within an individual species rather than among species.4. 4.|Secondary intrinsic contractions occur regularly in gut of ectotherms and much less frequently in mammalian gut. In ectothermic vertebrates, these thermally sensitive gut contractions are often at higher frequency than major contractions at high gut temperatures but cease at the same minimum temperatures.5. 5.|Unlike all other species tested, fish (bullheads, I. nebulosus) gut contractions were not rhythmic although they were thermally sensitive.6. 6.|Activation energies for thermally sensitive gut contractions in mammals are consistent with most values rangign from 14.5-18.5 Kcal/M while activation energies for secondary contractions were much more variable with a range of 4.4-29.0 Kcal/M.7. 7.|In laboratory mice, c.f. and c. amplitude are unaffected by pH in any biologically significant manner. Additionally, t.s. of neonatal (4-24 days old) lab mice are indicative of endotherms and are only slightly lower than adult levels 4 days after birth.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22943/1/0000510.pd

Effect of temperature on intrinsic intestinal motility in a hibernator

In vitro lowering and raising of the temperature of the initial segment of the small intestine of a homeotherm, the laboratory mouse; Mus musculus, and a hibernator, the big brown bat; Eptesicus fuscus indicate: 1. 1.|A direct relationship exists between frequency of contractions and gut temperature which is essentiallty linear in mice, with contractions ceasing at about 16[deg]C, and is curvilinear in gut segments from hibernationg Eptesicus, with contractions ceasing at about 7[deg]C2. 2.|Amplitude of contractions in both species are generally independent of temperature flux; however, in bat gut contraction amplitude drops to very low levels at low temperatures3. 3.|Relationships to temperature are similar during both cooling and warming of the intestine.4. 4.|Based on motility, the intestine of a hibernator continues to function at a much lower temperature than the gut of a homeotherm.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/21797/1/0000196.pd

Kynurenine–3–monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2 Acute mortality from AP-MODS exceeds 20%3 and for those who survive the initial episode, their lifespan is typically shorter than the general population4. There are no specific therapies available that protect individuals against AP-MODS. Here, we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism5, is central to the pathogenesis of AP-MODS. We created a mouse strain deficient for Kmo with a robust biochemical phenotype that protected against extrapancreatic tissue injury to lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against AP-MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS and open up a new area for drug discovery in critical illness