European journal of pharmacology
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Na(+)-H(+) exchanger activation on resuscitation following hemorrhagic shock has been shown to result in myocardial injury and dysfunction. Amiloride, an inhibitor of the Na(+)-H(+) exchanger has been shown to protect the myocardium against reperfusion injury in the ischemic hearts. However, the mechanism of protection remains unclear. ⋯ Arterial blood samples were collected from all groups at the end of the experimental period (90min) for cytokine measurements (TNF-α). Amiloride decreased the inflammatory response to hemorrhagic shock and resuscitation by lowering the levels of TNF. These results indicate that amiloride protects the myocardium by down regulating the inflammatory response to hemorrhagic shock and resuscitation.
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Comparative Study
Pharmacological characterization of the cannabinoid CB₁ receptor PET ligand ortholog, [³H]MePPEP.
MePPEP ((3R,5R)-5-(3-methoxy-phenyl)-3-((R)-1-phenyl-ethylamino)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one) is an inverse agonist shown to be an effective PET ligand for labeling cannabinoid CB₁ receptors in vivo. [¹¹C]MePPEP and structurally related analogs have been reported to specifically and reversibly label cannabinoid CB₁ receptors in rat and non-human primate brains, and [¹¹C]MePPEP has been used in human subjects as a PET tracer. We have generated [³H]MePPEP, an ortholog of [¹¹C]MePPEP, to characterize the molecular pharmacology of the cannabinoid CB₁ receptor across preclinical and clinical species. [³H]MePPEP demonstrates saturable, reversible, and single-site high affinity binding to cannabinoid CB₁ receptors. In cerebellar membranes purified from brains of rat, non-human primate and human, and cells ectopically expressing recombinant human cannabinoid CB₁ receptor, [³H]MePPEP binds cannabinoid CB₁ receptors with similar affinity with K(d) values of 0.09 nM, 0.19 nM, 0.14 nM and 0.16 nM, respectively. ⋯ No specific binding is present in autoradiographic sections from cannabinoid CB₁ receptor knockout mouse brains, demonstrating that [³H]MePPEP selectively binds cannabinoid CB₁ receptors in native mouse tissue. Furthermore, [³H]MePPEP binding to anatomical sites in mouse and rat brain is comparable to the anatomical profiles of [¹¹C]MePPEP in non-human primate and human brain in vivo, as well as the binding profiles of other previously described cannabinoid CB₁ receptor agonist and antagonist radioligands. Therefore, [³H]MePPEP is a promising tool for translation of preclinical cannabinoid CB₁ receptor pharmacology to clinical PET ligand and cannabinoid CB₁ receptor inverse agonist therapeutic development.
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Linaclotide is a first-in-class, orally administered 14-amino acid peptide that is in development for the treatment of irritable bowel syndrome with constipation and chronic constipation. We have characterized the solution structure of linaclotide, the in vitro binding and agonist activity to guanylate cyclase C receptors, the stability of linaclotide under conditions mimicking the gastric environment, oral bioavailability, and the pharmacodynamic effects in rat models of gastrointestinal transit and intestinal secretion. Nuclear magnetic resonance spectroscopy analysis determined that the molecular structure of linaclotide is stabilized by three intramolecular disulfide bridges. ⋯ Orally administered linaclotide elicited a significant, dose-dependent increase in gastrointestinal transit rates in rats at doses of ≥5 μg/kg. Exposure of surgically ligated small intestinal loops to linaclotide induced a significant increase in fluid secretion, accompanied by a significant increase in intraluminal cGMP levels. These results suggest that the guanylate cyclase C agonist linaclotide elicits potent pharmacological responses locally in the gastrointestinal tract, and that orally administered guanylate cyclase C agonists may be capable of improving bowel habits in patients suffering from irritable bowel syndrome with constipation and chronic constipation.
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Statins have been shown to downregulate the systemic inflammatory response after cardiopulmonary bypass. However, the role of statins as anti-inflammatory agents in heart tissue remains unknown. The aim of this study was to test whether statin pretreatment attenuates local inflammatory cytokines production in heart and to explore whether the underlying mechanism involves peroxisome proliferator-activated receptor (PPAR) γ. ⋯ However, there was an evident increase in the activity and expression of PPARγ. In conclusion, simvastatin pretreatment not only attenuates acute systemic and local inflammatory response induced by cardiopulmonary bypass. The anti-inflammatory effect of simvastatin in myocardium may be partly related to the activation of PPARγ and inhibition of NF-κB.
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Comparative Study
Systemic cannabinoids produce CB₁-mediated antinociception by activation of descending serotonergic pathways that act upon spinal 5-HT(7) and 5-HT(2A) receptors.
Serotonin (5-HT) plays an important role in the descending control of pain. We evaluated the role of descending serotonergic pathways and spinal 5-HT₇ and 5-HT(2A) receptors in comparison to that of 5-HT(1A) and 5-HT₃ receptors in the antinociceptive effects of systemically administered cannabinoids. Antinociceptive effects were evaluated by radiant heat tail-flick and hot plate tests in Balb-C mice. ⋯ The antinociceptive effects of WIN 55,212-2 and ACEA were totally absent in spinal 5-HT depleted and dorsolateral funiculus lesioned mice. I.th. administration of SB-269970, ketanserin, and risperidone, but not WAY 100635 or ondansetron, blocked both WIN 55,212-2- and ACEA-induced antinociception. These findings suggest that systemically administered cannabinoids interact with descending serotonergic pathways via CB₁-mediated mechanisms and exert a central antinociceptive effect involving spinal 5-HT₇ and 5-HT(2A) receptors.