The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Dec 2011
Farnesyltransferase inhibitor FTI-277 reduces mortality of septic mice along with improved bacterial clearance.
Treatment with statins, inhibitors of HMG-CoA reductase, extends the survival of septic mice. However, the molecular mechanisms underlying the cholesterol-lowering, independent beneficial effects of statins in sepsis are poorly understood. The inhibition of protein isoprenylation, namely farnesylation and geranylgeranylation, has been proposed as a mediator of the pleiotropic protective effects of statins, although direct evidence is lacking. ⋯ These results indicate that elevation in protein farnesylation plays a role in derangements in immune function and mortality of septic mice. These findings suggest that prevention of immune dysfunction might contribute to FTI-277-induced improvement in survival of septic mice. These data highlight protein farnesyltransferase as a novel potential molecular target to reduce the mortality of patients with sepsis.
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J. Pharmacol. Exp. Ther. · Dec 2011
5-Aminoimidazole-4-carboxyamide-ribonucleoside (AICAR)-stimulated hepatic expression of Cyp4a10, Cyp4a14, Cyp4a31, and other peroxisome proliferator-activated receptor α-responsive mouse genes is AICAR 5'-monophosphate-dependent and AMP-activated protein kinase-independent.
5-Aminoimidazole-4-carboxyamide-ribonucleoside (AICAR), a prodrug activator of AMP-activated protein kinase (AMPK), increased hepatic expression of cytochrome P450 4a10, 4a14, and 4a31 mRNAs 2-, 3-, and 4-fold, respectively, and liver microsomal lauric acid ω-hydroxylation increased 2.8-fold. Likewise, mRNA levels of the peroxisome proliferator-activated receptor α (PPARα)-responsive genes, Acox1, Acadm, Cpt1a, and Fabp1, were also increased by AICAR treatment. AICAR did not elicit these changes in PPARα null mice. ⋯ The PPARα-dependent responses were associated with increased concentrations of oleic acid, a potent PPARα agonist, and diminished levels of oleoyl-CoA. Oleoyl-CoA synthase activity was inhibited by ZMP and AMP with IC(50) values of 0.28 and 0.41 mM, respectively. These results suggest that PPARα is activated by increased concentrations of free fatty acids that may arise from impaired fatty acid metabolism caused by altered levels of ATP, AMP, and ZMP after AICAR or adenosine treatment.
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J. Pharmacol. Exp. Ther. · Dec 2011
Opening of small and intermediate calcium-activated potassium channels induces relaxation mainly mediated by nitric-oxide release in large arteries and endothelium-derived hyperpolarizing factor in small arteries from rat.
This study was designed to investigate whether calcium-activated potassium channels of small (SK(Ca) or K(Ca)2) and intermediate (IK(Ca) or K(Ca)3.1) conductance activated by 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309) are involved in both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-type relaxation in large and small rat mesenteric arteries. Segments of rat superior and small mesenteric arteries were mounted in myographs for functional studies. NO was recorded using NO microsensors. ⋯ HUVECs expressed mRNA for SK(Ca) and IK(Ca) channels, and NS309 induced increases in calcium, outward current, and NO release that were blocked by apamin and TRAM-34 or charybdotoxin. These findings suggest that opening of SK(Ca) and IK(Ca) channels leads to endothelium-dependent relaxation that is mediated mainly by NO in large mesenteric arteries and by EDHF-type relaxation in small mesenteric arteries. NS309-induced calcium influx appears to contribute to the formation of NO.
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J. Pharmacol. Exp. Ther. · Dec 2011
Transient lower esophageal sphincter relaxation pharmacokinetic-pharmacodynamic modeling: count model and repeated time-to-event model.
Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism for gastroesophageal reflux. Characterizations of candidate compounds for reduction of TLESRs are traditionally done through summary exposure and response measures and would benefit from model-based analyses of exposure-TLESR events relationships. Pharmacokinetic (PK)-pharmacodynamic (PD) modeling approaches treating TLESRs either as count data or repeated time-to-event (RTTE) data were developed and compared in terms of their ability to characterize system and drug characteristics. ⋯ Vehicle data were described by a baseline and a surge function; the surge peak was determined to be approximately 9.69 min by all approaches, and its width in time at half-maximal intensity was 5 min (1-min count and RTTE) or 10 min (5-min count). TLESR inhibition by WIN55212-2 was described by an I(max) model, with an IC(50) of on average 2.39 nmol · l(-1). Modeling approaches using count or RTTE data linked to a dynamic PK-PD representation of exposure are superior to using summary PK and PD measures and are associated with a higher power for detecting a statistically significant drug effect.
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J. Pharmacol. Exp. Ther. · Nov 2011
Differential effects of nociceptin/orphanin FQ (NOP) receptor agonists in acute versus chronic pain: studies with bifunctional NOP/μ receptor agonists in the sciatic nerve ligation chronic pain model in mice.
1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one (SR14150) and 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835) are moderately selective nociceptin/orphanin FQ (NOP) receptor agonists. In the [(35)S]guanosine 5'-O-(3-thiotriphosphate) assay in vitro, SR14150 is a partial agonist at both the NOP and μ-opioid receptors, whereas SR16835 is a full agonist at the NOP receptor and has low efficacy at μ receptors. These compounds were tested for antinociceptive and antiallodynic activity, using mice in chronic pain, subsequent to spinal nerve ligation (SNL) surgery. ⋯ It is possible that during a chronic pain state, an up-regulated NOP system in the spinal cord leads to NOP receptor-mediated antiallodynia, which is blocked by NOP antagonists. However, supraspinal up-regulation could lead to an attenuation of morphine antinociception and antiallodynia, which can be alleviated by an NOP receptor antagonist. Thus, although neither NOP agonists nor antagonists are effective as analgesics in acute pain, they may have efficacy as analgesics, either alone or in combination with morphine, for treatment of chronic pain.