Life sciences
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Role of Ras in ethanol modulation of angiotensin II activated p42/p44 MAP kinase in rat hepatocytes.
Angiotensin II plays a role in both liver cell proliferation and liver injury but the effects of ethanol on angiotensin II signaling in liver are not clearly understood. We have investigated the role of Ras in ethanol modulation of p42/p44 mitogen-activated protein kinase (MAPK) stimulated by angiotensin II (Ang II) in primary cultures of rat hepatocytes. Hepatocytes were incubated with ethanol (100 mM) for 24 h, then stimulated with Ang II (100 nM). ⋯ Ethanol alone elicited a small increase in basal Ras activity. Pretreatment with manumycin A (10 microM), a Ras farnesylation inhibitor, partially blocked both Ang II-activated and ethanol-potentiated MAPK activities. These data provided the first evidence that ethanol potentiation of Ang II stimulated p42/p44 MAPK is mediated, in part, by Ras in hepatocytes.
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It has been shown that the association of diclofenac with other analgesic agents can increase its antinociceptive activity, allowing the use of lower doses and thus limiting side effects. Therefore, the aim of the present study was to examine the possible pharmacological interaction between diclofenac and gabapentin at the peripheral level in the rat using the 5% formalin test and isobolographic analysis. Diclofenac, gabapentin or a fixed-dose ratio diclofenac-gabapentin combination were administrated locally in the formalin-injured paw and the antinociceptive effect was evaluated using the 5% formalin test. ⋯ The derived theoretical ED30 for the diclofenac-gabapentin combination was 597.5+/-87.5 microg/paw, being significantly higher than the actually observed experimental value, 170.9+/-26.07 microg/paw. These results correspond to a synergistic interaction between diclofenac and gabapentin at the peripheral level, potency being about three times higher with regard to that expected from the addition of the effects of the individual drugs. Data suggest that low doses of the diclofenac-gabapentin combination can interact synergistically at the peripheral level and therefore this drug association may represent a therapeutic advantage for the clinical treatment of inflammatory pain.