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《Chinese Pharmacological Bulletin》 2007-03
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Activation of cAMP-PKA signal pathway by CCK-8 in rat pulmonary interstitial macrophages

GAO Wei-juan, XU Shun-jiang, CONG Bin, LI Shu-jin, MA Chun-ling (Dept of Pathophysiology, Hebei Medical University, Shijiazhuang 050017, China)  
Aim To investigate the activation of CCK-8 on cAMP-PKA signaling pathway in rat pulmonary interstitial macrophages (PIMs). Methods PIMs were isolated and purified, and radioimmunoassay was used to detect the cAMP content and radioenzymatic assay to detect the protein kinase A (PKA) activity. Half-maximal inhibition (IC50) of receptor antagonist was calculated by log-probit method. Results Under quiescent condition, the cAMP content and PKA activity in PIMs of normal control group were(2.04±0.13)nmol·g-1 and(118.3±11.2)nmol·min-1·g-1 respectively. CCK-8 did not affect cAMP content and PKA activity significantly at low concentration [(10-12~10-10) mol·L-1](compared with normal control group: P0.05); but significantly increased cAMP content and PKA activity at high concentration [(10-9~10-5) mol·L-1] (compared with normal control group:P0.05). Stimulating PIMs with 10 mg·L-1 lipopolysaccharide (LPS) resulted in significant increase of cAMP content and PKA activity in the concentration of(5.15±0.12)nmol·g-1 and(188.6±13.5)nmol·min-1·g-1. When PIMs were incubated with different dosages of CCK-8 and LPS, the changes of cAMP content and PKA activity were similar to PIMs in quiescent condition under action of CCK-8. The inhibitory effects of CCK receptor antagonist proglumide, CR-1409 and CR-2945 on the CCK-8-resulted increasing of cAMP content were dose-dependent and the IC50 was(0.5×10-6,4.1×10-6,and 7.2×10-4)mol·L-1 respectively. The effects of CCK-8 on PKA activity were significantly attenuated by proglumide, CR-1409 and CR-2945, their inhibitory effects decreased gradually from proglumide to CR-1409 and CR-2945. Conclusion CCK-8 activates cAMP-PKA signaling pathway in a dose-dependent manner in rat PIMs under quiescent condition or induced by LPS through its receptors, this may be one of the mechanisms of CCK anti-inflammatory effects. Both CCK-AR and CCK-BR may be involved in this pathway, but CCK-AR may play a main role in this process.
【Fund】: 国家自然科学基金资助项目(No30270529);; 河北省自然科学基金资助项目(No303452);; 河北省普通高等学校博士科研资助基金项目(NoB2003111)
【CateGory Index】: R341
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