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Naoaki Harada, Kenji Okajima, Hirotaka Isobe, Mitsuhiro Uchiba
Antithrombin reduces endotoxin-induced hypotension by enhancing pulmonary sensory neuron activation in rats
Keywords: Antithrombin, Capsaicin-sensitive sensory neurons, calcitonin gene-related peptide, septic shock, protein kinase A
We recently demonstrated that activation of the pulmonary sensory neurons plays a critical role in prevention of endotoxininduced shock by releasing calcitonin gene-related peptide (CGRP) in rats. CGRP increased the endothelial production of prostacyclin (PGI2) in the lungs, thereby preventing endotoxininduced shock response by inhibiting tumor necrosis factor- (TNF-) production. Since antithrombin (AT) enhances sensory neuron activation, we hypothesized that AT might reduce endotoxin-induced hypotension by enhancing the activation of pulmonary sensory neurons in rats. We examined this possibility using a rat model of endotoxin shock. AT-induced effects including reduction of hypotension (n = 5) and inhibition of induction of iNOS (n = 4 or 5) and TNF- (n = 5) in the lungs of endotoxintreated animals were completely reversed by pretreatment with capsazepine (CPZ) (n = 4 or 5), a vanilloid receptor antagonist, or CGRP(837), a CGRP receptor antagonist (n = 4 or 5). AT enhanced endotoxin-induced increases in lung tissue levels of CGRP (n = 4), but this effect of AT was not seen in animals pretreated with CPZ (n = 4). CGRP produced therapeutic effects (n = 5) similar to those induced by AT, and such therapeutic effects were completely abrogated by pretreatment with indomethacin (n = 4). AT increased CGRP release from cultured dorsal root ganglion neurons only in the presence of anandamide (n = 5), and AT-induced increase in CGRP release was not observed in the presence KT5720, an inhibitor of protein kinase A (n = 5). AT markedly increased intracellular levels of cAMP in the presence of anandamide (n = 5). These results strongly suggested that AT might reduce endotoxin-induced hypotension in rats by enhancing activation of sensory neurons via activation of protein kinase A.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 95, 06/2006
Pages: 1011 - 1018