Antithrombin reduces endotoxin-induced hypotension by enhancing pulmonary sensory neuron activation in rats.
We recently demonstrated that activation of the pulmonary sensory neurons plays a critical role in prevention of endotoxin-induced shock by releasing calcitonin gene-related peptide (CGRP) in rats. CGRP increased the endothelial production of prostacyclin (PGI(2)) in the lungs, thereby preventing endotoxin-induced shock response by inhibiting tumor necrosis factor-alpha (TNF-alpha) 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- alpha (n = 5) in the lungs of endotoxin-treated animals were completely reversed by pretreatment with capsazepine (CPZ) (n = 4 or 5), a vanilloid receptor antagonist, or CGRP(8-37), 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.
Harada
Naoaki
N
Department of Biodefense Medicine, Nagoya City University, Graduate School of Medical Sciences, Kawasumi 1, 1-1-1 Nagoya 467-8601, Japan.
Okajima
Kenji
K
Isobe
Hirotaka
H
Uchiba
Mitsuhiro
M
D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D063388:Endocannabinoids; D004731:Endotoxins / Q000008:administration & dosage; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D007022:Hypotension / Q000097:blood / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000294:innervation*; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000991:Antithrombins; D001095:Arachidonic Acids; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002227:Carbazoles; D016861:Cyclooxygenase Inhibitors; D063388:Endocannabinoids; D004731:Endotoxins; D007211:Indoles; D009566:Nitrates; D009573:Nitrites; D010446:Peptide Fragments; D053284:Polyunsaturated Alkamides; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D018015:Receptors, Calcitonin Gene-Related Peptide; D050916:TRPV Cation Channels; D014409:Tumor Necrosis Factor-alpha; C058636:calcitonin gene-related peptide (8-37); C057416:KT 5720; D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002211:Capsaicin; C078814:anandamide; D007213:Indomethacin