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Antithrombin reduces endotoxin-induced hypotension by enhancing pulmonary sensory neuron activation in rats.
Thromb Haemost. 2006 Jun; 95(6):1011-8.TH

Abstract

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.

Authors+Show Affiliations

Department of Biodefense Medicine, Nagoya City University, Graduate School of Medical Sciences, Kawasumi 1, 1-1-1 Nagoya 467-8601, Japan.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16732381

Citation

Harada, Naoaki, et al. "Antithrombin Reduces Endotoxin-induced Hypotension By Enhancing Pulmonary Sensory Neuron Activation in Rats." Thrombosis and Haemostasis, vol. 95, no. 6, 2006, pp. 1011-8.
Harada N, Okajima K, Isobe H, et al. Antithrombin reduces endotoxin-induced hypotension by enhancing pulmonary sensory neuron activation in rats. Thromb Haemost. 2006;95(6):1011-8.
Harada, N., Okajima, K., Isobe, H., & Uchiba, M. (2006). Antithrombin reduces endotoxin-induced hypotension by enhancing pulmonary sensory neuron activation in rats. Thrombosis and Haemostasis, 95(6), 1011-8.
Harada N, et al. Antithrombin Reduces Endotoxin-induced Hypotension By Enhancing Pulmonary Sensory Neuron Activation in Rats. Thromb Haemost. 2006;95(6):1011-8. PubMed PMID: 16732381.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antithrombin reduces endotoxin-induced hypotension by enhancing pulmonary sensory neuron activation in rats. AU - Harada,Naoaki, AU - Okajima,Kenji, AU - Isobe,Hirotaka, AU - Uchiba,Mitsuhiro, PY - 2006/5/30/pubmed PY - 2006/9/22/medline PY - 2006/5/30/entrez SP - 1011 EP - 8 JF - Thrombosis and haemostasis JO - Thromb Haemost VL - 95 IS - 6 N2 - 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. SN - 0340-6245 UR - https://www.unboundmedicine.com/medline/citation/16732381/Antithrombin_reduces_endotoxin_induced_hypotension_by_enhancing_pulmonary_sensory_neuron_activation_in_rats_ L2 - http://www.thieme-connect.com/DOI/DOI?10.1160/TH05-09-0637 DB - PRIME DP - Unbound Medicine ER -