Ischemia/reperfusion-induced increase in the hepatic level of prostacyclin is mainly mediated by activation of capsaicin-sensitive sensory neurons in rats

2002 ◽  
Vol 139 (4) ◽  
pp. 218-226 ◽  
Author(s):  
Naoaki Harada ◽  
Kenji Okajima ◽  
Mitsuhiro Uchiba ◽  
Takeshi Katsuragi
Keyword(s):  
Sensory Neurons ◽  
Ischemia Reperfusion ◽  
Hepatic Level

Antithrombin reduces reperfusion-induced liver injury in mice by enhancing sensory neuron activation

2006 ◽  
Vol 95 (05) ◽  
pp. 788-795 ◽  
Author(s):  
Naoaki Harada ◽  
Mitsuhiro Uchiba ◽  
Hiroki Kurihara ◽  
Naomi Nakagata ◽  
Kenji Okajima
Keyword(s):  
Liver Injury ◽  
Sensory Neuron ◽  
Sensory Neurons ◽  
Ischemia Reperfusion ◽  
Dorsal Root Ganglion Neurons ◽  
Hepatic Tissue ◽  
Tissue Levels ◽  
Cgrp Release ◽  
Neuron Activation ◽  
Ganglion Neurons

SummaryWe recently demonstrated that antithrombin (AT) reduces ischemia/reperfusion (I/R)-induced liver injury in rats by increasing hepatic tissue levels of calcitonin gene-related peptide (CGRP),a neuropeptide released from the sensory nerve endings. In the present study, we examined the effect of AT on I/Rinduced liver injury in wild type mice (CGRP+/+) and congenitally αCGRP-deficient mice (CGRP−/−). We also investigated any effects of AT on CGRP release from dorsal root ganglion neurons (DRG) isolated from CGRP+/+. Based on results obtained in the present study, we attempted to determine if the anti-inflammatory activity of AT in vivo is dependent mainly on sensory neuron activation. AT enhanced ischemia/reperfusion-induced increases in hepatic tissue levels of CGRP and 6-keto-PGF1α , a stable metabolite of PGI2, in CGRP+/+, but it did not enhance these increases in CGRP−/−. AT inhibited reperfusion-induced increases in serum alanine aminotransferase levels by increasing hepatic tissue blood flow and by attenuating increases in hepatic levels of tumor necrosis factor and myeloperoxidase in CGRP+/+,although it showed neither of these therapeutic effects in CGRP−/−. AT increased CGRP release from cultured DRGs only in the presence of anandamide, and AT-induced increase in CGRP release was not observed in the presence KT5720, an inhibitor of protein kinase A (PKA).AT markedly increased intracellular levels of cAMP in the presence of anandamide. These results strongly suggest that AT might reduce I/R-induced liver injury by enhancing activation of the sensory neurons through activation of PKA in sensory neurons.

Contribution of capsaicin-sensitive sensory neurons to antithrombin-induced reduction of ischemia/reperfusion-induced liver injury in rats

2005 ◽  
Vol 93 (01) ◽  
pp. 48-56 ◽  
Author(s):  
Naoaki Harada ◽  
Mehtap Yuksel ◽  
Hirotaka Isobe ◽  
Kenji Okajima
Keyword(s):  
Liver Injury ◽  
Sensory Neurons ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Dorsal Root Ganglion Neurons ◽  
Hepatic Tissue ◽  
Tissue Blood Flow ◽  
Tissue Levels ◽  
Neuron Activation ◽  
Ganglion Neurons

SummaryWe previously reported that antithrombin (AT) reduced ischemia/ reperfusion (I/R)-induced liver injury in rats by increasing endothelial production of prostacyclin (PGI2). However, the mechanism(s) underlying this phenomenon remains to be fully elucidated. We also demonstrated that activation of capsaicinsensitive sensory neurons increased endothelial production of PGI2 by releasing calcitonin gene-related peptide (CGRP) in rats subjected to hepatic I/R. In the present study, we investigated whether AT increases endothelial production of PGI2 through activation of the sensory neurons in rats subjected to hepatic I/R. AT significantly enhanced the I/R-induced increases in hepatic tissue levels of CGRP in rats. Increases in hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2 , the increase in hepatic-tissue blood flow, and attenuation of both hepatic local inflammatory responses and liver injury in rats administered AT were completely reversed by administration of capsazepine, an inhibitor of sensory neuron activation and CGRP(8–37), a CGRP antagonist.AT did not show any protective effect on liver injury in animals undergoing functional denervation by administration of a large amount of capsaicin.AT significantly increased CGRP release from cultured dorsal root ganglion neurons isolated from rats in the presence of capsaicin.Taken together,these observations strongly suggested that AT might increase hepatic tissue levels of PGI2 via enhancement of hepatic I/R-induced activation of capsaicin-sensitive sensory neurons,thereby reducing liver injury in rats. In this process, CGRP-induced activation of both endothelial nitric oxide synthase and cyclooxygenase-1 might be critically involved.

scholarly journals Activation of Sensory Neurons Reduces Ischemia/Reperfusion-induced Acute Renal Injury in Rats

2009 ◽  
Vol 110 (2) ◽  
pp. 361-369 ◽  
Author(s):  
Akio Mizutani ◽  
Kenji Okajima ◽  
Kazunori Murakami ◽  
Sachiko Mizutani ◽  
Kyosuke Kudo ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Renal Tissue ◽  
Renal Ischemia ◽  
Sensory Nerves ◽  
Tissue Blood Flow ◽  
Myeloperoxidase Activity ◽  
Acute Renal Injury ◽  
Tissue Levels

Background Prostaglandin I2 (PGI2) produced by endothelial cells improves ischemia/reperfusion-induced acute renal injury by inhibiting leukocyte activation in rats. However, the underlying mechanism(s) of increased PGI2 production is not fully understood. Activation of sensory neurons increases endothelial PGI2 production by releasing calcitonin gene-related peptide (CGRP) in rats with hepatic ischemia or reperfusion. We examined here whether activation of sensory neurons increases PGI2 endothelial production, thereby reducing ischemia/reperfusion-induced acute renal injury. Methods Anesthetized rats were subjected to 45 min of renal ischemia/reperfusion. Rats were pretreated with CGRP, capsazepine (a vanilloid receptor-1 antagonist), CGRP(8-37) (a CGRP receptor antagonist), or indomethacin (a cyclooxygenase inhibitor), or subjected to denervation of primary sensory nerves before ischemia/reperfusion. Results Renal tissue levels of CGRP and 6-keto-prostaglandin F1alpha, a stable metabolite of PGI2, increased after renal ischemia/reperfusion, peaking at 1 h after reperfusion. Overexpression of CGRP was also noted at 1 h after reperfusion. Increases in renal tissue levels of 6-keto-prostaglandin F1alpha at 1 h after reperfusion were significantly inhibited by pretreatment with capsazepine, CGRP(8-37), and indomethacin. Pretreatment with capsazepine, CGRP(8-37), indomethacin, and denervation of primary sensory nerves significantly increased blood urea nitrogen and serum creatinine levels, renal vascular permeability, renal tissue levels of myeloperoxidase activity, cytokine-induced neutrophil chemoattractant, and tumor necrosis factor-alpha, and decreased renal tissue blood flow. However, pretreatment with CGRP significantly improved these changes. Conclusions Our results suggest activation of sensory neurons in the pathologic process of ischemia/reperfusion-induced acute renal injury. Such activation reduces acute renal injury by attenuating inflammatory responses through enhanced endothelial PGI2 production.

ANTITHROMBIN REDUCES ISCHEMIA/REPERFUSION INJURY OF RAT LIVER BY INCREASING THE HEPATIC LEVEL OF PROSTACYCLIN

1999 ◽  
Vol 27 (Supplement) ◽  
pp. 46A ◽  
Author(s):  
Naoaki Harada ◽  
Kenji Okajima ◽  
Shigeki Kushimoto ◽  
Hirotaka Isobe
Keyword(s):  
Reperfusion Injury ◽  
Rat Liver ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hepatic Level

DANAPAROID REDUCES ISCHEMIA/REPERFUSION-INDUCED ACUTE RENAL INJURY IN RATS BY ACTIVATION OF CAPSAICIN-SENSITIVE SENSORY NEURONS.

2005 ◽  
Vol 33 ◽  
pp. A147
Author(s):  
Akio Mizutani ◽  
Sachiko Mizutani ◽  
Takayuki Noguchi ◽  
Kyosuke Kudo ◽  
Seigo Hidaka ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Acute Renal Injury

Antithrombin Reduces Ischemia/Reperfusion Injury of Rat Liver by Increasing the Hepatic Level of Prostacyclin

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 157-164 ◽  
Author(s):  
Naoaki Harada ◽  
Kenji Okajima ◽  
Shigeki Kushimoto ◽  
Hirotaka Isobe ◽  
Keiichi Tanaka
Keyword(s):  
Blood Flow ◽  
Rat Liver ◽  
Hepatic Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hepatic Tissue ◽  
Tissue Blood Flow ◽  
Leukocyte Activation ◽  
Hepatic Tissue Blood Flow ◽  
Hepatic Level

Abstract We investigated whether antithrombin (AT) can reduce ischemia/reperfusion (I/R)-induced injury of rat liver by promoting prostacyclin release from endothelial cells. Although intravenous administration of AT (250 U/kg) markedly reduced hepatic injury, neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Hepatic levels of 6-keto-PGF1, a stable prostacyclin (PGI2) metabolite, were increased significantly after I/R of the rat liver. AT significantly increased the hepatic level of 6-keto-PGF1, whereas neither DEGR-Xa nor Trp49-modified AT increased it. Hepatic tissue blood flow was markedly reduced after I/R. Although AT significantly increased the hepatic tissue blood flow after I/R, neither DEGR-Xa nor Trp49-modified AT increased the blood flow. Hepatic levels of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO) were significantly increased after hepatic I/R. The levels of these two indicators were reduced by AT but were unaffected by either DEGR-Xa or Trp49-modified AT. Pretreatment of animals with indomethacin (IM) completely inhibited the protective effects of AT on the I/R-induced hepatic damage and the leukocyte activation as well as the AT-induced increase in hepatic 6-keto-PGF1 levels after I/R. Iloprost, a stable analog of PGI2, exhibited effects similar to those of AT and also significantly inhibited the exacerbation of liver injury, the decrease in hepatic tissue blood flow, and the increases in hepatic CINC and MPO levels seen in rats subjected to I/R but pretreated with IM. These findings suggest that AT may prevent I/R-induced hepatic injury by increasing the hepatic levels of PGI2 through the interaction of AT with cell-surface glycosaminoglycans, thus increasing hepatic tissue blood flow and inhibiting leukocyte activation in animals subjected to I/R.

Antithrombin Reduces Ischemia/Reperfusion Injury of Rat Liver by Increasing the Hepatic Level of Prostacyclin

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 157-164
Author(s):  
Naoaki Harada ◽  
Kenji Okajima ◽  
Shigeki Kushimoto ◽  
Hirotaka Isobe ◽  
Keiichi Tanaka
Keyword(s):  
Blood Flow ◽  
Rat Liver ◽  
Hepatic Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hepatic Tissue ◽  
Tissue Blood Flow ◽  
Leukocyte Activation ◽  
Hepatic Tissue Blood Flow ◽  
Hepatic Level

We investigated whether antithrombin (AT) can reduce ischemia/reperfusion (I/R)-induced injury of rat liver by promoting prostacyclin release from endothelial cells. Although intravenous administration of AT (250 U/kg) markedly reduced hepatic injury, neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Hepatic levels of 6-keto-PGF1, a stable prostacyclin (PGI2) metabolite, were increased significantly after I/R of the rat liver. AT significantly increased the hepatic level of 6-keto-PGF1, whereas neither DEGR-Xa nor Trp49-modified AT increased it. Hepatic tissue blood flow was markedly reduced after I/R. Although AT significantly increased the hepatic tissue blood flow after I/R, neither DEGR-Xa nor Trp49-modified AT increased the blood flow. Hepatic levels of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO) were significantly increased after hepatic I/R. The levels of these two indicators were reduced by AT but were unaffected by either DEGR-Xa or Trp49-modified AT. Pretreatment of animals with indomethacin (IM) completely inhibited the protective effects of AT on the I/R-induced hepatic damage and the leukocyte activation as well as the AT-induced increase in hepatic 6-keto-PGF1 levels after I/R. Iloprost, a stable analog of PGI2, exhibited effects similar to those of AT and also significantly inhibited the exacerbation of liver injury, the decrease in hepatic tissue blood flow, and the increases in hepatic CINC and MPO levels seen in rats subjected to I/R but pretreated with IM. These findings suggest that AT may prevent I/R-induced hepatic injury by increasing the hepatic levels of PGI2 through the interaction of AT with cell-surface glycosaminoglycans, thus increasing hepatic tissue blood flow and inhibiting leukocyte activation in animals subjected to I/R.

Glucuronyl 3-sulfate occurs exclusively on distal unmyelinated terminals of selected sensory neurons in the peripheral nervous system

1995 ◽  
Vol 53 ◽  
pp. 958-959
Author(s):  
S.S. Spicer ◽  
B.A. Schulte
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cerebral Cortex ◽  
Peripheral Nervous System ◽  
Sensory Neurons ◽  
Sensory Nerves ◽  
Tissue Antigens ◽  
The Central Nervous System ◽  
The Brain ◽  
Leu 7

Generation of monoclonal antibodies (MAbs) against tissue antigens has yielded several (VC1.1, HNK- 1, L2, 4F4 and anti-leu 7) which recognize the unique sugar epitope, glucuronyl 3-sulfate (Glc A3- SO4). In the central nervous system, these MAbs have demonstrated Glc A3-SO4 at the surface of neurons in the cerebral cortex, the cerebellum, the retina and other widespread regions of the brain.Here we describe the distribution of Glc A3-SO4 in the peripheral nervous system as determined by immunostaining with a MAb (VC 1.1) developed against antigen in the cat visual cortex. Outside the central nervous system, immunoreactivity was observed only in peripheral terminals of selected sensory nerves conducting transduction signals for touch, hearing, balance and taste. On the glassy membrane of the sinus hair in murine nasal skin, just deep to the ringwurt, VC 1.1 delineated an intensely stained, plaque-like area (Fig. 1). This previously unrecognized structure of the nasal vibrissae presumably serves as a tactile end organ and to our knowledge is not demonstrable by means other than its selective immunopositivity with VC1.1 and its appearance as a densely fibrillar area in H&E stained sections.

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