OBJECTIVE: We attempted to determine whether activation of the sensory neuron contributes to reduction of endotoxin-induced hypotension by inhibiting tumor necrosis factor (TNF)-alpha production via calcitonin gene-related peptide (CGRP) release in rats. DESIGN: Prospective, randomized, controlled study. SETTING: Research laboratory at a university medical center. SUBJECTS: Wistar rats weighing 220-280 g. INTERVENTIONS: Mean arterial blood pressure was measured in rats administered endotoxin intravenously. Animals were pretreated with capsazepine (a vanilloid receptor antagonist), CGRP(8-37) (a CGRP receptor antagonist), and indomethacin before endotoxin administration. Levels of CGRP, 6-keto-prostaglandin F1alpha, TNF-alpha, and cytokine-induced neutrophil chemoattractant (CINC) were measured by enzyme immunoassay methods. The concentration of NO2/NO3 was measured using the Griess reagent. Tissue levels of messenger RNA of the inducible form of nitric oxide synthase (iNOS) and TNF-alpha were determined by reverse transcription polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: Both lung levels of CGRP and plasma levels of 6-keto-prostaglandin F1alpha were increased after intravenous administration of endotoxin (5 mg/kg), peaking at 90 mins after endotoxin administration. Increases in plasma levels of 6-keto-prostaglandin F1alpha at 90 mins after endotoxin administration (766 +/- 134 pg/mL) were inhibited by pretreatment with capsazepine (373 +/- 44 pg/mL, p < .05), CGRP(8-37) (406 +/- 64 pg/mL, p < .05), and indomethacin (154 +/- 40 pg/mL, p < .05). Although none of the pretreatments affected a series of endotoxin-induced responses, including increases in lung tissue levels of TNF-alpha, CINC, and iNOS and the resultant hypotension in animals given 5 mg/kg endotoxin, such pretreatments enhanced these pathologic responses in animals given a smaller dose of endotoxin (1 mg/kg) to the same extent as those induced by 5 mg/kg of endotoxin, suggesting that shock responses induced by 5 mg/kg endotoxin are maximum responses and activation of sensory neurons in endotoxin-treated rats is essentially a reparative response. CONCLUSION: Activation of sensory neurons might contribute to reduction of endotoxin-induced hypotension by releasing CGRP, which is capable of promoting endothelial production of prostacyclin.
OBJECTIVE: We attempted to determine whether activation of the sensory neuron contributes to reduction of endotoxin-induced hypotension by inhibiting tumor necrosis factor (TNF)-alpha production via calcitonin gene-related peptide (CGRP) release in rats. DESIGN: Prospective, randomized, controlled study. SETTING: Research laboratory at a university medical center. SUBJECTS:Wistar rats weighing 220-280 g. INTERVENTIONS: Mean arterial blood pressure was measured in rats administered endotoxin intravenously. Animals were pretreated with capsazepine (a vanilloid receptor antagonist), CGRP(8-37) (a CGRP receptor antagonist), and indomethacin before endotoxin administration. Levels of CGRP, 6-keto-prostaglandin F1alpha, TNF-alpha, and cytokine-induced neutrophil chemoattractant (CINC) were measured by enzyme immunoassay methods. The concentration of NO2/NO3 was measured using the Griess reagent. Tissue levels of messenger RNA of the inducible form of nitric oxide synthase (iNOS) and TNF-alpha were determined by reverse transcription polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: Both lung levels of CGRP and plasma levels of 6-keto-prostaglandin F1alpha were increased after intravenous administration of endotoxin (5 mg/kg), peaking at 90 mins after endotoxin administration. Increases in plasma levels of 6-keto-prostaglandin F1alpha at 90 mins after endotoxin administration (766 +/- 134 pg/mL) were inhibited by pretreatment with capsazepine (373 +/- 44 pg/mL, p < .05), CGRP(8-37) (406 +/- 64 pg/mL, p < .05), and indomethacin (154 +/- 40 pg/mL, p < .05). Although none of the pretreatments affected a series of endotoxin-induced responses, including increases in lung tissue levels of TNF-alpha, CINC, and iNOS and the resultant hypotension in animals given 5 mg/kg endotoxin, such pretreatments enhanced these pathologic responses in animals given a smaller dose of endotoxin (1 mg/kg) to the same extent as those induced by 5 mg/kg of endotoxin, suggesting that shock responses induced by 5 mg/kg endotoxin are maximum responses and activation of sensory neurons in endotoxin-treated rats is essentially a reparative response. CONCLUSION: Activation of sensory neurons might contribute to reduction of endotoxin-induced hypotension by releasing CGRP, which is capable of promoting endothelial production of prostacyclin.