Neutral endopeptidase 3.4.24.11 inhibition potentiates the inhibitory effects of type-C natriuretic peptide on leukotriene D4-induced airway changes.
1. Microvascular leakage, a primary feature of inflammation, is well known for worsening the asthmatic condition. Gene expression of and a specific receptor for type-C natriuretic peptide (CNP), initially considered a neuropeptide, have been detected in the human vascular wall and secretion of CNP from vascular endothelial cells has recently been demonstrated. These facts suggest the presence of a vascular natriuretic peptide system and led us to expect that CNP may act beneficially on airway microvascular leakage in asthma. In the present study, we investigated the effects of CNP against leukotriene (LT) D4-induced airway microvascular leakage and bronchoconstriction and how these effects were potentiated by thiorphan, a potent neutral endopeptidase 3.4.24.11 (NEP) inhibitor. 2. Anaesthetized male guinea-pigs, ventilated via a tracheal cannula, were placed into a plethysmograph for 10 min, in order to measure pulmonary mechanics and mean blood pressure, after challenge with 2 micrograms/kg LTD4 and then the extravasation of 20 mg/kg Evans blue dye into airway tissue was investigated to indicate and evaluate microvascular leakage. 3. Intravenous administration of CNP (100, 300 and 1000 micrograms/kg) significantly inhibited the LTD4-induced microvascular leakage and bronchoconstriction in a dose-dependent manner. These inhibitory effects were enhanced by pretreatment with 20 mg/kg thiorphan, suggesting the important role of NEP in the pulmonary metabolism of CNP. 4. We believe that these results are encouraging for the further investigation of the therapeutic applications of exogenous CNP in asthma.
Ohbayashi
H
H
Second Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Yamaki
K
K
Suzuki
R
R
Kume
H
H
Takagi
K
K
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D017998:Leukotriene D4 / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology / Q000502:physiology*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D015244:Thiorphan / Q000494:pharmacology
D020098:Natriuretic Peptide, C-Type; D017998:Leukotriene D4; D015244:Thiorphan; D015260:Neprilysin