Attenuation of tachykinin-induced airflow obstruction and microvascular leakage in immature airways.
1. To study the effect of maturation on substance P (SP)- and neurokinin A (NKA)-induced airflow obstruction and airway microvascular leakage (MVL), we have measured changes in both lung resistance (RL) and extravasation of Evans blue dye in anaesthetized immature (aged 14 +/- 1 days) and adult guinea-pigs (aged 80 +/- 3 days). 2. RL and its recovery after hyperinflation at 5 min were measured for 6 min after i.v. SP (0.2, 1 and 30 nmol kg-1), NKA (1 and 10 nmol kg-1) or vehicle (0.9% NaCl). After measurement of RL, MVL in trachea, main bronchi and intrapulmonary airways was also examined. 3. The order of potency in inducing airflow obstruction did not change with age (NKA > SP) but immature animals required a larger dose of SP or NKA than adults to cause a significant increase in RL. 4. The order of potency in inducing airway microvascular leakage was SP > NKA in both immature and adult animals. The amount of extravasated dye after SP was significantly less in immature airways, especially in central airways. 5. Phosphoramidon (2.5 mg kg-1), a neutral endopeptidase (NEP) inhibitor, significantly increased RL after 0.2 nmol kg-1 SP only in adult airways. Phosphoramidon enhanced the dye extravasation after 0.2 nmol kg-1 SP in both immature and adult airways with a significantly greater amount of dye in adult animals, suggesting that mechanisms other than changes in NEP activity may be responsible for this age-related difference. 6. RL after hyperinflation following SP was not correlated with the degree of extravasation of Evans blue dye in immature animals, whereas it was closely correlated in adult animals. 7. SP and NKA may be less potent in causing both bronchoconstriction and microvascular leakage in immature airways. 8. Airway oedema caused by microvascular leakage may contribute less in immature airways to airflow obstruction after SP or NKA.
Tokuyama
K
K
Department of Pediatrics, Gunma University School of Medicine, Maebashi, Japan.
Yokoyama
T
T
Morikawa
A
A
Mochizuki
H
H
Kuroume
T
T
Barnes
P J
PJ
D000375:Aging / Q000502:physiology; D000402:Airway Obstruction; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D005070:Evans Blue; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D008168:Lung / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D015288:Neurokinin A / Q000494:pharmacology*; D012123:Pulmonary Ventilation / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology*
D006020:Glycopeptides; D013373:Substance P; D005070:Evans Blue; D015288:Neurokinin A; D015260:Neprilysin; C008890:phosphoramidon