Effects of the calcium ionophore A23187 on airway responsiveness to histamine and substance P in guinea pigs.
OBJECTIVE
We evaluated the mechanism of the airway hyperresponsiveness (AHR) induced by a calcium ionophore in guinea pigs.


METHODS
Airway responsiveness to intravenous histamine (HS) and substance P (SP) was measured 24 h after a 1-h exposure to aerosolized A23187 (0.03 or 0.1 mg/ml) or its vehicle (10% DMSO). Changes were assessed by calculating -logPC350HS and logPC350SP. Neutral endopeptidase (NEP) activity in the airway tissues, as well as the nitrite (NO2) levels and the cell population in bronchoalveolar lavage fluid (BALF) was determined after measurement of pulmonary function. Changes in SP-induced vascular permeability 24 h after exposure to A23187 were measured by the Evans Blue dye extravasation technique.


RESULTS
Exposure to A23187 caused a significant AHR to SP, along with a significant increase in the number of neutrophils and epithelial cells in the BALF. While there was no significant change in NEP activity in the airway tissues, the levels of nitrite in the BALF were significantly decreased in A23187-exposed animals. Significant correlations were found between the number of epithelial cells in the BALF and logPC350SP (r = 0.477, p < 0.05) and between nitrite levels in the BALF and -logPC350SP (r = 0.491, p < 0.05) A23187 exposure did not significantly change the SP-induced airway microvascular leakage.


CONCLUSIONS
These data suggest that A23187 exposure induced AHR to SP possibly by reducing NO levels in the airway tissues. This may be due to damaged airway epithelium and/or NO breakdown by activated inflammatory cells in the airways of these guinea pigs.
Uno
D
D
First Department of Internal Medicine, Gunma University School of Medicine, Japan.
Tsukagoshi
H
H
Hisada
T
T
Iwamae
S
S
Mori
M
M
D000818:Animals; D001980:Bronchi / Q000098:blood supply / Q000187:drug effects*; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D000001:Calcimycin / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology*; D007476:Ionophores / Q000494:pharmacology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology*; D014132:Trachea / Q000098:blood supply / Q000187:drug effects*
D007476:Ionophores; D013373:Substance P; D000001:Calcimycin; D006632:Histamine