Roles of calcitonin gene-related peptide (CGRP) in hyperpnea-induced constriction in guinea pigs.
It has been reported that hyperpnea-induced bronchoconstriction in guinea pigs is a potential model for exercise-induced asthma in humans. We hypothesized that calcitonin gene-related peptide (CGRP) could modulate leukotriene D4 (LTD4)-induced responses and be involved in the pathophysiology in this asthma model. We measured tracheal (Ptr) and alveolar pressure (PA) using alveolar capsules in open-chested, mechanically ventilated (f = 1 Hz, VT = 9 ml/kg, PEEP = 4 cm H2O) guinea pigs. Animals were intravenously pretreated with saline (SAL), CGRP(8-37) (CGRP receptor antagonist), CGRP, MK-571 (LTD4 receptor antagonist), MK-886 (5-lipoxygenase inhibitor), or CGRP(8-37) + MK-571, and then underwent dry gas hyperpnea challenge (HC, 95% 02-5% CO2, 150 breaths/min, 7 min). We calculated resistance of lung (RL), tissue (Rti), and airway (Raw). HC increased RL, Rti, and Raw in SAL controls (322 +/- 27, 430 +/- 59, 299 +/- 23% baseline, respectively). MK-571, MK-886, and CGRP significantly reduced the responses to HC, while CGRP(8-37) enhanced HC-induced responses. Pretreatment with CGRP(8-37) and MK-571 in combination attenuated HC-induced constriction. In addition, pretreatment with CGRP reduced responses induced by intravenous administration of LTD4. These observations suggest that CGRP might be involved in the pathophysiology of hyperpnea-induced constriction in guinea pigs via modulation of LTD4-elicited responses.
Department of Geriatrics, Faculty of Medicine, University of Tokyo, Japan.
T
T
Nagase
E
E
Ohga
H
H
Katayama
E
E
Sudo
T
T
Aoki
T
T
Matsuse
Y
Y
Ouchi
Y
Y
Fukuchi
D000818:Animals; D001250:Asthma, Exercise-Induced / Q000209:etiology / Q000503:physiopathology*; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology*; D004347:Drug Interactions; D006168:Guinea Pigs; D006985:Hyperventilation; D007211:Indoles / Q000494:pharmacology; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D008916:Miotics / Q000494:pharmacology; D008954:Models, Biological; D010446:Peptide Fragments / Q000494:pharmacology; D011175:Positive-Pressure Respiration; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012121:Respiration, Artificial; D002722:Chlorobenzenes
D001993:Bronchodilator Agents; D015740:Calcitonin Gene-Related Peptide; D007211:Indoles; D017998:Leukotriene D4; D016859:Lipoxygenase Inhibitors; D008916:Miotics; D010446:Peptide Fragments; D011422:Propionates; D011804:Quinolines; C060893:MK-886; D002722:Chlorobenzenes; C058636:calcitonin gene-related peptide (8-37); C059141:verlukast