ROLES OF CALCITONIN-GENE-RELATED PEPTIDE (CGRP) IN HYPERPNEA-INDUCED CONSTRICTION IN GUINEA-PIGS

It has been reported that hyperpnea-induced bronchoconstriction in gui nea pigs is a potential model for exercise-induced asthma in humans. W e hypothesized that calcitonin gene-related peptide (CGRP) could modul ate leukotriene D-4 (LTD(4))-induced responses and be involved in the pathophysiology in this asthma model. We measured tracheal (Ptr) and a lveolar pressure (PA) using alveolar capsules in open-chested, mechani cally 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 (LTD(4) receptor antagonist), MK-886 (5-lipoxygenase inhibitor), or CGRP(8-37) + MK-571, and then u nderwent dry gas hyperpnea challenge (HC, 95% O-2-5% 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 +/- 2 7, 430 +/- 59, 299 +/- 23% baseline, respectively). MK-571, MK-886, an d CGRP significantly reduced the responses to HC, while CGRP(8-37) enh anced HC-induced responses. Pretreatment with CGRP(8-37) and MK-571 in combination attenuated HC-induced constriction. In addition, pretreat ment with CGRP reduced responses induced by intravenous administration of LTD(4). These observations suggest that CGRP might be involved in the pathophysiology of hyperpnea-induced constriction in guinea pigs v ia modulation of LTD(4)-elicited responses.