The purpose of this study was to determine the time course of arterial blood gas (ABG) deterioration, increased calpain activity, and diaphragm injury during 4 d of resistive loading. Adult Sprague- Dawley rats were divided into control (C) animals and groups that were tracheally banded (TB) for 1 d (TB1), 2 d (TB2), 3 d (TB3), and 4 d (TB4). In TB rats, the carotid artery was cannulated and the trachea was banded during anesthesia. TB groups (TB1, TB2, TB3, and TB4) had a 67% smaller internal cross-sectional area of the trachea than did C animals. ABG samples from awake rats showed a decreased arterial oxygen tension (Pa(O(2))) and a respiratory acidosis in the TB1, TB2, and TB3 groups. Calpain activity was higher in the diaphragm of TB than of C rats; calpainlike activities in soluble fractions of diaphragm tissue were greater in all TB groups than in C rats, whereas those in bound fractions were greater in the TB2 and TB3 groups. Point counting of hematoxylin and eosin-stained cross-sections showed that the area fraction (A(A)) of normal diaphragm was lower and the A(A) of abnormal muscle and connective tissue was higher in TB3 than in C rats. Increased resistive loading induced by tracheal banding was associated with hypercapnic ventilatory failure, increased calpain activity, and diaphragm injury. Ventilatory failure in response to resistive loading may be due to diaphragm injury and/or to decreased minute ventilation.