McGuire, Michelle, Michael F. Carey, and John J. O'Connor. Almitrine and doxapram decrease fatigue and increase subsequent recovery in isolated rat diaphragm. J. Appl. Physiol. 83(1): 52-58, 1997.The effects of almitrine bimesylate and doxapram HCl on isometric force produced by in vitro rat diaphragm were studied during direct muscle activation at 37°C. Doxapram and almitrine ameliorate respiratory failure clinically by indirectly increasing phrenic nerve activity. This study was carried out to investigate possible direct actions of these agents on the diaphragm before and after fatigue of the fibers. Two age groups of animals were chosen [6-14 wk (group 1) and 50-55 wk (group 2)] because it is known that increasing age decreases a muscle fiber's resistance to fatigue. Muscle strips were isolated from both group 1 and group 2 and directly stimulated (2-ms pulse duration, 5-15 V) to produce twitch tensions of 1.3 and 2.1 N/cm², respectively. At low concentrations, doxapram (20 µg/ml) and almitrine (12 µg/ml) had no effect on twitch contraction or 100-Hz tetanic tension. However, 40 µg/ml doxapram and 30 µg/ml almitrine increased twitch tension by 9.0 ± 1.4 and 11.6 ± 1.9%, respectively, in animals of group 2 (n = 5). A fatigue protocol consisting of low-frequency stimulation (30-Hz trains, 250-ms duration every 2 s for 5 min) caused a reduction of twitch tension in animals of group 1 (48 ± 4% of control) and group 2 (28 ± 4% of control). At 90 min postfatigue, the twitch tension recovered to 72 ± 3 and 42 ± 2% of control values in group 1 and group 2, respectively. In the presence of doxapram (20 µg/ml), there was a significant increase in the recovery of twitch tension at 90 min in group 1 and group 2 (84.5 ± 3.2 and 80.1 ± 2.8%, respectively) compared with controls at 90 min postfatigue. In the presence of almitrine (12 µg/ml), there was a full recovery from fatigue in group 1 animals (100% of control) and a recovery to 95.6 ± 2.1% of control in group 2 animals at 90 min. These results demonstrate a significant improvement in the rapidity and magnitude of recovery from fatigue in the rat diaphragm muscle in the presence of both doxapram and, especially, almitrine. These effects may be due to changes in intracellular calcium, ADP/ATP ratios, or oxygen free radical scavenging.