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Although protein kinases are known to play a role in modulating a variety of intracellular functions, the direct effect of inhibition of these enzymes on skeletal muscle force production has not been studied. The purpose of the present study was to examine this issue by determining the effects produced on diaphragm force generation by two protein kinase inhibitors: (a) H7, an inhibitor of both cAMP-dependent protein kinase (PKA) and of protein kinase C, and (b) H89, a selective inhibitor of PKA. Experiments (n=15) were performed using isolated, arterially perfused, electrically stimulated rat diaphragms. Perfusate temperature was adjusted to maintain muscle temperature at 27 degrees C and arterial pressure was kept at 150 Torr. Animals were divided into three groups: (a) a control group perfused with Krebs-Henselheit solution equilibrated with 95% O(2)/5% CO(2), (b) a group in which H7 (2 microM) was added to the perfusate, and (c) a group perfused with solution containing H89 (4 microM). In all three groups, we assessed diaphragm twitch kinetics, force-frequency relationships and in vitro fatiguability. We found that both H7 and H89 administration slowed twitch relaxation, augmented force generation in response to low frequency stimulation, and increased the rate of development of fatigue. Specifically, for control, H7 and H89 groups, respectively, we found: (a) 1/2 relaxation time averaged 64+/-2 S.E.M., 87+/-6 and 90+/-2 ms, P0. 003, (b) force production during 10-Hz stimulation averaged 12.6+/-1. 1, 20.1+/-2.3, and 20.3+/-2.1 N/cm(2), P0.035, and (c) force fell to 14.3+/-2.0, 9.5+/-0.5 and 8.7+/-0.2% of its initial value after 20 min of fatiguing stimulation, P0.035. These data show that it is possible to produce large increases in low frequency skeletal muscle force generation by directly inhibiting PKA. We speculate that it may be possible to pharmacologically augment respiratory muscle force and pressure generation in clinical medicine by administration of PKA inhibitors.

The purpose of the present study was to analyze the manner in which series and parallel arrangements of respiratory muscles, contracting together, augment the forces and displacements applied to external elastic loads over those produced by a single muscle contracting alone. We first developed a series of mathematical expressions to describe the behavior of various arrangements of muscles contracting against elastic loads. We then compared the predictions of these equations with the results from experiments in which the forces and displacements produced by simple arrangements of muscles were measured. Both theoretical and experimental results indicate that, against high elastic loads, parallel arrangements of muscle strips produce greater forces and greater displacements than do single muscles; parallel arrangements do not, however, significantly increase the displacement or forced applied to low elastic loads. Conversely, series arrangements result in greater forces and greater displacement of low loads, but are no better than single muscles when contracting against high loads. Against moderate loads parallel and series arrangements of muscles appear to be equivalent in generating forces and displacements during contraction. This analysis suggests that a major determinant of the effects of contraction of various networks of inspiratory muscles is the magnitude and character of the respiratory impedance against which these muscles must work. The primary difference between series and parallel arrangemens of muscles is that muscles arranged in series are most effective against low elastic loads and muscles in parallel act most effectively against high loads.

Recent studies suggest that the parasternal muscles (PA) are primarily responsible for rib cage expansion during eupneic breathing with a much lesser role played by the interosseous external intercostals (EI). The purpose of the present investigation was to assess the capacity of the EI to expand the rib cage during spontaneous breathing in the absence of coincident ipsilateral PA activation. In 9 anesthetized dogs, we measured PA EMG and length in the 3rd interspace and EI EMG and length in the 3rd and 4th interspaces. During resting breathing, each muscle was electrically active and shortened to a similar degree, approximately 3% of resting length. Following ipsilateral PA denervation (1st through 6th interspaces), the level of EI shortening in the 3rd and 4th interspaces was maintained, but with an increase in neural drive to these muscles. The parasternal muscle in the 3rd interspace lengthened during inspiration. Subsequent sequential denervation of EI in the 3rd and 4th interspaces resulted in their lengthening. In 4 additional animals, axial motion of the 4th rib was measured in the mid axillary line. Ipsilateral PA denervation had no significant effect on rib motion. External intercostal denervation (3rd interspace), on the other hand, had a substantial impact on rib motion, causing the 4th rib to move in the caudal direction during inspiration. Our results indicate that: (a) the EI of the lateral rib cage are capable of elevating the ribs during inspiration independent of PA contraction; (b) PA contraction contributes to EI shortening during eupneic breathing and (c) regional loss of muscle activation results in local rib cage distortion, suggesting that the upper rib cage has multiple degrees of freedom.