To distinguish the effects of theophylline on respiratory muscle contractility from alterations in respiratory muscle interaction or blood flow, we examined in vitro contractile properties and fatigue of canine diaphragm in two series of experiments. In the first series, a 40-mg/kg aminophylline infusion was given to dogs, and diaphragm strips were removed for in vitro study when stable tissue fixation of the drug was reached. Compared with control bundles examined before aminophylline infusion, no alterations in twitch tension, tetanic tension, or force-frequency characteristics were observed. Moreover, theophylline-treated strips fatigued faster than control strips, whether subjected to repetitive submaximal or maximal contractions (p < 0.01). In the second series, diaphragm bundles were equilibrated with high theophylline doses (400 mg/L) in vitro, and inotropic effects compared with the results in the first series. Supratherapeutic theophylline concentrations increased force development at low stimulation frequencies (p < 0.05 at 10 Hz) and significantly elevated twitch-tetanus ratio (p < 0.01) but did not protect against development of in vitro muscle fatigue. Poor penetration of theophylline in diaphragm bundles in vitro was excluded, since drug concentrations in the muscle bundle and the muscle bath were virtually equal. We conclude that diaphragmatic tissue concentrations correlate well with therapeutic serum and supratherapeutic bath levels and that only high theophylline concentrations increase canine diaphragmatic contractility in vitro. None of the theophylline concentrations studied could protect diaphragm bundles against the development of low- or high-frequency fatigue in vitro.

We studied the effects of aminophylline on respiratory muscle interaction during quiet breathing by measuring (1) changes in rib cage and abdominal cross-sectional area, (2) tidal volume, (3) abdominal and esophageal pressure, (4) diaphragm and parasternal intercostal electromyogram (EMG) and parasternal intercostal intramuscular pressure, and (5) triangularis sternl and transversus abdominis EMG, in 14 supine anesthetized dogs. Measurements were done before and 5 and 10 min after administration of progressively increasing doses of aminophylline, reaching a total dose of 5, 10, 20, 40, and 80 mg/kg. In 12 of 14 dogs after aminophylline administration, quiet inspiration became biphasic, or if inspiration was already biphasic under control conditions, the first phase was clearly enhanced after aminophylline administration. Biphasic inspiration was defined as an inspiratory pattern in which rib cage and abdominal expansion showed two distinct phases. First, the onset of inspiration was characterized by a sudden increase in rib cage cross-sectional area often associated with a decrease in abdominal dimensions. During this initial part the parasternals and the diaphragm were electrically silent, confirming that it was achieved by relaxation of expiratory muscles. Further inspiration occurred predominantly through expansion of the abdomen. In the first phase, a pressure drop in the parasternal intercostals was present, presumably due to passive shortening of these muscles caused by expiratory muscle relaxation. On the average, 42 +/- 28% of the rib cage expansion was due to expiratory muscle relaxation at a dose of 80 mg/kg versus 17 +/- 21% under control conditions (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

In an attempt to obtain insight in the forces developed by the parasternal intercostal muscles during breathing, changes in parasternal intramuscular pressure (PIP) were measured in 14 supine anesthetized dogs using a microtransducer method. In six animals, during bilateral parasternal stimulation a linear relationship between contractile force exerted on the rib and PIP was demonstrated (r greater than 0.95). In eight animals, during quiet active inspiration, substantial (55 +/- 11.5 cmH2O) PIP was developed. During inspiratory resistive loading and airway occlusion the inspiratory rise in PIP increased in proportion to the inspiratory fall in pleural pressure (r = 0.82). Phrenicotomy and vagotomy resulted in an increase in the inspiratory rise in PIP of 21% and 99%, respectively. During passive deflation, when the parasternal intercostals were passively lengthened, large rises (320 +/- 221 cmH2O) in intramuscular pressure were observed. During passive inflation intramuscular pressure remained constant or even decreased slightly (-8 +/- 25 cmH2O) as expected on the basis of the passive shortening of the muscles. PIP thus invariably increased when tension increased either actively or passively. From PIP it is clear that the parasternals exert significant forces on the ribs during respiratory maneuvers.

We studied the mechanical effectiveness of the parasternal intercostals at FRC and near TLC in 14 supine, vagotomized, and anesthetized dogs. First, we determined the relationship between parasternal intramuscular pressure (Pps), measured with Gaeltec 12 CT-mini-transducers, and parasternal EMG activity (Eps) during breathing at FRC and near TLC. Second, we examined the changes in Pps and the changes in parasternal force (Fps) generated during bilateral parasternal stimulation at FRC and near TLC with a given supramaximal stimulus. Before phrenicotomy, the inspiratory increases in Pps remained relatively constant near TLC (FRC, 50.4 +/- 16.5 versus TLC, 48.7 +/- 13.3 cm H2O, NS), whereas the Eps clearly decreased (82.9 +/- 5.5% FRC, p less than 0.01). This indicates that the gain converting electrical activity into pressure for the parasternals is greater near TLC than at FRC. A similar pattern of changes in Pps and in Eps was observed during quiet inspiration at FRC and near TLC after phrenicotomy. During bilateral parasternal stimulation the increases in Pps near TLC tended to be greater than those at FRC (140.7 +/- 28.6 versus 100 +/- 28.3 cm H2O, NS), whereas the increases in Fps were significantly greater near TLC than at FRC (277.4 +/- 60.6 versus 214.2 +/- 47.1 g, p less than 0.05). Therefore, we conclude that the mechanical effectiveness of the parasternal contraction near TLC remains relatively unchanged and is even greater in relation to that at FRC.

We studied rib cage distortability and reexamined the mechanical action of the diaphragm and the rib cage muscles in six supine anesthetized dogs by measuring changes in upper rib cage cross-sectional area (Aurc) and changes in lower rib cage cross-sectional area (Alrc) and the respective pressures acting on them. During quiet breathing in the intact animal the rib cage behaved as a unit (Aurc: 14.6 +/- 7.9 vs. Alrc: 15.1 +/- 9.6%), whereas considerable distortions of the rib cage occurred during breathing after bilateral phrenicotomy (Aurc: 21.0 +/- 5.1 vs. Alrc: 7.0 +/- 4.8%). These distortions were even more pronounced during phrenic nerve stimulation and separate stimulation of the costal and crural parts of the diaphragm (e.g., phrenic nerve stimulation; Aurc: -7.1 +/- 5.1 vs. Alrc: 6.9 +/- 3.5%). During the latter maneuvers the upper rib cage deflated along the relationship between upper rib cage dimensions and pleural pressure obtained during passive deflation, whereas the lower rib cage inflated close to the relationship between lower rib cage dimensions and abdominal pressure obtained during passive inflation. The latter relationship is expected to differ between costal and crural stimulation, since costal action has both an appositional and insertional component and crural action only has an appositional component. The difference between costal and crural stimulation, however, was relatively small, and the slopes were only slightly steeper for the costal than for the crural stimulation (2.9 +/- 1.2 vs. 2.2 +/- 1.0%.(ABSTRACT TRUNCATED AT 250 WORDS)

When an isolated strip of skeletal muscle tissue is held at fixed length and stimulated electrically with a very brief pulse of electricity it responds with a transient increase in tension known as a twitch. If the same strip is stimulated repetitively with short pulses it produces a tension that can be considered to be composed of individual twitches arising from each stimulus. We present a subtractive method for decomposing a muscle tension curve into individual twitches of various heights. The locations of the twitches are known a priori from the times at which each stimulus was applied to the muscle. The shape of each twitch is assumed the same as that of a single twitch obtained just prior to the repetitive stimulation tension signal. We therefore find the heights of the individual twitches composing a tension curve. We find that most of a tension signal from isolated dog diaphragm strips can be accounted for as the sum of twitches of the same shape but different heights. We also derive a refractory factor for stimulation at a given frequency, that describes how the heights of the twitches in a tension curve are attenuated as a function of stimulation frequency.

We attempted to measure diaphragmatic tension by measuring changes in diaphragmatic intramuscular pressure (Pim) in the costal and crural parts of the diaphragm in 10 supine anesthetized dogs with Gaeltec 12 CT minitransducers. During phrenic nerve stimulation or direct stimulation of the costal and crural parts of the diaphragm in an animal with the chest and abdomen open, Pim invariably increased and a linear relationship between Pim and the force exerted on the central tendon was found (r greater than or equal to 0.93). During quiet inspiration Pim in general decreased in the costal part (-3.9 +/- 3.3 cmH2O), whereas it either increased or slightly decreased in the crural part (+3.3 +/- 9.4 cmH2O, P less than 0.05). Similar differences were obtained during loaded and occluded inspiration. After bilateral phrenicotomy Pim invariably decreased during inspiration in both parts (costal -4.3 +/- 6.4 cmH2O, crural -3.1 +/- 0.6 cmH2O). Contrary to the expected changes in tension in the muscle, but in conformity with the pressure applied to the muscle, Pim invariably increased during passive inflation from functional residual capacity to total lung capacity (costal +30 +/- 23 cmH2O, crural +18 +/- 18 cmH2O). Similarly, during passive deflation from functional residual capacity to residual volume, Pim invariably decreased (costal -12 +/- 19 cmH2O, crural -12 +/- 14 cmH2O). In two experiments similar observations were made with saline-filled catheters. We conclude that although Pim increases during contraction as in other muscles, Pim during respiratory maneuvers is primarily determined by the pleural and abdominal pressures applied to the muscle rather than by the tension developed by it.

We studied chest wall mechanics at functional residual capacity (FRC) and near total lung capacity (TLC) in 14 supine anesthetized and vagotomized dogs. During breathing near TLC compared with FRC, tidal volume decreased (674 +/- 542 vs. 68 +/- 83 ml; P less than 0.025). Both inspiratory changes in gastric pressure (4.5 +/- 2.5 vs. -0.2 +/- 2.0 cmH2O; P less than 0.005) and changes in abdominal cross-sectional area (25 +/- 17 vs. -1.0 +/- 4.2%; P less than 0.001) markedly decreased; they were both often negative during inspiration near TLC. Parasternal intercostal shortening decreased (-3.0 +/- 3.7 vs. -2.0 +/- 2.7%), whereas diaphragmatic shortening decreased slightly more in both costal and crural parts (costal -8.4 +/- 2.9 vs. -4.3 +/- 4.1%, crural -22.8 +/- 13.2 vs. -10.0 +/- 7.5%; P less than 0.05). As a result, the ratio of parasternal to diaphragm shortening increased near TLC (0.176 +/- 0.135 vs. 0.396 +/- 0.340; P less than 0.05). Electromyographic (EMG) activity in the parasternals slightly decreased near TLC, whereas the EMG activity in the costal and crural parts of the diaphragm slightly increased. We conclude that 1) the mechanical outcome of diaphragmatic contraction near TLC is markedly reduced, and 2) the mechanical outcome of parasternal intercostal contraction near TLC is clearly less affected.

We examined the relationship between changes in abdominal cross-sectional area, measured by respiratory inductive plethysmography, and changes in length in the costal and crural parts of the diaphragm, measured by sonomicrometry, in nine supine, anesthetized dogs. During passive inflation, both parts of the diaphragm shortened and abdominal cross-sectional area increased. During passive deflation, both parts of the diaphragm lengthened and abdominal cross-sectional area decreased. We subsequently used the relationship between costal and crural diaphragmatic length, respectively, and abdominal cross-sectional area during passive inflation-deflation to predict the length changes in the costal and crural diaphragm during quiet breathing before and after bilateral phrenicotomy. In the intact animal the inspiratory shortening in the crural diaphragm was almost invariably greater than predicted from the relationship during passive inflation. During inspiration after phrenicotomy the crural diaphragm invariably lengthened, whereas the costal diaphragm often shortened. In general there was a good correlation between the measured and predicted length change for the crural diaphragm (r = 0.72 before and 0.79 after phrenicotomy) and a poor one for the costal diaphragm (r = 0.05 before and 0.19 after phrenicotomy).

In an attempt to assess the physiological function(s) of the external (E) and internal interosseous (I) intercostal muscles, we measured the changes in intercostal muscle length during spontaneous breathing, during passive inflation, and during passive rotation of the trunk. Studies were performed on 46 muscles from 16 supine anesthetized dogs, and changes in muscle length were assessed by sonomicrometry. The changes were small during spontaneous breathing, whether before or after bilateral phrenicotomy, and the pattern was variable among animals and among interspaces. The E, however, particularly in the lower interspaces, often lengthened with inspiration, and the I, in particular in the upper interspaces, often shortened with inspiration. Only occasionally did the E and I in one interspace change in length in opposing directions. This was also true during passive inflation, where both E and I usually shortened in the upper interspaces and lengthened in the lower interspaces. By contrast, during passive rotation of the trunk, the E and I systematically changed in length in opposing directions, and either muscle could successively lengthen and shorten a substantial amount depending on the side of rotation. These results suggest that 1) the E and I in supine dogs do not behave as antagonistic muscles during moderate respiratory efforts; and 2) they do behave as antagonistic muscles during rotation of the trunk. A primary function of these muscles as rotators of the trunk, unlike breathing, may explain why two layers of intercostal muscles with different fiber orientation exist between the ribs.

The relationship between parasternal intercostal length and rib cage cross-sectional area was examined in nine supine dogs during passive inflation and during quiet breathing before and after phrenicotomy. Parasternal intercostal length (PSL) was measured with a sonomicrometry technique, and rib cage cross-sectional area (Arc) was measured with a Respitrace coil placed around the middle rib cage. During active inspiration as well as during passive inflation, PSL decreased as Arc increased. However, the relationship between PSL and Arc during active inspiration, whether in the intact or phrenicotomized animal, was almost invariably different from that during passive inflation, so that the same increase in Arc was associated with a greater decrease in PSL in the former than in the latter instance. This difference between passive inflation and active inspiration is probably due to the active contraction of the parasternals during inspiration and the consequent caudal displacement of the sternum. In upright humans, the sternum moves cephalad and not caudad during inspiration, so the relationship between PSL and Arc during active breathing might be similar to that during passive inflation.

The pressure swings under the costal (Pcos) and crural diaphragms (Pcru) and between the intestinal loops (Pint) were compared with the swings in gastric pressure (Pga) in 13 supine anesthetized dogs. Pcos, Pcru, and Pint were measured with air-filled latex balloons in eight dogs and saline-filled catheters in five. Pga was measured with an air-filled balloon in all dogs. During quiet breathing differences were often present, the directions of which were variable from animal to animal. During mechanical ventilation, all pressures increased, but both Pcos and Pcru increased more than Pga, whereas only a small change was observed in Pint. During bilateral stimulation of the costal diaphragm, Pcos invariably increased more than Pga and Pint, whereas almost no change was observed in Pcru. During bilateral stimulation of the crural diaphragm, Pcru invariably increased more than Pga, Pint, and Pcos. During abdominal muscle stimulation as during external abdominal compression, Pint always increased more than Pcos and Pcru. During lower rib cage compression, Pga, Pcos, and Pcru increased more than Pint. During sternocleidomastoid stimulation, all pressure swings were negative, but the change in Pint was always smaller than in Pcos, Pcru, or Pga. Inhomogeneities observed with balloons and saline-filled catheters were similar. After the abdomen was filled with 2 liters of saline all pressure swings became much more homogeneous.

To examine the mechanical effects of the fall in abdominal pressure (Pab) that occurs during inspiration in diaphragmatic paralysis, we studied lung inflation and rib cage expansion before and after the abdomen was opened in nine spontaneously breathing dogs with bilateral phrenicotomy . We measured Pab, tidal volume, and parasternal electromyographic (EMG) activity during quiet breathing and CO2-induced hyperpnea. In six dogs, we also measured changes in anteroposterior and transverse rib cage diameters, the resting length of the parasternal intercostal muscles, and the amount of shortening of these muscles during inspiration. Opening the abdomen caused a marked reduction in the fall in Pab during inspiration and invariably resulted in a decrease in tidal volume (mean decrease, 13%), which contrasted with marked increases in inspiratory rib cage expansion and in the amount of parasternal intercostal shortening. The procedure, however, did not affect the resting length or inspiratory EMG activity of the parasternals . These findings indicate that although the fall in Pab, which occurs during inspiration in diaphragmatic paralysis, causes paradoxical inward displacement of the ventral abdominal wall, it has a salutary effect on tidal volume. This phenomenon is probably due to the fact that the diaphragm is part of the abdominal wall.