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© 2001 International Anesthesia Research Society
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Abstract |
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We studied the effects of colforsin daropate, a water-soluble forskoline derivative, on contractility in fatigued canine diaphragm. Dogs were randomly divided into 4 groups of 8 each. In each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. Immediately after the end of a fatigue-produc-ing period, Group 1 received no study drug, Group 2 was infused with small-dose colforsin daropate (0.2 µg · kg-1 · min-1), Group 3 was infused with large-dose colforsin daropate (0.5 µg · kg-1 · min-1), and Group 4 was infused with nicardipne (5 µg · kg-1 · min-1) during colforsin daropate (0.5 µg · kg-1 · min-1) administration. After the fatigue-producing period, in each group transdiaphragmatic pressure (Pdi) at low-frequency (20-Hz) stimulation decreased from baseline values (P < 0.05), whereas there was no change in Pdi at high-frequency (100-Hz) stimulation. In Groups 2 and 3, during colforsin daropate administration, Pdi to each stimulus increased from fatigued values (P < 0.05). The increase in Pdi was larger in Group 3 than in Group 2 (P < 0.05). In Group 4, the augmentation of Pdi by colforsin daropate was abolished in fatigued diaphragm with an infusion of nicardipine. The integrated diaphragmatic electric activity did not change in any of the groups. We conclude that colforsin daropate improves, in a dose-dependent manner, contractility in fatigued canine diaphragm via its effect on transmembrane calcium movement.
Implications: Diaphragmatic fatigue is implicated as a cause of respiratory failure in normal subjects and in patients with chronic obstructive lung disease. Colforsin daropate improves contractile properties during diaphragmatic fatigue.
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Introduction |
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Phosphodiesterase (PDE) III inhibitors have been used to evaluate their therapeutic potentials for the treatment of congestive heart failure (1,2). In addition to these pharmacological properties, amrinone, milrinone, and olprinone enhance contractility in fatigued diaphragm and are implicated as a cause of respiratory failure (3–5). Unlike PDE III inhibitors, colforsin daropate, a water-soluble forskolin derivative, (+)-(3R,4aR,5S,6S,6aS,10S,10aR,10bS-5-acetoxyl- 6-(3-dimethylaminopropionyloxy)-dodecahydro-10, 10b-dihydroxy-3,4a,7,7,10a-pentamethyl-3-vinyl- 1H-naphtho[2,1-b]pyran-1-one monohydrochloride (Adehl®; Nihonkayaku, Tokyo, Japan), exhibits positive inotropic action by directly activating adenylate cyclase (6) and thereby increases cardiac performance in patients with acute heart failure (7). The purpose of this study was to examine the efficacy of colforsin daropate for the augmentation of contractility in fatigued canine diaphragm.
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Methods |
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The protocol was approved by our animal research committee, and the care of animals was in agreement with guidelines for ethical animal research. Thirty-two healthy mongrel dogs weighing 10–15 kg were anesthetized with pentobarbital (25 mg/kg initial dose plus 2 mg · kg-1 · h-1 maintenance dose) IV to abolish spontaneous movement. Muscle relaxants were not used. Animals were placed in the supine position, their tracheas were intubated with a cuffed tracheal tube, and the lungs were mechanically ventilated with a mixture of oxygen and air (fraction of inspired oxygen 0.4) to maintain PaO2 > 100 mm Hg, PaCO2 35–40 mm Hg, and arterial pH 7.35–7.45. The right femoral artery was cannulated to monitor arterial blood pressure and to obtain blood samples for blood gas analysis. Arterial blood gas tensions were measured every 30 min. The right femoral vein was cannulated to administer maintenance fluids (10 mL · kg-1 · h-1 lactated Ringer’s solution), pentobarbital, and bicarbonate to keep the plasma HCO3- concentration within normal ranges. The left femoral vein was cannulated for the administration of colforsin daropate. A flow-directed pulmonary artery catheter was advanced via the right external jugular vein into the pulmonary artery for the measurement of cardiac output (CO) by thermodilution technique. Rectal temperature was continuously monitored and maintained at 37°C ± 1°C.
The phrenic nerves were bilaterally exposed at the neck, and the stimulating electrodes were placed around them. Transdiaphragmatic pressure (Pdi) was measured by using two thin-walled latex balloons: one positioned in the stomach and the other positioned in the middle third of the esophagus. The balloons were connected to a differential pressure transducer and an amplifier. Supramaximal electrical stimuli (10–15 V) of 0.1-ms duration were applied for 2 s at low-frequency (20-Hz) and high-frequency (100-Hz) stimulation with an electrical stimulator. The isometric contractility of the diaphragm was evaluated by the measurement of the maximal Pdi after airway occlusion at the functional residual capacity. Transpulmonary pressure, the difference between airway and esophageal pressures, was kept constant by maintaining the same lung volume before each phrenic stimulation. End-expiratory diaphragmatic geometry and muscle fiber length during contraction were kept constant by placing a close-fitting plaster cast around the abdomen and lower one-third of the ribcage. The electrical activity of the crural (Edi-cru) and costal (Edi-cost) parts of the diaphragm was recorded by using two pairs of fishhook electrodes placed through a midline laparotomy; electrodes were positioned into the anterior portion of the crural part near the central tendon and the anterior portion of the costal part (away from the zone of apposition) in the left hemidiaphragm. Each pair was placed in parallel fibers 5–6 mm apart. The abdomen was then sutured in layers. The signal was rectified and integrated with a leaky integrator (Type 1322; NEC, Tokyo, Japan) with a time constant of 0.1 s and was regarded as the integrated diaphragmatic electrical activity (Edi-cru, Edi-cost).
Dogs were randomly divided into four groups of eight each. After baseline measurements of Pdi, Edi-cru, Edi-cost, and hemodynamic variables—including heart rate, mean arterial pressure, right atrial pressure, mean pulmonary arterial pressure, pulmonary artery occlusion pressure, and CO—in each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation applied for 30 min at a frequency of 20 Hz, an entire cycle of 4 s, and a duty cycle of 0.5 s (i.e., low-frequency fatigue) (8). Immediately after the end of the fatigue-producing period, in Groups 2 (small-dose: 0.2 µg · kg-1 · min-1) and 3 (large-dose: 0.5 µg · kg-1 · min-1), colforsin daropate was continuously administered IV via an electrical infusion pump for 30 min. In Group 4, nicardipine (5 µg · kg-1 · min-1) inhibiting calcium influx into diaphragmatic muscles (9) was continuously infused IV during colforsin daropate (0.5 µg · kg-1 · min-1) administration after the established diaphragmatic fatigue. At 30 min after the onset of the study drug administration, Pdi, Edi-cru, Edi-cost, hemodynamic variables, and CO were measured. In Group 1, no study drug was administered IV, and the same measurements were performed as those in other groups.
All values were expressed as mean ± SD. Statistical analysis was performed by using analysis of variance for repeated measurements with Bonferroni adjustment for multiple comparison and Student’s t-test, where appropriate. A P value of <0.05 was considered significant.
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Results |
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No difference in baseline hemodynamic variables was observed among the groups. With an infusion of large-dose colforsin daropate (Group 3) or combined colforsin daropate and nicardipine (Group 4), compared with baseline values, increases in heart rate and CO (P < 0.05) and decreases in mean arterial pressure, mean pulmonary arterial pressure, and pulmonary artery occlusion pressure (P < 0.05) were observed. In Groups 1 and 2, no hemodynamic changes were observed ( Table 1).
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The Pdi values at different stages and the changes of Edi-cru and Edi-cost (%Edi-cru and %Edi-cost, respectively) from baseline values are shown in Table 2. In each group, after producing fatigue, Pdi at low-frequency (20-Hz) stimulation decreased from baseline values (P < 0.05), and Pdi at high-frequency (100-Hz) stimulation did not change. In Group 1, Pdi to each stimulus did not recover from fatigued values. In Groups 2 and 3, Pdi at both stimuli increased from fatigued values (P < 0.05) during colforsin daropate administration. The Pdi values were larger in Group 3 than in Group 2 (P < 0.05). In Group 4, the augmentation of Pdi by colforsin daropate in fatigued diaphragm was abolished by administering nicardipine. No changes in %Edi-cru and %Edi-cost were observed throughout the experiment in any of the groups.
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Discussion |
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The major findings of this study are that colforsin daropate increases, in a dose-dependent manner, the contractility (assessed by Pdi) in fatigued diaphragm without any change in Edi and that the positive inotropic effect of colforsin daropate was abolished by the simultaneous administration of nicardipine.
The contractility of the diaphragm is assessed by force-frequency characteristics (10,11) and is often evaluated by the measurement of Pdi, which is affected by the length and geometry of the diaphragm during precontracted condition (8). A major determinant of diaphragmatic length and geometry is lung volume. Conceivably, the change in Pdi may be secondary to changes in the end-expiratory lung volume. In this study, however, the airway was occluded at the end-expiratory lung volume during measurements, and its constancy was monitored by the measuring of the end-expiratory transpulmonary pressure. Therefore, changes in lung volume throughout the experiment can reasonably be excluded. The plaster cast around the abdomen and lower one-third of the ribcage was also placed for the prevention of deformation of thoracoabdominal structures.
Hypoxemia, hypercapnia, and metabolic acidosis decrease contractility in fatigued diaphragm (12,13). In this study, however, PaO2, PaCO2, arterial pH, and HCO3- concentration were monitored every 30 minutes and were controlled within normal ranges. Therefore, these factors, which could have affected diaphragmatic contractility, were eliminated. Because the dogs were basically anesthetized with pentobarbital, the combined effects of colforsin daropate and pentobarbital on diaphragmatic contractility were examined. However, pentobarbital, at the doses (2 mg · kg-1 · h-1) used in this experiment, does not affect diaphragmatic contractility (14).
Low-frequency fatigue is of particular clinical importance because the spontaneous, natural rate of phrenic nerve discharge is mainly in the low-frequency ranges (i.e., 5 to 30 Hz) (15). Therefore, the effect of colforsin daropate on contractility in fatigued diaphragm induced by 20 Hz stimulation (i.e., low-frequency fatigue) was examined.
The results of Group 1, in which Pdi was obtained without an administration of colforsin daropate in fatigued diaphragm, showed that Pdi to each stimulus did not recover from fatigued values and that Edi did not change at any frequency of stimulation. This was in agreement with our previous studies (3–5).
We demonstrated that Pdi at 20-Hz and 100-Hz stimulation increased from fatigued values (P < 0.05) with an infusion of colforsin daropate in Groups 2 and 3, and we also demonstrated that Pdi at both stimuli was increased more in Group 3 than in Group 2 (P < 0.05). This suggests that colforsin daropate increases, in a dose-dependent manner, contractility in fatigued diaphragm. The exact mechanism by which colforsin daropate improves contractility in fatigued diaphragm remains unclear. Colforsin daropate is thought to augment contractility in cardiac muscle by increasing cyclic adenosine monophosphate by direct stimulation of adenyl cyclase, which, in turn, induces to activate calcium transport from the sarcoplasmic reticulum (6,7). To clarify the mechanism responsible for the positive inotropic effect of colforsin daropate on contractility in fatigued diaphragm, a combination of colforsin daropate and nicardipine that inhibits calcium influx into diaphragmatic muscle (9) was administered. We previously showed that nicardipine had little effect on contractility in fatigued diaphragm (16). Our results of Group 4 showed that augmentation of Pdi by colforsin daropate in fatigued diaphragm was abolished by administering nicardipine, suggesting that colforsin daropate may increase contractility in fatigued diaphragm by influencing calcium transport across the cell membrane. Further studies are needed to elucidate the mechanism of colforsin daropate for the improvement of contractile properties in fatigued diaphragm.
We previously evaluated the efficacy of PDE III inhibitors, including amrinone, milrinone, and olprinone, at clinical doses used for the improvement of contractility in fatigued diaphragm, and we demonstrated that amrinone (10 µg · kg-1 · min-1) increases diaphragmatic contractility by 55% at low-frequency (20-Hz) stimulation and by 9% at high-frequency stimulation, milrinone (0.5 µg · kg-1 · min-1) increases its contractility by 69% and by 23% at each stimulus, and olprinone (0.3 µg · kg-1 · min-1) increases its contractility by 85% and by 35% at each stimulus (3–5). Thus, olprinone is more effective than amrinone or milrinone for the augmentation of contractility in fatigued diaphragm. In this study, diaphragmatic contractility increased by 89% at 20-Hz stimulation and by 40% at 100-Hz stimulation during colforsin daropate (0.5 µg · kg-1 · min-1) administration. This suggests that colforsin daropate, compared with PDE III inhibitors, is effective against diaphragmatic fatigue. The reason for this difference is unknown, but it may be attributed to the difference in a positive inotropic action on diaphragmatic contractility.
The increase in blood flow to diaphragm is one of major factors for the improvement of contractility in fatigued diaphragm (15), and CO is an important factor in the regulation of diaphragmatic blood flow (17). Thus, the increase in CO observed in Groups 3 (large-dose colforsin daropate) and 4 (colforsin daropate plus nicardipine) may have led to the increase in blood flow to the diaphragm and thereby may have increased contractility in fatigued diaphragm. However, our results showed that augmentation of contractility to each stimulus in fatigued diaphragm by colforsin daropate was abolished with an infusion of nicardipine (Group 4). Therefore, the increase in blood flow to the diaphragm induced by colforsin daropate may be a relatively small factor for the augmentation of contractility in fatigued diaphragm.
In conclusion, colforsin daropate improves, in a dose-dependent manner, contractility in fatigued canine diaphragm via its effect on transmembrane calcium movement.
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