Anesth Analg 2003;96:1032-1034
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
The Effect of Inhaled Colforsin Daropate on Contractility of Fatigued Diaphragm in Dogs
Yoshitaka Fujii, MD,
Aki Uemura, MD, and
Hidenori Toyooka, MD
Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba City, Ibaraki, Japan
Address correspondence and reprint requests to Yoshitaka Fujii, MD, Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, 2-1-1, Amakubo, Tsukuba City, Ibaraki 305-8576, Japan. Address e-mail to yfujii{at}md.tsukuba.ac.jp
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Abstract
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We studied the effect of inhaled colforsin daropate, a water-soluble forskolin derivative, on the contractility of fatigued diaphragm in dogs. Animals were divided into 3 groups of 8. In each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20-Hz stimulation applied for 30 min. Immediately after the end of the fatigue-producing period, Group 1 received inhaled vehicle, Group 2 received inhaled colforsin daropate 0.1 mg/mL, and Group 3 received inhaled colforsin daropate 0.2 mg/mL. We assessed diaphragmatic contractility by transdiaphragmatic pressure (Pdi). After fatigue was produced, in each group, Pdi at low-frequency (20-Hz) stimulation decreased from baseline values (P < 0.05), and there was no change in Pdi at high-frequency (100-Hz) stimulation. In Groups 2 and 3, during colforsin daropate inhalation, Pdi at both stimuli increased from fatigued values (P < 0.05). The increase in Pdi was significantly larger in Group 3 than in Group 2. The integrated electrical activity of the diaphragm did not change in any group. We conclude that inhaled colforsin daropate causes an increase in contractility of fatigued canine diaphragm in a dose-related fashion.
IMPLICATIONS: Diaphragmatic fatigue may contribute to the development of respiratory failure. Inhaled colforsin daropate improves, in a dose-dependent manner, the contractility of fatigued diaphragm in dogs.
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Introduction
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Colforsin daropate, a water-soluble forskolin derivative (Adehl®; Nihonkayaku, Tokyo, Japan), compared with phosphodiesterase III inhibitors, is effective against diaphragmatic fatigue (1). Recently, Uemura et al. (2) have demonstrated that inhaled olprinone improves contractility in fatigued diaphragm. We performed this study to assess the efficacy of inhaled colforsin daropate for the improvement of contractility of fatigued diaphragm in dogs.
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Methods
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The procedure was approved by our animal research committee, and the care of animals was in agreement with guidelines for ethical animal research. We studied 24 healthy mongrel dogs (10–15 kg). Animal preparation was similar to that described previously (1). Briefly, anesthesia was maintained with pentobarbital 2 mg · kg-1 · h-1 IV. No neuromuscular blocking drugs were used. The animal’s trachea was intubated, and ventilation was mechanically controlled with a mixture of oxygen and air (fraction of inspired oxygen, 0.4) to maintain PaO2, PaCO2, and arterial pH within normal ranges. The femoral artery was cannulated for monitoring arterial blood pressure, and the right femoral vein was cannulated for administering maintenance fluids. Transdiaphragmatic pressure (Pdi) was measured by using two thin-walled latex balloons: one was positioned in the stomach and the other in the middle third of the esophagus. Balloons were connected to a differential pressure transducer and an amplifier. Bilateral phrenic nerves were exposed at the neck, and stimulating electrodes were placed around them. Supramaximal electrical stimuli (10–15 V) (1.2 times the current required to elicit maximal Pdi) 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. Isometric contractility of the diaphragm was evaluated by measuring the maximal Pdi after airway occlusion at the functional residual capacity. Electrical activity of the diaphragm was recorded by two pairs of fishhook electrodes, and it was rectified and integrated with an integrator with a time constant of 0.1 s. This was regarded as the integrated electrical activity of the crural (Edi-cru) and costal (Edi-cost) parts of the diaphragm. The changes of Edi-cru and Edi-cost (%Edi-cru and %Edi-cost, respectively) from baseline values were measured.
Dogs were divided into 3 groups of 8. After measurement in each group of baseline values of heart rate (HR), mean arterial blood pressure (MAP), Pdi, Edi-cru, and Edi-cost, 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 (i.e., low-frequency fatigue) (3). Immediately after the end of a fatigue-producing period, the dogs inhaled vehicle (Group 1), colforsin daropate 0.1 mg/mL (Group 2), or colforsin daropate 0.2 mg/mL (Group 3) from a DeVilbiss 646 nebulizer operated by compressed air at 5 L/min. The nebulizer output was 0.14 mL/min. Two concentrations of colforsin daropate were prepared by dilution with saline 10 mL: 0.1 mg/mL (1 mg) and 0.2 mg/mL (2 mg). Thirty minutes after the start of inhalation, in each group, HR, MAP, Pdi, Edi-cru, and Edi-cost were measured. The changes of Edi-cru and Edi-cost (%Edi-cru and %Edi-cost) from baseline values were also measured.
Values are mean ± SD. Statistical analysis was performed by using analysis of variance for repeated measurements with Bonferroni’s adjustment for multiple comparisons and Student’s t-test, as appropriate. P < 0.05 was considered significant.
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Results
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No differences in baseline variables (HR, MAP, Pdi, %Edi-cru, and %Edi-cost) were observed among the groups. 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, no hemodynamic changes were observed throughout the experiment, and Pdi at 20-Hz stimulation during the fatigued condition did not change 30 min after the end of the fatigue-producing period. With inhalation of colforsin daropate, in Groups 2 and 3, HR increased (P < 0.05) and MAP decreased (P < 0.05) from baseline values. The Pdi at both stimuli increased from fatigued values (P < 0.05) during colforsin daropate inhalation. The increase in Pdi was more in Group 3 than in Group 2 (P < 0.05). No changes in %Edi-cru and %Ed-cost were observed throughout the study in any group (Table 1).
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Discussion
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Colforsin daropate administered IV is effective for the improvement of contractility in fatigued diaphragm (1). In this experiment, when colforsin daropate was inhaled, Pdi at 20- and 100-Hz stimulation increased from fatigued values (P < 0.05) in Groups 2 and 3, and the increase in Pdi at both stimuli was significantly larger in Group 3 than in Group 2 (P < 0.05). These findings suggest that olprinone, when administered by inhalation, as well as infusion, improves, in a dose-dependent manner, the contractility of fatigued diaphragm.
In our previous report (1), to clarify the mechanism responsible for the efficacy of colforsin daropate administered IV for the improvement of contractility in fatigued diaphragm, combined colforsin daropate and nicardipine, inhibiting calcium influx into the diaphragm muscle, was administered. Consequently, augmentation of Pdi by colforsin daropate in fatigued diaphragm was abolished by administering nicardipine. This suggests that colforsin daropate may increase the contractility of fatigued diaphragm by influencing calcium transport across the cell membrane. The mechanism of inhaled colforsin daropate for the augmentation of contractility in fatigued diaphragm is not known, but is probably similar to that of colforsin daropate administered IV.
The therapeutic usefulness of inhaled colforsin daropate in diaphragmatic fatigue remains unclear in the clinical setting. Recently, Wajima et al. (4) have shown a bronchodilator effect of colforsin daropate administered IV in humans and have speculated that colforsin daropate may be useful as a bronchodilator in the treatment of bronchial asthma. Similarly, on the basis of our results, inhaled colforsin daropate would be useful for the treatment of diaphragmatic fatigue, which is implicated as a cause of respiratory failure (5,6) , in humans. In addition, there is a possibility that inhalation therapy with colforsin daropate may play an important role in outpatients with chronic end-stage lung diseases and/or in long-term inpatients with chronic obstructive pulmonary diseases if IV access cannot be attained. However, further clinical studies are required to confirm these speculations.
In conclusion, inhaled colforsin daropate causes an increase in the contractility of fatigued canine diaphragm in a dose-related fashion.
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References
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- Fujii Y, Hoshi T, Toyooka H. Colforsin daropate improves contractility in fatigued canine diaphragm. Anesth Analg 2001; 92: 762–6.[Abstract/Free Full Text]
- Uemura A, Fujii Y, Toyooka H. Inhaled olprinone improves contractility of fatigued canine diaphragm. Br J Anaesth 2002; 88: 409–11.
- Aubier M, Farkas G, DeTroyer A, et al. Detection of diaphragmatic fatigue in man by phrenic nerve stimulation. J Appl Physiol 1981; 50: 538–44.[Abstract/Free Full Text]
- Wajima Z, Yoshikawa T, Ogura A, et al. Intravenous colforsin daropate, a water-soluble forskolin derivative, prevents thiamylal-fentanyl-induced bronchoconstriction in humans. Crit Care Med 2002; 30: 820–6.[ISI][Medline]
- Macklem PT, Roussos C. Respiratory muscle fatigue: a cause of respiratory failure. Clin Sci Mol Med 1977; 53: 419–22.[ISI][Medline]
- Cohen CA, Zagelbaum G, Gross D, et al. Clinical manifestations of inspiratory muscle fatigue. Am J Med 1982; 73: 308–16.[ISI][Medline]
Accepted for publication November 26, 2002.
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Abstract
Introduction
