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Canadian Journal of Anesthesia 49:877-879 (2002)
© Canadian Anesthesiologists' Society, 2002
Cardiothoracic Anesthesia, Respiration and Airway

High-dose colforsin daropate increases diaphragmatic contractility in dogs

[De fortes doses de daropate de colforsine augmentent la contractilité diaphragmatique chez les chiens]

Yoshitaka Fujii, MD and Hidenori Toyooka, MD

From the Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba City, Ibaraki, Japan.

Dr. Y. Fujii, Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, 2-1-1, Amakubo, Tsukuba City, Ibaraki 305-8576, Japan. Phone: +81-298-53-3763; Fax: +81-298-53-3765; E-mail yfujii{at}igaku.md.tsukuba.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: To evaluate the effects of colforsin daropate, a water-soluble derivate known to improve contractility in fatigued canine diaphragm, at two different doses (low-dose and high-dose) on contractility of the non-fatigued diaphragm of dogs.

Methods: Twenty-four pentobarbitone-anesthetized dogs were divided into three groups of eight each: Group I received no study drug; Group II received low-dose (0.2 µg•kg-1•min-1) colforsin daropate; Group III received high-dose (0.5 µg•kg-1•min-1) colforsin daropate. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi).

Results: In Group III, with an infusion of high-dose colforsin daropate, Pdi at low-frequency (20 Hz) and high-frequency (100 Hz) stimulation increased from baseline values (P < 0.05). Compared with Group I, Pdi at both stimuli increased during colforsin daropate administration in Group III (P < 0.05). In Group II, with an infusion of low- dose colforsin daropate, Pdi to each stimulus did not change.

Conclusion: Colforsin daropate, only when administered at high-dose, increases contractility of non-fatigued diaphragm in dogs.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
LIKE phosphodiesterase (PDE) III inhibitors, colforsin daropate improves contractility in fatigued canine diaphragm1 that is implicated as a cause of respiratory failure2 while PDE III inhibitors have no effects on non-fatigued diaphragm.3–5 No data are available for colforsin daropate and contractility in the non-fatigued diaphragm. The purpose of this study was to evaluate the effects of colforsin daropate at two different doses (low-dose and high-dose) on diaphragm muscle function during non-fatigued condition in dogs.


   Methods
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 Abstract
 Introduction
 Methods
Results
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 References
 
The protocol was approved by our Animal Research Committee and care of the animals was in agreement with the guidelines of Ethical Animal Research. Twenty-four healthy mongrel dogs (10–15 kg) were used. Animal preparation was similar to that described previously.1 Briefly, anesthesia was maintained with pentobarbitone 2 mg•kg-1•hr-1 iv. No muscle relaxant was used. The animal’s trachea was intubated, and ventilation was mechanically controlled with a mixture of O2 and air (FiO2 = 0.4) to maintain PaO2, PaCO2, and pHa within normal ranges. A flow-directed pulmonary artery catheter was advanced via the right external jugular vein into the pulmonary artery to measure cardiac output (CO) by thermodilution technique. Transdiaphragmatic pressure (Pdi) was measured by means of two thin-walled latex balloons; one positioned in the stomach, the other in the middle third of the esophagus. Balloons were connected to a differential pressure transducer and an amplifier. Both phrenic nerves were exposed at the neck, and stimulating electrodes were attached. Supramaximal electrical stimuli (10–15 volts) of 0.1 msec duration were applied for two seconds 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 functional residual capacity. Electrical activity of the diaphragm was recorded by two pairs of electrodes, and it was rectified and integrated with a leaky integrator with a time constant of 0.1 sec. This was regarded as the integrated electrical activity of the crural (Edi-cru) and costal (Edi-cost) parts of diaphragm. The changes of Edi-cru (%Edi-cru) and Edi-cost (%Edi-cost) from baseline values are evaluated.

Dogs were randomly divided into three groups of eight each. Baseline measurements included Pdi, Edi-cru, Edi- cost, and hemodynamic variables, including heart rate (HR), mean arterial pressure (MAP), right atrial pressure (RAP), mean pulmonary arterial pressure (MPAP), pulmonary artery occlusion pressure (PAOP), and CO. In Group I, no study drug was administered. Group II received low-dose (0.2 µg•kg-1•min-1) colforsin daropate via an electrical infusion pump for 30 min; Group III received high-dose (0.5 µg•kg-1•min-1) colforsin daropate. After administering colforsin daropate, the same variables were measured.

Values are presented as mean ± SD. Statistical analysis was performed by ANOVA with Bonferroni’s adjustment for multiple comparison and Student’s t test, as appropriate. P < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
No differences in baseline values were observed among the groups. In Groups I and II, no changes in hemodynamics and Pdi were observed throughout the experiment. With the infusion of high-dose colforsin daropate in Group III, HR, CO, and Pdi at both stimuli increased and MAP, MPAP, and PAOP decreased from baseline values (P < 0.05). Compared with Group I, Pdi increased during high-dose colforsin daropate administration in Group III (P < 0.05). No changes in %Edi-cru and %Edi-cost were observed throughout the experiment in any group (TableGo).


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  		TABLE Changes in hemodynamics, Pdi (cm H2O), and %Edi
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this experiment, the dogs were basically anesthetized with pentobarbitone, and thereby combined effects of colforsin daropate and pentobarbitone on diaphragmatic contractility were examined. However, pentobarbitone, at the doses (2 mg•kg-1•hr-1) used in this study, does not affect diaphragmatic contractility.6 This is also in agreement with our results in Group I showing no change in Pdi throughout the experiment.

We demonstrated that Pdi at 20 Hz and 100 Hz stimulation increased from baseline values (P < 0.05) with the infusion of high-dose colforsin daropate in Group III; Pdi at both frequencies increased in Group III compared with Group I (P < 0.05); no changes in Pdi at both frequencies were observed in Group II. These findings suggest that high-dose colforsin daropate increases contractility in non-fatigued diaphragm. The precise mechanism by which high-dose colforsin daropate increases diaphragmatic contractility is not known. Colforsin daropate is thought to augment contractility in cardiac muscle by increasing cyclic adenosine monophosphate by direct stimulation of adenyl cyclase, which, in turn, activates calcium transport from the sarcoplasmic reticulum.7,8 Like in cardiac muscle, it is thought that colforsin daropate increases diaphragmatic contractility by influencing calcium transport across the cell membrane, since the augmentation of Pdi by colforsin daropate in fatigued diaphragm is abolished by nicardipine that inhibits calcium influx into diaphragm muscles.1

Diaphragmatic contractility depends on the energy supplies to the diaphragm, which are related to its blood supply. CO is one of the major factors determining diaphragmatic blood flow.9 The increase in CO observed in Group III with an infusion of high-dose colforsin daropate may have led to an increase in diaphragmatic blood flow, and thereby may have increased diaphragmatic contractility. We showed that CO did not increase from baseline values in Group II during low-dose colforsin daropate administration, and that Pdi did not change. Thus, there is a possibility that augmentation of Pdi in Group III (P < 0.05) during high-dose colforsin daropate administration may be attributed to an increase in CO and diaphragmatic blood flow.

We previously showed that colforsin daropate at low-dose (0.2 µg•kg-1•min-1) and high-dose (0.5 µg•kg-1•min-1) increased Pdi at 20 Hz and 100 Hz stimulation in the fatigued diaphragm.1 In the present study, however, we demonstrated that only high-dose colforsin daropate increased diaphragmatic contractility during non-fatigued condition. The exact reason for this difference remains unknown.

In conclusion, colforsin daropate, when used at high-doses (0.5 µg•kg-1•min-1), increases contractility in non- fatigued canine diaphragm.

Revision received July 10, 2002. Accepted for publication April 18, 2002.


   References
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Fujii Y, Hoshi T, Toyooka H. Colforsin daropate improves contractility in fatigued canine diaphragm. Anesth Analg 2001; 92: 762–6.[Abstract/Free Full Text]

2 Macklem PT, Roussos CS. Respiratory muscle fatigue: a cause of respiratory failure? Clin Sci Mol Med 1977; 53: 419–22.[Medline]

3 Fujii Y, Toyooka H, Amaha K. Amrinone improves contractility of fatigued diaphragm in dogs. Can J Anaesth 1995; 42: 80–6.[Abstract/Free Full Text]

4 Fujii Y, Takahashi S, Toyooka H. The effects of milrinone and its mechanism in the fatigued diaphragm in dogs. Anesth Analg 1998; 87: 1077–82.[Abstract/Free Full Text]

5 Fujii Y, Toyooka H. Different effects of olprinone on contractility in nonfatigued and fatigued diaphragm in dogs. Can J Anesth 2000; 47: 1243–8.[Abstract]

6 Ide T, Kochi T, Isono S, Mizuguchi T. Effect of sevoflurane on diaphragmatic contractility in dogs. Anesth Analg 1992; 74: 739–46.[Abstract/Free Full Text]

7 Hosono M, Kanbe E, Noguchi M, et al. Effects of NKH477, a novel forskolin derivative, in isolated cardiac muscles (Japanese). Clin Pharmacol Ther 1996; 6: 1061–72.

8 Hosoda S, Motomiya T, Katagiri T, et al. Acute effect of NKH477, a novel forskolin derivative, in patients with acute heart failure: a multicenter placebo-controlled double-blind trial (Japanese). Jpn J Clin Pharmacol Ther 1997; 28: 583–602.

9 Robertson CH Jr, Foster GH, Johnson RL Jr. The relationship of respiratory failure to the oxygen consumption of, lactate production by, and distribution of blood flow among respiratory muscles during increasing inspiratory resistance. J Clin Invest 1977; 59: 31–42.





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