Aminophylline increases ventilation and diaphragm contractility in awake canines

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Abstract

Traditional theophylline bronchodilators are still used clinically, especially in COPD. However, the effect of theophyllines on ventilation and respiratory muscles remains uncertain and these effects have not been measured directly in any awake, intact mammal. We hypothesized that aminophylline in the usual therapeutic dosage range, would elicit in the awake mammal, a significant increase in ventilation, and a significant increase in costal diaphragm shortening and contractility as recorded directly from the muscle. Therefore, we studied 13 awake canines, which had been chronically implanted with fine-wire EMG electrodes and sonomicrometer crystals in the costal segment of the diaphragm. Ventilatory parameters, moving average muscle EMG activity and muscle length and shortening, were measured at baseline and with aminophylline, during resting and hypercapnic stimulated breathing. Experiments were carried out prior to administration of aminophylline (baseline), and 1.5 h after loading and ongoing infusion with aminophylline. Minute ventilation, tidal volume and respiratory frequency all increased significantly with aminophylline, both during resting breathing and at equivalent levels of hypercapnic stimulated breathing. Costal diaphragm baseline muscle length was entirely unchanged with aminophylline. Costal diaphragm shortening increased significantly with aminophylline while corresponding costal diaphragm EMG activity remained constant, consistent with increased diaphragm contractility. Thus, in awake, intact mammals, aminophylline in usual therapeutic dosage elicits increased ventilation and increased contractility of respiratory muscles.

Introduction

The traditional theophylline bronchodilators and aminophylline are still in use today, mostly in the treatment of chronic obstructive pulmonary disease (COPD) and severe asthma (Barnes, 2003). Although the mechanisms of action of theophylline and aminophylline remain uncertain, the methylxanthines seem to offer benefits beyond simple bronchodilation, including mucociliary clearance (Wanner, 1985) and anti-inflammatory properties (Barnes, 2003). Some patients with airways obstruction may benefit from the additional respiratory stimulant and muscle inotropic actions of the theophyllines (Berry et al., 1991, Mahler et al., 1984). However, these latter attributes are a source of some controversy.

Aminophylline seems to reliably increase ventilation at rest, amplifies the human hypoxic response (Lakshminarayan et al., 1978), and attenuates the ventilatory depression that ensues with hypoxia (Easton and Anthonisen, 1988, Georgopoulos et al., 1989, Kawai et al., 1995, Nishii et al., 2008). What remains unsettled is the effect of aminophylline on mammalian respiratory muscles, notably the costal diaphragm, in the intact and awake state. It is this latter potential muscle inotropic effect which is of particular interest for clinical medicine and is the focus of this study.

In vitro studies of theophylline with skeletal muscle fibers, and in vivo anesthetized animal studies are generally consistent in support of a significant effect of aminophylline to enhance diaphragm contraction (Delbono and Kotsias, 1990, Delbono and Kotsias, 1993, Losavio and Kotsias, 1991). However, human studies examining the muscle inotropic effects of the methylxanthines offer some contradictions. In awake humans, trans-diaphragmatic pressure may increase significantly with aminophylline (Aubier et al., 1981) or alternatively trans-diaphragmatic pressure may not increase (Levy et al., 1990). Exercise capability in some COPD patients may improve with theophyllines (Fink et al., 1994, McKay et al., 1993), but exercise in normal subjects after aminophylline may not improve (Violante et al., 1989). These contradictions may be attributed to the inevitable methodological restrictions of each type of study: in vitro studies may not quite reproduce the human aminophylline therapeutic dose range; in vivo animal studies employ anesthetic; human studies deduce diaphragm contractility by indirect pressure recordings such as transdiaphragmatic pressure. To date there has not been an opportunity to measure the effect of aminophylline upon ventilation and diaphragm function, at a therapeutic dosage, in an awake mammal, using techniques that record directly from the target muscle, namely the costal diaphragm.

Therefore, the aim of this study was to specifically re-examine the ventilatory and diaphragm inotropic effect of aminophylline, within the human clinical dose range, in the awake state without confounding anesthetic, by high precision, simultaneous direct measurement of muscle length and EMG activity, avoiding indirect deductions about diaphragm function derived from global pressure measurements. We hypothesized that aminophylline in a clinical therapeutic dosage range, would elicit in the awake mammal, a significant increase in ventilation, and a significant enhancement in costal diaphragm shortening and contractility when directly measured. To test this hypothesis, we studied 13 awake canines, which had previously been chronically implanted with sonomicrometry ultrasound transducers and EMG electrodes in the costal diaphragm.

Section snippets

Implantation of transducers and electrodes

The project was approved by the animal care committee at the University of Calgary. Each mongrel canine had pairs of sonomicrometry transducers and bipolar fine wire electromyogram (EMG) electrodes implanted in left costal diaphragm segments. Animals were studied after diaphragm segmental shortening had recovered fully. This technique of chronic sonomicrometry and EMG implantation, and the 7–10 day progressive recovery of diaphragm segmental shortening, has been described in detail elsewhere (

Results

Measurements were made in 13 chronically instrumented canines with a mean weight of 30.3 kg (range 24–43 kg). The studies were conducted an average of 25 days (range 10–34 days) after chronic implantation of sonomicrometry transducers and EMG electrodes. At the conclusion of the aminophylline protocol, the mean serum aminophylline (±SD) for the group was 68.9 ± 7.49 μmol/L, midway within the normal clinical therapeutic range of 55–100 μmol/L.

Aminophylline actions and dosage

Although aminophylline has retreated to a role as a 3rd line bronchodilator, it persists in clinical medicine. The durability of theophylline is attributable partly to recognized auxiliary benefits beyond bronchodilation, including mucociliary clearance (Wanner, 1985) and anti-inflammatory properties partly through histone deacetylase activation (Barnes, 2003) which may recommend this old drug as a new adjunct to contemporary corticosteroids (Barnes, 2003, Mahler, 2008). Yet the longevity of

Acknowledgments

Supported by grants from the Canadian Institutes of Health Research. Expert technical assistance was provided by Mr. Maros Pazej, Mr. Michael Ji and Ms. Leslie Jacques. The provision of all suture materials by Ethicon Sutures Ltd., a Johnson & Johnson Company, is gratefully acknowledged.

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