The<i>β</i><sub>2</sub>‐adrenoceptor agonist terbutaline recovers rat pharyngeal dilator muscle force decline during severe hypoxia

McDonald, Fiona B.; Skelly, J. Richard; O’Halloran, Ken D.

doi:10.1111/odi.12247

Cited by 6 publications

(4 citation statements)

References 76 publications

(108 reference statements)

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“…Ten minutes following the force-frequency protocol, fatigue was assessed in response to repeated tetanic contractions (40 Hz, 300 ms train duration) every 2 s for 5 min. This is a well-established protocol for the study of respiratory muscle (Cantillon and Bradford, 1998 , 2000 ; O'Halloran, 2006 ; McMorrow et al, 2011 ; Skelly et al, 2011 , 2012 ; McDonald et al, 2015a , b ). At the end of the experiment, the L o and weight of each muscle blotted dry was recorded in order to calculate cross-sectional area.…”

Section: Methodsmentioning

confidence: 99%

Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during Adulthood

2016

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Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.

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Section: Methodsmentioning

confidence: 99%

Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during Adulthood

2016

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“…Diaphragm muscle function was assessed ex vivo under isometric conditions using a standardized protocol as previously reported (McMorrow et al, 2011 ; Skelly et al, 2012 ; McDonald et al, 2014 , 2015a , b , 2016 ; Shortt et al, 2014 ). Each experimental group at P22 (30–63 g) and P42 (112–290 g) consisted of rats randomized from multiple litters.…”

Section: Methodsmentioning

confidence: 99%

Effects of Gestational and Postnatal Exposure to Chronic Intermittent Hypoxia on Diaphragm Muscle Contractile Function in the Rat

2016

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Alterations to the supply of oxygen during early life presents a profound stressor to physiological systems with aberrant remodeling that is often long-lasting. Chronic intermittent hypoxia (CIH) is a feature of apnea of prematurity, chronic lung disease, and sleep apnea. CIH affects respiratory control but there is a dearth of information concerning the effects of CIH on respiratory muscles, including the diaphragm—the major pump muscle of breathing. We investigated the effects of exposure to gestational CIH (gCIH) and postnatal CIH (pCIH) on diaphragm muscle function in male and female rats. CIH consisted of exposure in environmental chambers to 90 s of hypoxia reaching 5% O2 at nadir, once every 5 min, 8 h a day. Exposure to gCIH started within 24 h of identification of a copulation plug and continued until day 20 of gestation; animals were studied on postnatal day 22 or 42. For pCIH, pups were born in normoxia and within 24 h of delivery were exposed with dams to CIH for 3 weeks; animals were studied on postnatal day 22 or 42. Sham groups were exposed to normoxia in parallel. Following gas exposures, diaphragm muscle contractile, and endurance properties were examined ex vivo. Neither gCIH nor pCIH exposure had effects on diaphragm muscle force-generating capacity or endurance in either sex. Similarly, early life exposure to CIH did not affect muscle tolerance of severe hypoxic stress determined ex vivo. The findings contrast with our recent observation of upper airway dilator muscle weakness following exposure to pCIH. Thus, the present study suggests a relative resilience to hypoxic stress in diaphragm muscle. Co-ordinated activity of thoracic pump and upper airway dilator muscles is required for optimal control of upper airway caliber. A mismatch in the force-generating capacity of the complementary muscle groups could have adverse consequences for the control of airway patency and respiratory homeostasis.

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“…Because β2-adrenergic vasodilatation plays a dominant role in maintaining normal tissue blood flow (Blauw et al 1995;Marshall 2000;Weisbrod et al 2001), the stimulation of β2 adrenoceptors could indeed improve oxygen transport to tissues by acting locally: terbutaline, the active metabolite of bambuterol, has reported abilities to restore the contractile force of isolated hypoxic skeletal muscle in vitro, highlighting its potential efficacy in hypoxic peripheral tissues in vivo (McDonald et al 2015).…”

Section: R a F Tmentioning

confidence: 99%

The novel combination of theophylline and bambuterol as a potential treatment of hypoxemia in humans

Strand

Khiabani

Boico

et al. 2017

Can. J. Physiol. Pharmacol.

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Hypoxemia can be life-threatening, both acutely and chronically. Because hypoxemia causes vascular dysregulation that further restricts oxygen availability to tissue, it can be pharmacologically addressed. We hypothesized that theophylline can be safely combined with the β2-adrenergic vasodilator bambuterol to improve oxygen availability in hypoxemic patients. Ergogenicity and hemodynamic effects of bambuterol and theophylline were measured in rats under hypobaric and normobaric hypoxia (12% O). Feasibility in humans was assessed using randomized, double-blind testing of the influence of combined slow-release theophylline (300 mg) and bambuterol (20 mg) on adverse events (AEs), plasma K, pulse, blood pressure, and drug interaction. Both drugs and their combination significantly improved hypoxic endurance in rats. In humans, common AEs were low K (<3.5 mmol/L; bambuterol: 12, theophylline: 4, combination: 13 episodes) and tremors (10, 0, 14 episodes). No exacerbation or serious AE occurred when drugs were combined. A drop in plasma K coincided with peak bambuterol plasma concentrations. Bambuterol increased heart rate by approximately 13 bpm. Drug interaction was present but small. We report promise, feasibility, and relative safety of combined theophylline and bambuterol as a treatment of hypoxemia in humans. Cardiac safety and blood K will be important safety endpoints when testing these drugs in hypoxemic subjects.

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Theβ₂‐adrenoceptor agonist terbutaline recovers rat pharyngeal dilator muscle force decline during severe hypoxia

Abstract: The β(2) -adrenoceptor agonist terbutaline completely recovers hypoxic depression of upper airway muscle force. β(2) -adrenoceptor agonists warrant investigation in animal models of OSAS reporting upper airway and diaphragm muscle dysfunction.

Cited by 6 publications

References 76 publications

Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during Adulthood

Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during Adulthood

Effects of Gestational and Postnatal Exposure to Chronic Intermittent Hypoxia on Diaphragm Muscle Contractile Function in the Rat

The novel combination of theophylline and bambuterol as a potential treatment of hypoxemia in humans

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Theβ2‐adrenoceptor agonist terbutaline recovers rat pharyngeal dilator muscle force decline during severe hypoxia

Abstract: The β(2) -adrenoceptor agonist terbutaline completely recovers hypoxic depression of upper airway muscle force. β(2) -adrenoceptor agonists warrant investigation in animal models of OSAS reporting upper airway and diaphragm muscle dysfunction.

Cited by 6 publications

References 76 publications

Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during Adulthood

Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during Adulthood

Effects of Gestational and Postnatal Exposure to Chronic Intermittent Hypoxia on Diaphragm Muscle Contractile Function in the Rat

The novel combination of theophylline and bambuterol as a potential treatment of hypoxemia in humans

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Theβ₂‐adrenoceptor agonist terbutaline recovers rat pharyngeal dilator muscle force decline during severe hypoxia