Search PubMed⌕ Search

Biomedical subjects

Aidan Bradford

Publications and source records attributed to Aidan Bradford.

9 recordsLinked to original sources

Does episodic hypoxia affect upper airway dilator muscle function? Implications for the pathophysiology of obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is characterised by repetitive collapse of the upper airway during sleep owing to a sleep-related decrement in upper airway muscle activity with consequent failure of the pharyngeal dilator muscles to oppose the collapsing pressure that is generated by the diaphragm and accessory muscles during inspiration. The causes of upper airway obstruction during sleep are multi-factorial but there is evidence implicating intrinsic upper airway muscle function and impaired central regulation of the upper airway muscles in the pathophysiology of OSA. The condition is associated with episodic hypoxia due to recurrent apnoea. However, despite its obvious importance very little is known about the effects of episodic hypoxia on upper airway muscle function. In this review, we examine the evidence that chronic intermittent hypoxia can affect upper airway muscle structure and function and impair CNS control of the pharyngeal dilator muscles. We review the literature and discuss results from our laboratory showing that episodic hypoxia/asphyxia reduces upper airway muscle endurance and selectively impairs pharyngeal dilator EMG responses to physiological stimulation. Our observations lead us to speculate that episodic hypoxia--a consequence of periodic airway occlusion--is responsible for progression of OSA through impairment of the neural control systems that regulate upper airway patency and through altered respiratory muscle contractile function, leading to the establishment of a vicious cycle of further airway obstruction and hypoxic insult that chronically exacerbates and perpetuates the condition. We conclude that chronic intermittent hypoxia/asphyxia contributes to the pathophysiology of sleep-disordered breathing.

Animals↗

Simultaneous recording of breathing and respiratory related neuronal activity in the brainstem of conscious rats.

One aim of integrative neurophysiology is to understand the relationship between neuronal activity and normal evolution of other physiological parameters. In this respect, anaesthetics or paralyzing agents, that have been shown to have a significant effect on several vital physiological processes, can be seen as a real problem for the interpretation of observations. Eletrophysiological recording in awake animals avoids this problem. Recordings in forebrain areas are now used routinely but a number of specific difficulties have limited their application to the medullary areas. In this paper, we describe a preparation that allows us to simultaneously record neuronal activity in the dorsal brainstem and respiratory activity in awake rats, while applying different types of respiratory challenges.

Action Potentials↗

Intravascular thrombosis after hypoxia-induced pulmonary hypertension: regulation by cyclooxygenase-2.

BACKGROUND: Pulmonary hypertension induced by chronic hypoxia is characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, and right-heart failure. Prostacyclin analogues reduce pulmonary pressures in this condition; raising the possibility that cycloxygenase-2 (COX-2) modulates the response of the pulmonary vasculature to hypoxia. METHODS AND RESULTS: Sprague-Dawley rats in which pulmonary hypertension was induced by hypobaric hypoxia for 14 days were treated concurrently with the selective COX-2 inhibitor SC236 or vehicle. Mean pulmonary arterial pressure (mPAP) was elevated after hypoxia (28.1+/-3.2 versus 17.2+/-3.1 mm Hg; n=8, P<0.01), with thickening of small pulmonary arteries and increased COX-2 expression and prostacyclin formation. Selective inhibition of COX-2 aggravated the increase in mPAP (42.8+/-5.9 mm Hg; n=8, P<0.05), an effect that was attenuated by the thromboxane (TX) A2/prostaglandin endoperoxide receptor antagonist ifetroban. Urinary TXB2 increased during hypoxia (5.9+/-0.9 versus 1.2+/-0.2 ng/mg creatinine; n=6, P<0.01) and was further increased by COX-2 inhibition (8.5+/-0.7 ng/mg creatinine; n=6, P< 0.05). In contrast, urinary excretion of the prostacyclin metabolite 6-ketoprostaglandin F1alpha decreased with COX-2 inhibition (8.6+/-3.0 versus 27.0+/-4.8 ng/mg creatinine; n=6, P< 0.05). Platelet activation was enhanced after chronic hypoxia. COX-2 inhibition further reduced the PFA-100 closure time and enhanced platelet deposition in the smaller pulmonary arteries, effects that were attenuated by ifetroban. Mice with targeted disruption of the COX-2 gene exposed to chronic hypoxia had exacerbated right ventricular end-systolic pressure, whereas targeted disruption of COX-1 had no effect. CONCLUSIONS: COX-2 expression is increased and regulates platelet activity and intravascular thrombosis in hypoxia-induced pulmonary hypertension.

Animals↗

Effects of chronic intermittent asphyxia on haematocrit, pulmonary arterial pressure and skeletal muscle structure in rats.

Sleep-disordered breathing in humans is a common condition associated with serious cardiovascular and other abnormalities. The prevalence and pathogenesis of increased haematocrit and pulmonary hypertension is controversial and it has been suggested that these changes only occur in patients who also have daytime continuous hypoxaemia. The hypothesis tested here is that the chronic intermittent hypoxia and asphyxia associated with sleep-disordered breathing causes erythropoiesis and pulmonary hypertension and that this occurs in the absence of periods of continuous hypoxia. In humans and animals with obstructive sleep apnoea, there are abnormalities of upper airway muscle structure that have been ascribed to increased load placed on these muscles. An alternative hypothesis is that chronic intermittent hypoxia and asphyxia cause changes in upper airway muscle structure and function. To test these hypotheses, rats were exposed to intermittent hypoxia and asphyxia for 8 h per day for 5 weeks. This caused an increase in haematocrit, right ventricular weight and pulmonary arterial pressure. There were only slight changes in diaphragm, upper airway and limb muscle structure and force production but in general, muscle fatigability was increased. In conclusion chronic intermittent hypoxia and asphyxia cause an increase in haematocrit and pulmonary arterial pressure in the absence of periods of continuous hypoxia. Chronic intermittent hypoxia and asphyxia have little effect on skeletal muscle structure and force production but increase muscle fatigue. Increased upper airway muscle fatigue could lead to a vicious cycle of further compromise in upper airway patency and further hypoxia and asphyxia.

Animals↗

Effects of chronic intermittent asphyxia on rat diaphragm and limb muscle contractility.

OBJECTIVE: In obstructive sleep apnea (OSA), there is intermittent upper airway (UA) collapse due to an imbalance between the collapsing force generated by the diaphragm and the stabilizing force of the UA muscles. This results in chronic intermittent asphyxia (CIA). We have previously shown that CIA affects UA muscle fatigue, but little is known about the effects of chronic hypoxia on diaphragm or on limb muscle contractile properties and structure. DESIGN: Rats were exposed to asphyxia and normoxia twice per minute for 8 h/d for 5 weeks to simulate the intermittent asphyxia of OSA in humans. Isometric contractile properties were determined from strips of isolated diaphragm, extensor digitorum longus (EDL), and soleus muscles in Krebs solution at 30 degrees C. EDL and soleus type 1 (slow, fatigue resistant), type 2A (fast, fatigue resistant), and type 2B (fast, fatigable) fiber distribution was determined using adenosine triphosphatase staining. RESULTS: CIA caused a significant increase in diaphragm, EDL, and soleus fatigue, and reduced recovery from fatigue. Most of the other contractile properties were unaffected aside from a small reduction in diaphragm half-relaxation time and EDL twitch tension and a small shift to the left in the EDL force-frequency curve. There was no change in soleus fiber-type distribution and a small increase in EDL type 2A fibers (46.1 +/- 1.2% vs 49.9 +/- 1.4%, control vs CIA [mean +/- SD]). CONCLUSIONS: CIA increases diaphragm, EDL, and soleus muscle fatigue. We speculate that if this also occurs in OSA, it would contribute to the pathophysiology of the condition.

Animals↗

Chronic intermittent asphyxia impairs rat upper airway muscle responses to acute hypoxia and asphyxia.

BACKGROUND: Obstructive sleep apnea (OSA) is a major clinical disorder that is characterized by multiple episodes of upper airway obstruction due to the failure of the upper airway dilator muscles to maintain upper airway patency. This results in chronic intermittent asphyxia (CIA) due to repetitive apneas, but very little is known about the effects of CIA on upper airway muscle function. OBJECTIVE: To test the hypothesis that CIA affects upper airway muscle activity and electromyogram (EMG) responses to acute hypoxia and asphyxia. DESIGN: Record upper airway EMG responses to acute hypoxia and asphyxia in control and CIA-treated rats. SETTING: Department of Physiology, Royal College of Surgeons in Ireland, Dublin, Ireland. MEASUREMENTS: Sternohyoid (SH) muscle and diaphragm (DIA) muscle EMG activities were recorded in both groups during normoxia, hypoxia (7.5% O(2) in N(2)), and asphyxia (7.5% O(2) and 3% CO(2)) under pentobarbitone anesthesia. RESULTS: Baseline SH EMG activity was significantly elevated in the CIA-treated rats compared to the controls, whereas DIA EMG activity was similar in the two groups. In addition, CIA significantly reduced SH EMG but not DIA EMG responses to acute hypoxia and asphyxia. CONCLUSIONS: The elevated upper airway muscle activity associated with OSA in humans during wakefulness is due at least in part to CIA. We propose that a reduction in the response of upper airway dilator muscles to acute asphyxia following upper airway obstruction is likely to cause further asphyxic insult, leading to a vicious feed-forward cycle exacerbating the condition. Our results suggest that CIA contributes to the pathophysiology of sleep-disordered breathing.

Analysis of Variance↗

Effects of chronic episodic hypoxia on rat upper airway muscle contractile properties and fiber-type distribution.

OBJECTIVE: Contraction of upper airway (UA) muscles such as the geniohyoids and sternohyoids dilates and/or stabilizes the UA, thereby maintaining its patency. Obstructive sleep apnea (OSA) is caused by episodes of UA collapse, and this results in chronic episodic hypoxia. Chronic continuous hypoxia affects skeletal muscle structure and function, but the effects of chronic episodic hypoxia on UA muscle structure and function are unknown. DESIGN: Rats were exposed to alternating periods of hypoxia and normoxia twice per minute for 8 h/d for 5 weeks in order to mimic the intermittent hypoxia of OSA in humans. Isometric contractile properties were determined using strips of isolated geniohyoid and sternohyoid muscles in physiologic saline solution at 30 degrees C. Fiber-type distribution was determined using adenosine triphosphatase staining. RESULTS: Chronic episodic hypoxia had no significant effect on twitch or tetanic tension, twitch/tetanic tension ratio, contractile kinetics, tension-frequency relationship, or fiber-type distribution for either the sternohyoid or geniohyoid muscle. However, chronic episodic hypoxia did significantly increase sternohyoid and geniohyoid fatigue and reduced recovery from fatigue. CONCLUSIONS: Chronic episodic hypoxia increases UA muscle fatigue, an effect that may compromise the maintenance of UA patency.

Animals↗

The effects of chronic episodic hypercapnic hypoxia on rat upper airway muscle contractile properties and fiber-type distribution.

OBJECTIVE: Obstructive sleep apnea (OSA) is caused by episodes of upper airway (UA) obstruction due to an inability of UA muscles such as the geniohyoids and sternohyoids to maintain airway patency. This results in chronic episodic hypercapnic hypoxia. Chronic continuous hypoxia and episodic hypocapnic hypoxia affect skeletal muscle structure and function, but the effects of chronic episodic hypercapnic hypoxia on UA muscle structure and function are unknown. DESIGN: Rats breathed air and hypercapnic hypoxic gas twice per minute for 8 h/d for 5 weeks in order to mimic the intermittent hypercapnic hypoxia of OSA in humans. Isometric contractile properties were determined using strips of isolated geniohyoid and sternohyoid muscles in physiologic saline solution at 30 degrees C. Fiber-type distribution was determined by adenosine triphosphatase staining. RESULTS: For both muscles, chronic episodic hypercapnic hypoxia had no significant effect on twitch or tetanic tension, twitch/tetanic tension ratio, and tension-frequency relationship. There was a significant (p < 0.05) increase in geniohyoid fatigue (50.5 +/- 6.6% vs 43.6 +/- 5.8% of initial tension), but sternohyoid fatigue was reduced (31.5 +/- 5.2% vs 37.8 +/- 6.0% of initial tension). Geniohyoid type 1 fibers were reduced and type 2B fibers increased, whereas sternohyoid muscle had an increase in type 1 and 2A fibers and a decrease in type 2B fibers. CONCLUSIONS: Chronic episodic hypercapnic hypoxia alters UA muscle structure and function, changes that may affect the regulation of UA patency.

Animals↗