Andrew M Coney

University of Birmingham · Institute of Clinical Sciences

Introduction Mitochondrial succinate metabolism in the heart during acute or chronic hypoxia is a major cause of cellular death and dysfunction. However, its impact on cardiac electrical function is largely unknown. This could be of importance given that atrial and ventricular arrhythmias are very common following ischaemia/reperfusion. This study...

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia (Hindricks et al., 2021). Emerging evidence suggests that the association of AF with conditions such as obstructive sleep apnoea, COPD and heart failure may be partly attributable to atrial autonomic remodelling in the setting of chronic hypoxia (CH) and chronic-intermittent h...

Obstructive sleep apnoea (OSA) is a strong independent risk factor for atrial fibrillation (AF). Emerging clinical data cite adverse effects of OSA on AF induction, maintenance, disease severity, and responsiveness to treatment. Prevention using continuous positive airway pressure (CPAP) is effective in some groups but is limited by its poor compli...

Angiotensin II (Ang II) is a hormone that plays a major role in maintaining homeostasis. The Ang II receptor type 1 (AT1R) is expressed in acute O2 sensitive cells, including carotid body (CB) type I cells and pheochromocytoma 12 (PC12) cells, and Ang II increases cell activity. While a functional role for Ang II and AT1Rs in increasing the activit...

It is generally acknowledged that the carotid body (CB) type I cell mitochondria are unique, being inhibited by relatively small falls in PaO2 well above those known to inhibit electron transport in other cell types. This feature is suggested to allow for the CB to function as an acute O2 sensor, being stimulated and activating systemic protective...

This work represents the findings of a novel contactless technique, Structured Light Plethysmography used in the detection of patterns of dysfunctional breathing through measuring the tidal breathing parameters from the thoraco-abdominal movements in Post-COVID-19 recovered patients 3 months after discharge from different units; Intensive care unit...

Introduction: There is relatively little published on the effects of COVID-19 on respiratory physiology, particularly breathing patterns. We sought to determine if there were lasting detrimental effect following hospital discharge and if these related to the severity of COVID-19. Methods: We reviewed lung function and breathing patterns in COVID...

Reflex increases in breathing in response to acute hypoxia are dependent on activation of the carotid body (CB)—A specialised peripheral chemoreceptor. Central to CB O2-sensing is their unique mitochondria but the link between mitochondrial inhibition and cellular stimulation is unresolved. The objective of this study was to evaluate if ex vivo int...

Introduction: There is relatively little published on the effects of COVID-19 on respiratory physiology, particularly breathing patterns. We sought to determine if there were lasting detrimental effect following hospital discharge and if these related to the severity of COVID-19. Methods: We reviewed lung function and breathing patterns in COVID-19...

Introduction Structured Light Plethysmography (SLP) is a novel non-invasive, contactless technique utilising only a grid of white light and cameras to track, measure, capture Throraco-Abdominal (TA) displacement and record quiet tidal breathing. Repeatability is used to assess the measurements from two devices for the same test subject when recorde...

Carotid body (CB) hyperactivity promotes hypertension in response to chronic intermittent hypoxia (CIH). The plasma concentration of adrenaline is reported to be elevated in CIH and our previous work suggests that adrenaline directly activates the CB. However, a role for chronic adrenergic stimulation in mediating CB hyperactivity is currently unkn...

The laboratory practical reported here is based in Poiseuille’s law and utilizes low-cost laboratory consumable items, thereby making it easy to deploy in any teaching laboratory. In the practical, students take an experimental approach of individually changing physical variables and measuring fluid flow rates. Plotting these results allows them to...

The carotid body (CB) is an important organ located at the carotid bifurcation that constantly monitors the blood supplying the brain. During hypoxia, the CB immediately triggers an alarm in the form of nerve impulses sent to the brain. This activates protective reflexes including hyperventilation, tachycardia and vasoconstriction, to ensure blood...

The mammalian carotid body (CB) is the primary arterial chemoreceptor that responds to acute hypoxia, initiating systemic protective reflex responses that act to maintain O2 delivery to the brain and vital organs. The CB is unique in that it is stimulated at O2 levels above those that begin to impact on the metabolism of most other cell types. Whil...

Ventilatory and neuroendocrine counter-regulatory responses during hypoglycaemia are essential in order to maintain glycolysis and prevent rises in PaCO2 leading to systemic acidosis. The mammalian carotid body has emerged as an important driver of hyperpnoea and glucoregulation in hypoglycaemia. However, the adequate stimulus for CB stimulation in...

Some neuropsychiatric disease, including schizophrenia, may originate during prenatal development, following periods of gestational hypoxia and placental oxidative stress. Here we investigated if gestational hypoxia promotes damaging secretions from the placenta that affect fetal development and whether a mitochondria-targeted antioxidant MitoQ mig...

Key points: Carotid body dysfunction is recognized as a cause of hypertension in a number of cardiorespiratory diseases states and has therefore been identified as a potential therapeutic target. Purinergic transmission is an important element of the carotid body chemotransduction pathway. We show that inhibition of ecto-5'-nucleotidase (CD73) in...

Hypoglycaemia (HG) evokes a counter‐regulatory response to restore arterial blood glucose levels. Additionally, HG has also been shown to evoke an increase in ventilation whilst maintaining normocapnia suggesting the ventilation remained matched to metabolism. Whilst it has been shown that HG induces an increase in CO 2 sensitivity, there is a lack...

Key points: Hypoglycaemia is counteracted by release of hormones and an increase in ventilation and CO2 sensitivity to restore blood glucose levels and prevent a fall in blood pH. The full counter-regulatory response and an appropriate increase in ventilation is dependent on carotid body stimulation. We show that the hypoglycaemia-induced increase...

Models of chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnoea (OSA), have demonstrated dysregulation of the cardiovascular and respiratory systems resulting in hypertension, cardiac hypertrophy and alterations in the hypoxic ventilatory response (HVR) due to changes in sympathetic and respiratory control by the carotid...

Ageing leads to impaired endothelium‐dependent vasodilatation and sympathetically‐mediated vasoconstriction in many tissues including brain. We hypothesised cerebral autoregulation is modulated by these influences and ageing is associated with impaired autoregulation at the upper limit (UL). In anaesthetised young (Y) male Wistar rats (6‐8 weeks, n...

The role of sympathetic fibres in cerebral circulation is unclear. Evidence suggests sympathetic activity exerts a tonic constrictor influence on cerebral blood flow (CBF) and protects against increases in arterial blood pressure (ABP) at the upper limit (UL) of autoregulation. Ageing impairs sympathetic functioning, but how this affects cerebral c...

Vascular tone in cerebral circulation is partly determined by NO‐mediated dilatation. NO has also been implicated in the cerebral vasodilatation in response to hypercapnia/hypoxia and at the lower limit of autoregulation. However the role of NO at the upper limit (UL) is unclear. Further, as ageing leads to impaired endothelium‐dependent vasodilata...

Adverse conditions prenatally increase the risk of cardiovascular disease, including hypertension. Chronic hypoxia in utero (CHU) causes endothelial dysfunction, but whether sympathetic vasoconstrictor nerve functioning is altered is unknown. We, therefore, compared in male CHU and control (N) rats muscle sympathetic nerve activity, vascular sympat...

In Alfaxan‐anaesthetised, male Wistar rats, we infused phenylephrine (0.1‐200µg/kg/min i.v.) to raise arterial pressure (ABP). Dual‐line least‐squares analysis of gross cerebral blood flow (CBF), recorded from the common carotid with external carotid ligated, vs ABP, gave an autoregulatory upper limit (UL) of 168±3mmHg (n=14). By contrast, after ne...

Hypoglycaemia in vivo induces a carotid body‐dependent increase in ventilation suggested to reflect a direct action of reduced blood glucose on the CB, but an indirect effect via an action of counter‐regulatory hormones, including epinephrine, has not been discounted. Ventilation (VE) was recorded during insulin‐induced hypoglycaemia (2.9±0.08mM) a...

Muscle sympathetic vasoconstriction is blunted in CH, however, there is no change in the modulatory role of NO. Exercise intolerance and CH are features of diseases such as COPD, this may reflect alterations in FS and fatigability. In accordance with UK legislation, experiments were performed on anaesthetised CH rats (3 weeks acclimation to 12% O2)...

FS is the exercise attenuation of sympathetic vasoconstriction. It is unclear if NO is the major mediator of FS or if the size of FS is graded to the level of exercise. Experiments were performed on anaesthetised rats (under UK legislation). Sympathetic vasoconstriction was induced by stimulation of the lumbar sympathetic chain (LSC). EDL contracti...

We have previously shown that when pregnant Wistar dams are housed in a chamber containing 12% O2, the adult male offspring (CHU) show altered skeletal muscle vasodilator responses to acute hypoxia (breathing 8% O2). Relative to normal (N) rats, these dilator responses showed a reduced functional role for nitric oxide (NO) in rats exposed to CHU fo...

Suboptimal conditions in utero can have long-lasting effects including increased risk of cardiovascular disease in adult life. Such programming effects may be induced by chronic systemic hypoxia in utero (CHU). We have investigated how CHU affects cardiovascular responses evoked by acute systemic hypoxia in adult male offspring, recognising that ad...

Acute cooling significantly increases energy demand in non-hibernators for the defence of core temperature but the contribution of the liver to thermogenesis is poorly understood. A two-tracer method to estimate lipid metabolism in cold-naïve control (CON) and cold-acclimated (CA) rats was employed to quantify hepatic rates of fat metabolism. Both...

There is evidence that sympathetically evoked vasoconstriction in skeletal muscle is blunted in systemic hypoxia, but the mechanisms underlying this phenomenon are not clear. In Saffan-anaesthetized Wistar rats, we have studied the role of alpha(2)-adrenoceptors and neuropeptide Y (NPY) Y(1) receptors in mediating vasoconstriction evoked by direct...

Background:Atherosclerosis is a chronic multi-step inflammatory process with similarities to rheumatoid inflammation. As endothelial dysfunction (ECD), the first step in atherogenesis, can be reversed by the TNF blockade that induces remission in RA, we hypothesised that sphingolipid mediators may link inflammatory cytokines to both depression of T...

We studied the role of nitric oxide (NO) in blunting sympathetically evoked muscle vasoconstriction during acute and chronic systemic hypoxia. Experiments were performed on anaesthetized normoxic (N) and chronically hypoxic (CH) rats that had been acclimated to 12% O(2) for 3-4 weeks. The lumbar sympathetic chain was stimulated for 1 min with burst...

Necrotising enterocolitis (NEC) is a potentially devastating disorder of preterm infants but its aetiology remains unclear. The aim of these studies was to develop a neonatal piglet model for NEC and to then use the model to investigate the role of platelet activating factor (PAF) in its pathogenesis. Anaesthetised newborn piglets were divided into...

Background: Hypoxia and bacterial colonisation are major risk factors for NEC. Aim: To investigate the role of hypoxia and endotoxin (lipopolysaccharide, LPS), both singly and in combination, on the degree of intestinal damage in a neonatal piglet model of NEC. Methods: 29 anaesthetised piglets, median age 2 days and weight 1861 g, were studied. A...

Muscle vasodilatation evoked by systemic hypoxia is adenosine mediated and nitric oxide (NO) dependent: recent evidence suggests the increased binding of NO at complex IV of endothelial mitochondria when O2 level falls leads to adenosine release. In this study on anaesthetised rats, the increase in femoral vascular conductance (FVC) evoked by syste...

Previous studies have shown that systemic hypoxia evokes vasodilatation in skeletal muscle that is mediated mainly by adenosine acting on A1 receptors, and that the vasoconstrictor effects of sympathetic nerve activity are depressed during hypoxia. The aim of the present study was to investigate the role of adenosine in this depression. In anaesthe...

Adenosine, prostaglandins (PG) and nitric oxide (NO) have all been implicated in hypoxia-evoked vasodilatation. We investigated whether their actions are interdependent. In anaesthetised rats, the PG synthesis inhibitors diclofenac or indomethacin reduced muscle vasodilatation evoked by systemic hypoxia or adenosine, but not that evoked by iloprost...

In anesthetized rats, we characterized the contributions of norepinephrine (NE) and ATP to changes in tail and hindlimb (femoral) vascular resistances (TVR and FVR, respectively) evoked by three patterns of sympathetic stimulation: 1) couplets (2 impulses at 20 Hz), 2) short trains (20 impulses at 20 Hz), and 3) a natural irregular pattern previous...

We have previously shown that exogenous PAF causes lesions in piglets which are identical to NEC. We therefore devised and evaluated a unique experimental model for NEC (using recognised precipitating factors) to assess the role of PAF antagonists (PAFA) as possible therapeutic agents. Methods: 15 anaesthetised neonatal piglets formed 3 groups: Con...

In anaesthetized rats, we have examined the role of adenosine in vasodilatation evoked in the cerebral cortex by systemic hypoxia (breathing 8 % O 2 ). Red cell flux was recorded from the surface of the exposed parietal cortex (CoRCF) by a laser Doppler probe, cortical vascular conductance (CoVC) being computed as CoRCF divided by mean arterial blo...