Experimental Physiology

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Dissociation between blood pressure and heart rate response to hypoxia after bilateral carotid body removal in men with systolic heart failure

01 March 2014

While the ventilatory response to hypoxia is known to be mediated by the carotid bodies, the origin of the haemodynamic alterations evoked by hypoxia is less certain. Bilateral carotid body removal (CBR) performed to treat congestive heart failure may serve as a model to improve our understanding of haemodynamic responses to hypoxia in humans. We studied six congestive heart failure patients before and 1 month after CBR [median (interquartile range): age, 58.5 (56–61) years old; and ejection fraction, 32 (25–34)%]. Peripheral chemosensitivity (hypoxic ventilatory response) was equated to the slope relating lowest oxygen saturation to highest minute ventilation following exposures to hypoxia. Likewise, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) slopes were calculated as slopes relating the lowest oxygen saturations to the highest SBP, DBP and HR responses. We found that CBR reduces the hypoxic ventilatory response (91%, P < 0.05), SBP (71%, P < 0.05) and DBP slopes (59%, P = 0.07). In contrast, the HR slope remained unchanged. The dissociation between the blood pressure and HR responses after CBR shows involvement of a different chemoreceptive site(s) maintaining the response to acute hypoxia. We conclude that carotid bodies are responsible for ventilatory and blood pressure responses, while the HR response might be mediated by the aortic bodies. The significant reduction of the blood pressure response to hypoxia after CBR suggests a decrease in sympathetic tone, which is of particular clinical relevance in congestive heart failure.

The effect of increased physical activity on pulmonary diffusing capacity in unfit women

01 March 2014

The purpose of the study was to determine whether short-term high-intensity aerobic interval training improves resting pulmonary diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO). Twenty-eight sedentary women [mean (SD) age 32 (11) years, body mass index 24.3 (5.7) kg m–2] were randomly assigned to either a self-directed moderate-intensity physical activity (n = 14) group or a supervised high-intensity aerobic interval training group (n = 14). The moderate physical activity group and the aerobic interval training group increased weekly physical activity energy expenditure by 800 and 1600 kcal week–1, respectively. After 6 weeks, aerobic capacity increased to a similar exent in both groups (mean improvement 8%, effect size 0.39). The DLNO, but not DLCO, increased to a similar extent in both groups, by 4% or 3.0 (5.7) [95% confidence interval 0.8, 5.2] ml min–1 mmHg–1 m–2 from pre- to post-training (effect size 0.27). There was no correlation between the change in aerobic capacity and the change in DLNO (P > 0.05) or between the change in aerobic capacity and the change in total weekly physical activity energy expenditure (P > 0.05). Interval training does not provide additional improvements in DLNO or aerobic capacity compared with self-directed moderate-intensity physical activity (4–6 metabolic equivalent tasks, 800 kcal week–1, for 6 weeks) in unfit women. Despite the slight improvement in both DLNO and aerobic capacity, true meaningful physiological changes in these parameters remain questionable.

Phox2b-expressing retrotrapezoid neurons and the integration of central and peripheral chemosensory control of breathing in conscious rats

01 March 2014

Chemoreception is the classic mechanism by which the brain regulates breathing in response to changes in tissue CO2/H+. A brainstem region called the retrotrapezoid nucleus (RTN) contains a population of Phox2b-expressing glutamatergic neurons that appear to function as important chemoreceptors. In the present study, we ask whether the destruction of a type of pH-sensitive interneuron that expresses the transcription factor Phox2b and is non-catecholaminergic (Phox2b+TH–) could affect breathing in conscious adult rats. The injection of substance P (1 nmol in a volume of 50 nl) into the RTN increased respiratory frequency, tidal volume, minute ventilation and mean arterial pressure. Bilateral injections of the toxin substance P conjugated with saporin (SSP–SAP) into the RTN destroyed Phox2b+TH– neurons but spared facial motoneurons, catecholaminergic and serotonergic neurons and the ventral respiratory column caudal to the facial motor nucleus. Bilateral inhibition of RTN neurons with SSP–SAP (0.6 ng in 30 nl) reduced resting ventilation and the increase in ventilation produced by hypercapnia (7% CO2) in conscious rats with or without peripheral chemoreceptors. In anaesthetized rats with bilateral lesions of around 90% of the Phox2b+TH– neurons, acute activation of the Bötzinger complex, the pre-Bötzinger complex or the rostral ventral respiratory group with NMDA (5 pmol in 50 nl) elicited normal cardiorespiratory output. In conclusion, the destruction of the Phox2b+TH– neurons is a plausible cause of the respiratory deficits observed after injection of SSP–SAP into the RTN. Our results also suggest that RTN neurons activate facilitatory mechanisms important to the control of breathing in resting or hypercapnic conditions in conscious adult rats.

Assessment of dynamic cerebral autoregulation and cerebrovascular CO2 reactivity in ageing by measurements of cerebral blood flow and cortical oxygenation

01 March 2014

With ageing, cerebral blood flow velocity (CBFV) decreases; however, to what extent dynamic cerebral autoregulation and cerebrovascular CO2 reactivity are influenced by ageing is unknown. The aim was to examine the dynamic responses of CBFV and cortical oxygenation to changes in blood pressure (BP) and arterial CO2 across different ages. Fifty-eight participants in three age groups were included, as follows: young (n = 20, 24 ± 2 years old), elderly (n = 20, 66 ± 1 years old), and older elderly (n = 18, 78 ± 3 years old). The CBFV was measured using transcranial Doppler ultrasound, simultaneously with oxyhaemoglobin (O2Hb) using near-infrared spectroscopy and beat-to-beat BP measurements using Finapres. Postural manoeuvres were performed to induce haemodynamic fluctuations. Cerebrovascular CO2 reactivity was tested with hyperventilation and CO2 inhalation. With age, CBFV decreased (young 59 ± 12 cm s–1, elderly 48 ± 7 cm s–1 and older elderly 42 ± 9 cm s–1, P < 0.05) and cerebrovascular resistance increased (1.46 ± 0.58, 1.81 ± 0.36 and 1.98 ± 0.52 mmHg cm–1 s–1, respectively, P < 0.05). Normalized gain (autoregulatory damping) increased with age for BP–CBFV (0.88 ± 0.18, 1.31 ± 0.30 and 1.06 ± 0.34, respectively, P < 0.05) and CBFV–O2Hb (0.10 ± 0.09, 0.12 ± 0.04 and 0.17 ± 0.08, respectively, P < 0.05) during the repeated sit–stand manoeuvre at 0.05 Hz. Even though the absolute changes in CBFV and cerebrovascular resistance index during the cerebrovascular CO2 reactivity were higher in the young group, the percentage changes in CBFV, cerebrovascular resistance index and O2Hb were similar in all age groups. In conclusion, there was no decline in dynamic cerebral autoregulation and cerebrovascular CO2 reactivity with increasing age up to 86 years. Despite the decrease in cerebral blood flow velocity and increase in cerebrovascular resistance with advancing age, CBFV and cortical oxygenation were not compromised in these elderly humans during manoeuvres that mimic daily life activities.

Editorial Board

01 February 2014

The neural regulation of the kidney in hypertension and renal failure

01 February 2014
New Findings

  • What is the topic of this review?

    Reports that bilateral renal denervation in resistant hypertensive patients results in a long-lasting reduction in blood pressure raise the question of the underlying mechanisms involved and how they may be deranged in pathophysiological states of hypertension and renal failure.

  • What advances does it highlight?

    The renal sensory afferent nerves and efferent sympathetic nerves work together to exert an important control over extracellular fluid volume, hence the level at which blood pressure is set. This article emphasizes that both the afferent and the efferent renal innervation may contribute to the neural dysregulation of the kidney that occurs in chronic renal disease and resistant hypertension.

  • Autonomic control is central to cardiovascular homeostasis, and this is exerted not only at the level of the heart and blood vessels but also at the kidney. At the kidney, the sympathetic neural regulation of renin release and fluid reabsorption may influence fluid balance and, in the longer term, the level at which blood pressure is set. The role of the renal innervation in the regulation of blood pressure has received renewed attention over the past few years, following the reports that bilateral renal denervation of resistant hypertensive patients resulted in a marked reduction in blood pressure, which has been maintained for several years. Such has been the interest that this approach of renal denervation is being applied in other patient groups with diabetes, obesity and renal failure, with the hope that there may be a sustained reduction in blood pressure as well as the amelioration of some aspects of the metabolic syndrome. However, the factors that come into play to cause the rise in blood pressure in these patient groups, particularly the resistant hypertensive patients, are far from clear. Moreover, the mechanisms leading to the fall in blood pressure following renal denervation of resistant hypertensive patients currently elude our understanding and is therefore an area that requires much more investigation to enhance our insight.

    Vagal modulation of cardiac ventricular arrhythmia

    01 February 2014
    New findings

  • What is the topic of this review?

    This article addresses the relationship between vagus nerve activity and malignant ventricular arrhythmias. It focuses on the clinical association of an impaired vagal tone in cardiac disease states with high mortality from sudden cardiac death and the potential underlying mechanisms.

  • What advances does it highlight?

    The article summarizes the mounting evidence that vagal innervation in the cardiac ventricle plays a key direct role in the prevention of the initiation of ventricular fibrillation. Data are presented on the role that nitric oxide plays in mediating the effects of vagal protection against ventricular fibrillation, supporting the notion that a separate non-muscarinic, nitrergic population of vagal neurons is responsible for this protection.

  • Sudden cardiac death remains a significant unresolved clinical problem, with many of the deaths being due to malignant ventricular arrhythmias. Markers of abnormal autonomic function have been shown to be strong prognostic predictors, highlighting the important relationship between reduced vagal tone and malignant ventricular arrhythmias, such as ventricular fibrillation, in cardiac patients. Exploring the mechanisms underlying the autonomic modulation of ventricular fibrillation, my group has shown that vagus nerve stimulation protects against ventricular fibrillation in the innervated isolated heart preparation. We have provided direct evidence that nitric oxide is released in the ventricle with cervical vagus nerve stimulation and NO mediates the antifibrillatory actions of vagus nerve stimulation in the ventricle. Classical physiology teaches that vagal postganglionic nerves modulate the heart via acetylcholine acting at muscarinic receptors and, dogmatically, that there is little vagal effect in the ventricle, as innervation was believed to be sparse. Mounting evidence from many species now supports the presence of a rich vagal innervation in the ventricle. Data from my group showing that the protective actions of vagus nerve stimulation against ventricular fibrillation and NO release are preserved in the presence of muscarinic block support the notion that a population of nitrergic neurons could be responsible. This potentially exploitable downstream pathway together with the availability of vagus nerve stimulators make it an exciting time to investigate the development of an effective strategy of vagal protection against ventricular fibrillation in the clinical setting.

    Autonomic control of the heart during exercise in humans: role of skeletal muscle afferents

    01 February 2014
    New findings

  • What is the topic of this review?

    The autonomic nervous system plays a key role in bringing about the cardiovascular responses to exercise necessitated by the increased metabolic requirements of the active skeletal muscle. The complex interaction of central and peripheral neural control mechanisms evokes a decrease in parasympathetic activity and an increase sympathetic activity to the heart during exercise.

  • What advances does it highlight?

    This review presents some of the recent insights provided by human studies into the role of mechanically and metabolically sensitive skeletal muscle afferents in the regulation of cardiac autonomic control during exercise.

  • The autonomic responses to exercise are orchestrated by the interactions of several central and peripheral neural mechanisms. This report focuses on the role of peripheral feedback from skeletal muscle afferents in the autonomic control of the heart during exercise in humans. Heart rate responses to passive calf stretch are abolished with cardiac parasympathetic blockade, indicating that the activation of mechanically sensitive skeletal muscle afferents (muscle mechanoreceptors) can inhibit cardiac parasympathetic activity and is likely to contribute to the increase in heart rate at the onset of exercise. Recent experiments show that the partial restriction of blood flow to the exercising skeletal muscles, to augment the activation of metabolically sensitive skeletal muscle afferents (muscle metaboreceptors) in humans, evokes an increase in heart rate that is attenuated with β1-adrenergic blockade, thus suggesting that this response is principally mediated via an increase in cardiac sympathetic activity. Heart rate remains at resting levels during isolated activation of muscle metaboreceptors with postexercise ischaemia following hand grip, unless cardiac parasympathetic activity is inhibited, whereupon a sympathetically mediated increase in heart rate is unmasked. During postexercise ischaemia following leg cycling exercise, heart rate appears to remain elevated due to withdrawal of parasympathetic tone and/or the activation of sympathetic activity to the heart. Although the importance of skeletal muscle afferent feedback to the autonomic control of the heart during exercise is incontrovertible, the complexity of cardiac sympathetic–parasympathetic interactions and the absence of direct intraneural recordings in humans mean that it remains incompletely understood.

    Muscle afferents and cardiorespiratory control: the Birmingham connection

    01 February 2014
    New findings

  • What is the topic of this review?

    This brief review describes the work of Professor John Coote and colleagues at the University of Birmingham, which has contributed to understanding of the role of muscle afferent involvement in cardiorespiratory control in exercise.

  • What advances does it highlight?

    The seminal findings of John Coote's early work are highlighted, as well as more recent developments in the field, especially the role of muscle afferents in the control of human ventilation during exercise.

  • Through the work of John Coote, research into the role of muscle afferent involvement in cardiorespiratory control has had strong links with Birmingham since the late 1960s. This brief review gives an historical background to John's early work and how his research and mentorship of colleagues continues to have a profound influence on the field today.

    Cardiovascular control from cardiac and pulmonary vascular receptors

    01 February 2014
    New Findings

  • What is the topic of this review?

    The purpose of this review is to summarize present knowledge of the function of the afferent nerves arising from the heart and the coronary and pulmonary arteries. Although there is abundant evidence that atrial receptor stimulation influences heart rate and urine flow, with little or no effect elsewhere, and that ventricular receptors are strongly excited only by chemical stimuli, there is still the erroneous belief that they act as a homogeneous group causing cardiovascular depression.

  • What advances does it highlight?

    Coronary receptors deserve to be recognized as a potentially important additional group of baroreceptors. Stimulation of pulmonary arterial baroreceptors at physiological pressures causes reflex vasoconstriction and could have a hitherto unacknowledged important role in cardiovascular control, for example in exercise.

  • Although there has been a tendency to regard cardiac and pulmonary receptors as a single population of ‘cardiopulmonary receptors’, this cannot be justified as the various receptor types all induce their own particular pattern of responses. Stimulation of atrial receptors increases activity in sympathetic nerves to the sino-atrial node, causing tachycardia, but there is no effect on activity to the myocardium or to most blood vessels. Renal nerve activity, however, is decreased, and secretion of antidiuretic hormone is inhibited, causing diuresis. Ventricular receptors induce a powerful depressor response, but only in response to abnormal chemical stimulation and possibly to myocardial injury. Coronary arterial receptors function as baroreceptors, but have a lower threshold and a more prolonged effect than other baroreceptors. Pulmonary arterial baroreceptors induce vasoconstriction and respiratory stimulation at physiological pressures and may be of importance in mediating some of the responses to exercise, as well as in hypoxic conditions.

    Deep brain stimulation and autonomic control

    01 February 2014
    New Findings

  • What is the topic of this review?

    This article reviews data from studies on human participants and animal models showing how electrical stimulation in deep brain structures (deep brain stimulation) can influence autonomic function.

  • What advances does it highlight?

    Focusing on the control of the cardiovascular system and bladder function, it highlights the potential for development of deep brain stimulation as a new treatment option for patients with autonomic dysfunction.

  • Deep brain stimulation (DBS) in humans has come of age as a tool to treat movement disorders including Parkinson's disease tremor and dystonia as well as a panoply of other disease states including headache, epilepsy, obesity, eating disorders, depression, obsessive compulsive disorder, Tourette's syndrome, addiction and chronic pain. Increasingly, practitioners of DBS are reporting autonomic side effects, which intriguingly, sometimes result in improved autonomic function. Focussing on the effects of stimulation at periaqueductal and periventricular sites on cardiovascular function and control of micturition, this review shows that data obtained from studies in animals is now being confirmed in humans. Lowering of blood pressure and improved baroreflex function can be evoked in humans by DBS at these midbrain sites as well as increased bladder capacity. The findings highlight the tantalizing possibility that DBS could be developed for treatment of dysfunctional autonomic states in humans.

    Cortical control of the autonomic nervous system

    01 February 2014
    New Findings

  • What is the topic of this review?

    The pathways in the brain by which visceral information, in particular cardiopulmonary afferents, ascend to the cerebral cortex have been delineated in animal models. Studies using functional magnetic resonance imaging in humans have confirmed what was known from the animal studies and established the critical sites in the cerebral cortex of humans for autonomic control and the significance of these sites for cognitive emotional function.

  • What advances does it highlight?

    Stimulation of cardiopulmonary afferents in humans has consistently resulted in activation in the insular cortex and the anterior cingulate cortex. It has been shown that individuals who are characterized as cardiovascular responders to mental stress have a different pattern of activity in the cortex related to the cardiac changes.

  • A number of animal studies in the rat and cat have been particularly useful for determining the pathways and the sites in the forebrain and cortex that are responsible for autonomic control. For example, these experiments have demonstrated that there is a viscerotopically organized pathway, with the first site of termination in the nucleus of the solitary tract and with subsequent relays in the parabrachial nucleus and the ventroposterior parvocellular nucleus of the thalamus before final visceral afferent inputs in the insular cortex. Several neuroimaging studies in humans, using cardiopulmonary manipulations, have confirmed the importance of the insular cortex as a site of for visceral afferent inputs. The anterior cingulate cortex has also been implicated in cardiopulmonary control. Both the insular cortex and the infralimbic cortex have been shown to be involved in descending control of the cardiovascular system. Neuroimaging with functional magnetic resonance imaging has demonstrated that the cortical autonomic control pathways are different in individuals who are characterized as cardiovascular reactors to mental stress. There is evidence that this alteration in pathways in the cortex may be due to past experiences, including childhood trauma.

    The paraventricular nucleus and heart failure

    01 February 2014
    New Findings

  • What is the topic of this review?

    This review gives an update on the cellular and molecular mechanisms within the autonomic nervous system involved in non-pathological and pathological cardiovascular regulation.

  • What advances does it highlight?

    For cardiovascular homeostasis in non-pathological conditions to be maintained, discrete neural networks using specified signalling mechanisms at both cellular and molecular levels are required. In heart failure, the cell signalling protein partners CAPON and PIN decrease the bioavailability of nitric oxide by inhibiting neuronal nitric oxide synthase activity, leading to the removal of tonic neuronal inhibition. Following a myocardial infarction, pro-inflammatory cytokines in the paraventricular nucleus and the subsequent generation of reactive oxygen species, via angiotensin II activation of the angiotensin II type 1 receptor, increase neuronal excitability further, leading to sympathetic excitation.

  • A pathological feature of heart failure is abnormal control of the sympathetic nervous system. The paraventricular nucleus of the hypothalamus (PVN) is one of the most important central sites involved in regulating sympathetic tone and is, in part, responsible for the dysregulation of the sympathetic nervous system evident in heart failure. Generation of sympathetic tone in response to fluctuations in cardiovascular regulation uses discrete anatomical pathways and neurochemical modulators. Direct and indirect projections from the PVN pre-autonomic neurons innervate the sympathetic preganglionic neurons in the spinal cord, which in turn innervate sympathetic ganglia that give rise to the sympathetic nerves. Pre-autonomic neurons of the PVN themselves receive an afferent input arising from the nucleus tractus solitarii, and viscerosensory receptors convey cardiovascular fluctuations to the nucleus tractus solitarii. The PVN contains excitatory and inhibitory neurons, whose balance determines the sympathetic tone. In non-pathological conditions, the tonic inhibition of the PVN pre-autonomic neurons is mediated by GABA- and NO-releasing neurons. In heart failure, the pre-autonomic neurons are disinhibited by the actions of the excitatory neurotransmitters glutamate and angiotensin II, leading to increased sympathetic activity. A key feature of the disinhibition is a reduction in the bioavailability of NO as a consequence of disrupted CAPON and PIN signalling mechanisms within the neuron. Another critical feature that contributes to increased neuronal excitation within the PVN is the production of pro-inflammatory cytokines immediately following a myocardial infarction, the activation of the angiotensin II type 1 receptor and the production of reactive oxygen species. By examining the changes associated with the sympathetic nervous system pathway, we will progress our understanding of sympathetic regulation in heart failure, identify gaps in our knowledge and suggest new therapeutic strategies.

    Differential effect of sympathetic activation on tissue oxygenation in gastrocnemius and soleus muscles during exercise in humans

    01 February 2014
    New Findings

  • What is the central question of this study?

    The normal ability of sympathetic nerves to cause vasoconstriction is blunted in exercising skeletal muscle, a phenomenon termed ‘functional sympatholysis’. Animal studies suggest that functional sympatholysis appears to occur preferentially in fast-twitch type II glycolytic compared with slow-twitch type I oxidative skeletal muscle. We asked whether these findings can be extended to humans.

  • What is the main finding and its importance?

    We show that skeletal muscles composed largely of fast-twitch type II fibres may also be more sensitive to functional sympatholysis in humans, particularly at lower exercise intensities. Additionally, independent of muscle fibre type composition, the magnitude of sympatholysis is strongly related to exercise-induced increases in metabolic demand.

  • Animal studies suggest that functional sympatholysis appears to occur preferentially in glycolytic (largely type II) compared with oxidative (largely type I) skeletal muscle. Whether these findings can be extended to humans currently remains unclear. In 12 healthy male subjects, vasoconstrictor responses in gastrocnemius (i.e. primarily type II) and soleus muscles (i.e. primarily type I) were measured using near-infrared spectroscopy to detect decreases in muscle oxygenation (HbO2) in response to sympathetic activation evoked by a cold pressor test (CPT). The HbO2 responses to a CPT at rest were compared with responses during steady-state plantar flexion exercise (30 repetitions min–1) performed at 10, 20 and 40% maximal voluntary contraction (MVC) for 6 min. In resting conditions, HbO2 at the gastrocnemius (–14 ± 1%) and soleus muscles (–16 ± 1%) decreased significantly during CPT, with no differences between muscles. During planter flexion at 20% MVC, the change in HbO2 in response to the CPT was blunted in gastrocnemius but not soleus, whereas during 40% MVC both muscles exhibited a significant attenuation to sympathetic activation. The decreases in HbO2 in response to the CPT during exercise were significantly correlated with the metabolic demands of exercise (the decreases in HbO2 in response to steady-state plantar flexion) in both gastrocnemius and soleus muscles. Collectively, these results suggest that skeletal muscles composed mainly of glycolytic type II fibres are more sensitive to functional sympatholysis, particularly at lower intensities of exercise. Moreover, the blunting of sympathetic vasoconstriction during exercise is strongly related to metabolic demand; an effect that appears independent of fibre type composition.

    Differential visceral pain sensitivity and colonic morphology in four common laboratory rat strains

    01 February 2014
    New Findings

  • What is the central question of this study?

    Does stress sensitivity and susceptibility to inflammation innate to certain rat strains make them vulnerable to bowel dysfunction?

  • What is the main finding and its importance?

    Of four different rat strains, the Lewis rat, which displays both susceptibility to gastrointestinal inflammation and sensitivity to stress, exhibits the most aberrant gastrointestinal morphology and visceral pain sensitivity. Given the similarities to human functional bowel disorders, such as irritable bowel syndrome, this may make it a good model of this disease.

  • Irritable bowel syndrome is a common, debilitating gastrointestinal (GI) disorder characterized by episodic exacerbations of symptoms such as abdominal pain, bloating and altered bowel habit. Contributory factors for the development of irritable bowel syndrome include genetics, childhood trauma and prior GI infection leading to chronic low-grade inflammation or immune activation. Additional considerations in comprehending the chronic relapsing pattern that typifies irritable bowel syndrome symptoms are the effects of both psychosocial and infection-related stresses. Background stress and immune profiles can influence gut permeability and visceral pain sensitivity. This study examined whether innate susceptibility to inflammation and stress sensitivity in four rat strains is associated with bowel dysfunction. The pain threshold to colorectal distension was assessed in Lewis, Fischer (F344) and spontaneously hypertensive rats and compared with Sprague–Dawley control animals. Colons were subsequently excised and morphologically assessed for total length, goblet cell hyperplasia and muscle and mucosal thickness. Lewis rats displayed visceral hypersensitivity compared with other strains. At a morphological level, the gastrointestinal tract from these rats displayed mucosal goblet cell hyperplasia and alterations in muscle layer thickness. The Lewis rat strain, which is reported to have increased susceptibility to GI inflammation in addition to stress sensitivity, had the most prominent features of physiological and morphological GI dysfunction. These data support the hypothesis that background strain is a key factor in the development and exacerbation of bowel dysfunction in rodent models.