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Distention of the proximal colon may have inhibitory or excitatory effects on the rectum and vice versa. The reflexes between the proximal colon and the rectum have not been well studied due to difficulties in accessing the proximal colon. The aim of this study was to investigate the reflex responses and their mechanisms between the proximal colon and the rectum in consideration of distention-related changes in tone and compliance of these regions as well as anal sphincter relaxation in a canine model. Proximal colon/rectal tone, compliance, and anal sphincter relaxation were investigated in six dogs chronically implanted with a proximal colon cannula while in the fasting state and during proximal colon distention or rectal distention. It was found that: 1) both rectal distention and proximal colon distention significantly and substantially decreased the compliance of the opposite regions, and guanethidine abolished proximal colon distention-induced changes in rectal compliance; 2) rectal/proximal colon distension decreased proximal colonic/rectal tone, and guanethidine abolished both of these inhibitory effects; 3) the anal sphincter was more sensitive to rectal distention than proximal colon distention; and 4) the minimal distention pressure required to induce anal inhibitory reflex was lower for rectal distention than proximal colon distention. It was concluded that distention-related changes in tone and compliance suggest the long inhibitory reflexes between the proximal colon and the rectum with the sympathetic involvement in rectal responses. The anal sphincter is more sensitive to the distention of the rectum than that of the proximal colon. gastrointestinal motility; gastrointestinal reflex; sympathetic pathway doi: 10.1152/ajpregu.00439.2009.

Endothelial cells play a vital role in the maintenance of cardiovascular homeostasis. Epoxyeicosatrienoic acids (EETs), cytochrome P-450 (CYP) epoxygenase metabolites of arachidonic acid in endothelial cells, possess potent and diverse biological effects within the vasculature. We evaluated the effects of overexpression of CYP epoxygenases on tumor necrosis factor-[alpha] (TNF-[alpha])-induced apoptosis in bovine aortic endothelial cells. CYP epoxygenase overexpression significantly increased endothelial cell viability and inhibited TNF-[alpha] induction of endothelial cell apoptosis as evaluated by morphological analysis of nuclear condensation, DNA laddering, and fluorescent-activated cell sorting (FACS) analysis. CYP epoxygenase overexpression also significantly inhibited caspase-3 activity and downregulation of Bcl-2 expression induced by TNF-[alpha]. The antiapoptotic effects of CYP epoxygenase overexpression were significantly attenuated by inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK signaling pathways; however, inhibition of endothelial nitric oxide synthase activity had no effect. Furthermore, CYP epoxygenase overexpression significantly attenuated the extent of TNF-[alpha]-induced ERK1/2 dephosphorylation in a time-dependent manner and significantly increased PI3K expression and Akt phosphorylation in both the presence and absence of TNF-[alpha]. Collectively, these results suggest that CYP epoxygenase overexpression, which is known to increase EET biosynthesis, significantly protects endothelial cells from apoptosis induced by TNF-[alpha]. This effect is mediated, at least in part, through inhibition of ERK dephosphorylation and activation of PI3K/Akt signaling. epoxyeicosatrienoic acid; arachidonic acid doi:10.1152/ajpheart.00783.2006

Necrotizing enterocolitis (NEC) is a major inflammatory disease of the premature human intestine that can be prevented by glucocorticoids if given prenatally before the 34th wk of gestation. This observation suggests that a finite period of steroid responsiveness exists as has been demonstrated in animal models. Human intestinal xenografts were used to determine whether a glucocorticoid responsive period exists in the developing human intestine. Developmental responsiveness was measured by lactase activity and inflammatory responsiveness by IL-8, IL-6, and monocyte chemotactic protein-1 (MCP-1) induction after an endogenous (IL-1[beta]) or exogenous (LPS) proinflammatory stimulus, respectively. Functional development of ileal xenografts were monitored for 30 wk posttransplantation, and the lactase activity recapitulated that predicted by in utero development. Cortisone acetate accelerated the ontogeny of lactase at 20 wk (immature) but the effect was lost by 30 wk (mature) posttransplant. Concomitant with accelerated maturation, the IL-8 response to both IL-1[beta] and LPS was significantly dampened (from 6- to 3-fold) by glucocorticoid pretreatment in the immature but not mature xenografts. The induction of IL-8 was reflected at the level of IL-8 mRNA, suggesting transcriptional regulation. The excessive activation of IL-8 in the immature gut was mediated by a prolonged activation of ERK and p38 kinases and nuclear translocation of NF-[kappa]B due to low levels of I[kappa]B. Steroid pretreatment in immature intestine dampens activation of all three signaling pathways in response to proinflammatory stimuli. Therefore, accelerating intestinal maturation by glucocorticoids within the responsive period by accelerating functional and inflammatory maturation may provide an effective preventive therapy for NEC. cortisone acetate; interleukin-8; human ileum; intestinal inflammation; signal transduction

Effective and widely available strategies are needed to diagnose colonic motility dysfunction. We investigated whether ultrasonography could generate spatiotemporal maps combined with motor pattern frequency analysis, to become a noninvasive method to characterize human colon motor patterns. Abdominal colonic ultrasonography was performed on healthy subjects (N = 7), focusing on the detailed recording of spontaneous haustral activities. We developed image segmentation and frequency analysis software to analyze the motor patterns captured. Ultrasonography recordings of the ascending, transverse, and descending colon identified three distinct rhythmic motor patterns: the 1 cycle/min and the 3 cycles/min cyclic motor pattern were seen throughout the whole colon, whereas the 12 cycles/min cyclic motor pattern was identified in the ascending colon. The rhythmic motor patterns of the human colon that are associated with interstitial cells of Cajal-associated pacemaking activity can be accurately identified and quantified using ultrasound. NEW & NOTEWORTHY Ultrasonography in the clinical field is an underutilized tool for assessing colonic motility; however, with the addition of frequency analysis techniques, it provides a method to identify human colonic motor patterns. Here we report on the 1, 3, and 12 cpm rhythmic motor patterns. Ultrasound has the potential to become a bedside assessment for colonic dysmotility and may reveal the health of interstitial cells of Cajal (ICC) pacemaker activities.

Deep breathing exercises are the second most used complementary health approach in the United States. Two heart rate variability (HRV) parameters, the root mean square of successive differences (RMSSD) and the respiratory sinus arrhythmia (RSA), are used to assess parasympathetic reactivity to deep breathing, but they are often not in agreement. Our purpose was to determine the cause of the disagreement. We investigated HRV parameters in 38 subjects during baseline, deep breathing, and recovery. Here we show that RMSSD as a measure of parasympathetic reactivity is unreliable; it does not reflect the increase in HRV during deep breathing as determined by RSA. We observed a decrease in RMSSD values despite a marked increase in HRV as determined by RSA and the standard deviation of normal heartbeat interval (SDNN) in healthy subjects and patients with functional bowel disorders. We show that RSA captures all aspects of HRV, whereas successive differences in heart rate intervals are only a small part of HRV, with decreasing variability during deep breathing in most subjects. We present a new measure of calculating RSA during deep breathing that may become an essential tool for researchers and clinicians. We also provide a unique visualization of the increased heart rate variability during deep breathing. Hence, RMSSD cannot be used to assess parasympathetic reactivity during deep breathing; using RSA is recommended. The use of RMSSD in previous influential studies may have led to erroneous conclusions about parasympathetic reactivity during deep breathing. Its continued use may undervalue the effects of the autonomic nervous system in slow deep breathing.

The machinery maintaining fecal continence prevents involuntary loss of stool and is based on the synchronized interplay of multiple voluntary and involuntary mechanisms, dependent on cooperation between motor responses of the musculature of the colon, pelvic floor, and anorectum, and sensory and motor neural pathways. Knowledge of the physiology of fecal continence is key toward understanding the pathophysiology of fecal incontinence. The idea that involuntary contraction of the internal anal sphincter is the primary mechanism of continence and that the external anal sphincter supports continence only by voluntary contraction is outdated. Other mechanisms have come to the forefront, and they have significantly changed viewpoints on the mechanisms of continence and incontinence. For instance, involuntary contractions of the external anal sphincter, the puborectal muscle, and the sphincter of O'Beirne have been proven to play a role in fecal continence. Also, retrograde propagating cyclic motor patterns in the sigmoid and rectum promote retrograde transit to prevent the continuous flow of content into the anal canal. With this review, we aim to give an overview of primary and secondary mechanisms controlling fecal continence and evaluate the strength of evidence.

Our understanding of human colonic motility, and autonomic reflexes that generate motor patterns, has increased markedly through high-resolution manometry. Details of the motor patterns are emerging related to frequency and propagation characteristics that allow linkage to interstitial cells of Cajal (ICC) networks. In studies on colonic motor dysfunction requiring surgery, ICC are almost always abnormal or significantly reduced. However, there are still gaps in our knowledge about the role of ICC in the control of colonic motility and there is little understanding of a mechanistic link between ICC abnormalities and colonic motor dysfunction. This review will outline the various ICC networks in the human colon and their proven and likely associations with the enteric and extrinsic autonomic nervous systems. Based on our extensive knowledge of the role of ICC in the control of gastrointestinal motility of animal models and the human stomach and small intestine, we propose how ICC networks are underlying the motor patterns of the human colon. The role of ICC will be reviewed in the autonomic neural reflexes that evoke essential motor patterns for transit and defecation. Mechanisms underlying ICC injury, maintenance, and repair will be discussed. Hypotheses are formulated as to how ICC dysfunction can lead to motor abnormalities in slow transit constipation, chronic idiopathic pseudo-obstruction, Hirschsprung's disease, fecal incontinence, diverticular disease, and inflammatory conditions. Recent studies on ICC repair after injury hold promise for future therapies.

Contraction patterns of the human colon are rarely discussed from the perspective of its haustra. Colonic motility was analyzed in 21 healthy subjects using 84-sensor manometry catheters with 1-cm sensor spacing. Capsule endoscopy and manometry showed evidence of narrow rhythmic circular muscle contractions. X-ray images of haustra and sensor locations allowed us to identify manometry motor activity as intrahaustral activity. Two common motor patterns were observed that we infer to be associated with individual haustra: rhythmic pressure activity confined to a single sensor, and activity confined to a section of the colon of 3-6 cm length. Intrahaustral activity was observed by 3-4 sensors. Approximately 50% of the haustra were intermittently active for ∼30% of the time; 2,402 periods of haustral activity were analyzed. Intrahaustral activity showed rhythmic pressure waves, propagating in mixed direction, 5-30 mmHg in amplitude at a frequency of ∼3 cpm (range 2-6) or ∼12 cpm (range 7-15), or exhibiting a checkerboard segmentation pattern. Boundaries of the haustra showed rhythmic pressure activity with or without elevated baseline pressure. Active haustra often showed no boundary activity probably allowing transit to neighboring haustra. Haustral boundaries were seen at the same sensor for the 6- to 8-h study duration, indicating that they did not propagate, thereby likely contributing to continence. The present study elucidates the motility characteristics of haustral boundaries and the nature of intrahaustral motor patterns and paves the way for investigating their possible role in pathophysiology of defecation disorders. NEW & NOTEWORTHY Here, we present the first full characterization and quantification of motor patterns that we infer to be confined to single haustra, both intrahaustral activity and haustral boundary activity, in the human colon using high-resolution manometry. Haustral activity is intermittent but consistently present in about half of the haustra. Intrahaustral activity presents as a cyclic motor pattern of mixed propagation direction dominated by simultaneous pressure waves that can resolve into checkerboard segmentation, allowing for mixing, absorption, and stool formation.

Characterization of high-amplitude propagating pressure waves (HAPWs or HAPCs) plays a key role in diagnosis of colon dysmotility using any type of colonic manometry. With the introduction of high-resolution manometry, more insight is gained into this most prominent propulsive motor pattern. Here, we use a water-perfused catheter with 84 sensors with intervals between measuring points of 1 cm throughout the colon, for 6-8 h, in 19 healthy subjects. The catheter contained a balloon to evoke distention. We explored as stimuli a meal, balloon distention, oral prucalopride, and bisacodyl injection, with a goal to optimally evoke HAPWs. We developed a quantitative measure of HAPW activity, the "HAPW Index." Our protocol elicited 290 HAPWs. 21% of HAPWs were confined to the proximal colon with an average amplitude of 75.3 ± 3.3 mmHg and an average HAPW Index of 440 ± 58 mmHg·m·s. 29% of HAPWs started in the proximal colon and ended in the transverse or descending colon, with an average amplitude of 87.9 ± 3.1 mmHg and an average HAPW Index of 3,344 ± 356 mmHg·m·s. Forty-nine percent of HAPWs started and ended in the transverse or descending colon with an average amplitude of 109.3 ± 3.3 mmHg and an average HAPW Index of 2,071 ± 195 mmHg·m·s. HAPWs with and without simultaneous pressure waves (SPWs) initiated the colo-anal reflex, often abolishing 100% of anal sphincter pressure. Rectal bisacodyl and proximal balloon distention were the most optimal stimuli to evoke HAPWs. These measures now allow for a confident diagnosis of abnormal motility in patients with colonic motor dysfunction. NEW & NOTEWORTHY High-amplitude propagating pressure waves (HAPWs) were characterized using 84 sensors throughout the entire colon in healthy subjects, taking note of site of origin, site of termination, amplitude, and velocity, and to identify optimal stimuli to evoke HAPWs. Three categories of HAPWs were identified, including the associated colo-anal reflex. Proximal balloon distention and rectal bisacodyl were recognized as reliable stimuli for evoking HAPWs, and a HAPW Index was devised to quantify this essential colonic motor pattern.

The rabbit proximal colon is similar in structure to the human colon. Our objective was to study interactions of different rhythmic motor patterns focusing on haustral boundary contractions, which create the haustra, using spatiotemporal mapping of video recordings. Haustral boundary contractions were seen as highly rhythmic circumferential ring contractions that propagated slowly across the proximal colon, preferentially but not exclusively in the anal direction, at ∼0.5 cycles per minute; they were abolished by nerve conduction blockers. When multiple haustral boundary contractions propagated in the opposite direction, they annihilated each other upon encounter. Ripples, myogenic propagating ring contractions at ∼9 cycles per min, induced folding and unfolding of haustral muscle folds, creating an anarchic appearance of contractile activity, with different patterns in the three intertaenial regions. Two features of ripple activity were prominent: frequent changes in propagation direction and the occurrence of dislocations showing a frequency gradient with the highest intrinsic frequency in the distal colon. The haustral boundary contractions showed an on/off/on/off pattern at the ripple frequency, and the contraction amplitude at any point of the colon showed waxing and waning. The haustral boundary contractions are therefore shaped by interaction of two pacemaker activities hypothesized to occur through phase-amplitude coupling of pacemaker activities from interstitial cells of Cajal of the myenteric plexus and of the submuscular plexus. Video evidence shows the unique role haustral folds play in shaping contractile activity within the haustra. Muscarinic agents not only enhance the force of contraction, they can eliminate one and at the same time induce another neurally dependent motor pattern., (Copyright © 2016 the American Physiological Society.)

Phase-amplitude coupling of two pacemaker activities of the small intestine, the omnipresent slow wave activity generated by interstitial cells of Cajal of the myenteric plexus (ICC-MP) and the stimulus-dependent rhythmic transient depolarizations generated by ICC of the deep muscular plexus (ICC-DMP), was recently hypothesized to underlie the orchestration of the segmentation motor pattern. The aim of the present study was to increase our understanding of phase-amplitude coupling through modeling. In particular the importance of propagation velocity of the ICC-DMP component was investigated. The outcome of the modeling was compared with motor patterns recorded from the rat or mouse intestine from which propagation velocities within the different patterns were measured. The results show that the classical segmentation motor pattern occurs when the ICC-DMP component has a low propagation velocity (<0.05 cm/s). When the ICC-DMP component has a propagation velocity in the same order of magnitude as that of the slow wave activity (∼1 cm/s), cluster type propulsive activity occurs which is in fact the dominant propulsive activity of the intestine. Hence, the only difference between the generation of propagating cluster contractions and the Cannon-type segmentation motor pattern is the propagation velocity of the low-frequency component, the rhythmic transient depolarizations originating from the ICC-DMP. Importantly, the proposed mechanism explains why both motor patterns have distinct rhythmic waxing and waning of the amplitude of contractions. The hypothesis is brought forward that the velocity is modulated by neural regulation of gap junction conductance within the ICC-DMP network., (Copyright © 2015 the American Physiological Society.)

For determining the implications of circulating endothelial progenitor cells (cEPCs) and cellular membrane microparticles (MPs) in diabetic stroke, levels of EPCs, EPC-MPs, and endothelium-derived MPs (EMPs) and their correlations with blood glucose concentration, cerebral microvascular density (cMVD), and ischemic damage were investigated in type 2 diabetic db/db and db/+ (wild-type control) mice. Therapeutic efficacy of EPC infusion (preincubated with MPs) was also explored. Ischemic stroke was induced by middle cerebral artery occlusion (MCAO) surgery. Ischemic damage and cMVD were determined using histological analyses. The levels of cEPCs and MPs were determined using flow cytometric analyses. EPC generation and functions were evaluated by in vitro cell cultures. Results showed the following. 1) In db/db mice, the basal level of cEPCs was less and cMVDs were lower, but the levels of circulating EPC-MPs and EMPs were more; 2) MCAO induced a larger infarct volume and less of an increase in cEPCs in db/db mice; 3) the level of cEPCs correlated with blood glucose concentration (negatively), cMVD (positively), and ischemic damage (negatively), but the levels of EPC-MPs and EMPs correlated inversely with those parameters; 4) EPCs were reduced and dysfunctional in db/db mice, and preincubation with db/db MPs impaired EPC functions; and 5) infusion of EPCs preincubated with db/+ MPs increased the level of cEPCs and reduced ischemic damage, and these beneficial effects were reduced or lost in EPCs preincubated with db/db MPs. These data suggest that reduced cEPCs, impaired EPC generation/function, and increased production of MPs might be the mechanisms responsible for increased ischemic damage seen in db/db mice.

The role of the somatosensory cortices (SI and SII) in pain perception has long been in dispute. Human imaging studies demonstrate activation of SI and SII associated with painful stimuli, but results have been variable, and the functional relevance of any such activation is uncertain. The present study addresses this issue by testing whether the time course of somatosensory activation, evoked by painful heat and nonpainful tactile stimuli, is sufficient to discriminate temporal differences that characterize the perception of these stimulus modalities. Four normal subjects each participated in three functional magnetic resonance imaging (fMRI) sessions, in which painful (noxious heat 45-46 degrees C) and nonpainful test stimuli (brushing at 2 Hz) were applied repeatedly (9-s stimulus duration) to the left leg in separate experiments. Activation maps were generated comparing painful to neutral heat (35 degrees C) and nonpainful brushing to rest. Directed searches were performed in SI and SII for sites reliably activated by noxious heat and brush stimuli, and stimulus-dependent regions of interest (ROI) were then constructed for each subject. The time course, per stimulus cycle, was extracted from these ROIs and compared across subjects, stimulus modalities, and cortical regions. Both innocuous brushing and noxious heat produced significant activation within contralateral SI and SII. The time course of brush-evoked responses revealed a consistent single peak of activity, approximately 10 s after the onset of the stimulus, which rapidly diminished upon stimulus withdrawal. In contrast, the response to heat pain in both SI and SII was characterized by a double-peaked time course in which the maximum response (the 2nd peak) was consistently observed approximately 17 s after the onset of the stimulus (8 s following termination of the stimulus). This prolonged period of activation paralleled the perception of increasing pain intensity that persists even after stimulus offset. On the other hand, the temporal profile of the initial minor peak in pain-related activation closely matched that of the brush-evoked activity, suggesting a possible relationship to tactile components of the thermal stimulation procedure. These data indicate that both SI and SII cortices are involved in the processing of nociceptive information and are consistent with a role for these structures in the perception of temporal aspects of pain intensity.