Circumferential Stretch Research Articles

Forced KdV equation in a fluid-filled elastic tube with variable initial stretches

In this work, by utilizing the nonlinear equations of motion of an incompressible, isotropic thin elastic tube subjected to a variable initial stretches both in the axial and the radial directions and the approximate equations of motion of an incompressible inviscid fluid, which is assumed to be a model for blood, we have studied the propagation of nonlinear waves in such a medium under the assumption of long wave approximation. Employing the reductive perturbation method we obtained the variable coefficient forced KdV equation as the evolution equation. By use of proper transformations for the dependent field and independent coordinate variables, we have shown that this evolution equation reduces to the conventional KdV equation, which admits the progressive wave solution. The numerical results reveal that the wave speed is variable in the axial coordinate and it decreases for increasing circumferential stretch (or radius). Such a result seems to be plausible from physical considerations. We further observed that, the wave amplitude gets smaller and smaller with increasing time parameter along the tube axis.

Mechanical behavior of human aortas: Experiments, material constants and 3-D finite element modeling including residual stress

Segments of fresh human ascending, thoracic descending and abdominal aortas from eight male sexagenarians were pressurized under closed-end and free extension conditions. The median unpressurized inner radii for the ascending, thoracic and abdominal locations were 14.21, 9.67 and 7.16 mm, respectively. The median thickness was similar in the ascending and thoracic regions, at about 1.6 mm, while it was 1.2 mm in the abdominal region. The opening angle was not statistically different between regions, with a median of −38°. Under 13.3 kPa pressure, the median circumferential stretch ratio was about 1.26 in all three aortic locations; the median longitudinal stretch ratio was similar in the ascending and thoracic regions, at about 1.13, while it was 1.05 in the abdominal region. Material constants for a three-dimensional hyperelastic anisotropic constitutive model were determined. Experimental, analytical and finite element results showed excellent agreement, validating the novel experimental approach and the numerical methods used. When residual stress was not taken into account, stresses were highest on the inside of the aorta, with a gradient across the wall of about 200 and 50 kPa in the circumferential and longitudinal directions, respectively. When residual stress was included as described by negative opening angles, stresses were highest on the outside of the aorta, with a gradient across the wall in excess of 400 kPa for the circumferential direction, and on the order of 150 kPa for the longitudinal direction. The mechanical consequences of negative opening angles had not been appreciated so far, and deserve further investigation.

Transmural Myocardial Mechanics During Isovolumic Contraction

We sought to resolve the 3-dimensional transmural heterogeneity in myocardial mechanics observed during the isovolumic contraction (IC) phase. Although myocardial deformation during IC is expected to be little, recent tissue Doppler imaging studies suggest dynamic myocardial motions during this phase with biphasic longitudinal tissue velocities in left ventricular (LV) long-axis views. A unifying understanding of myocardial mechanics that would account for these dynamic aspects of IC is lacking. We determined the time course of 3-dimensional finite strains in the anterior LV of 14 adult mongrel dogs in vivo during IC and ejection with biplane cineradiography of implanted transmural markers. Transmural fiber orientations were histologically measured in the heart tissue postmortem. The strain time course was determined in the subepicardial, midwall, and subendocardial layers referenced to the end-diastolic configuration. During IC, there was circumferential stretch in the subepicardial layer, whereas circumferential shortening was observed in the midwall and the subendocardial layer. There was significant longitudinal shortening and wall thickening across the wall. Although longitudinal tissue velocity showed a biphasic profile; tissue deformation in the longitudinal as well as other directions was almost linear during IC. Subendocardial fibers shortened, whereas subepicardial fibers lengthened. During ejection, all strain components showed a significant change over time that was greater in magnitude than that of IC. Significant transmural gradient was observed in all normal strains. IC is a dynamic phase characterized by deformation in circumferential, longitudinal, and radial directions. Tissue mechanics during IC, including fiber shortening, appear uninterrupted by rapid longitudinal motion created by mitral valve closure. This study is the first to report layer-dependent deformation of circumferential strain, which results from layer-dependent deformation of myofibers during IC. Complex myofiber mechanics provide the mechanism of brief clockwise LV rotation (untwisting) and significant wall thickening during IC within the isovolumic constraint.

Rate‐sensitive contractile responses of lymphatic vessels to circumferential stretch

Phasic contractile activity in rat portal vein is more sensitive to the rate of change in length than to absolute length and this response is widely assumed to be a general characteristic of myogenic behaviour for vascular smooth muscle. Previously, we found that rat lymphatic vessels exhibit phasic contractile behaviour similar to that of portal vein. In the present study, we hypothesized that lymphatic muscle would exhibit rate-sensitive contractile responses to stretch. The hypothesis was tested on rat mesenteric lymphatics (90-220 microm, i.d.) using servo-controlled wire- and pressure-myograph systems to enable ramp increases in force or pressure at different rates. Under isometric conditions in wire-myograph preparations, both the amplitude and the frequency of phasic activity were enhanced at more optimal preloads, but superimposed upon this effect were bursts of contractions that occurred only during fast preload ramps. In such cases, the ratio of contraction frequency during the ramp to that at the subsequent plateau (at optimal preload) was > 1. Further, the frequency ratio increased as a function of the preload ramp speed, consistent with a rate-sensitive mechanism. In contrast, the amplitude ratio was < 1 and declined further with higher ramp speeds. Downward preload ramps produced corresponding rate-sensitive inhibition of contraction frequency but not amplitude. Similar findings were obtained in pressurized lymphatics in response to pressure ramps and steps. Our results suggest that lymphatics are sensitive to the rate of change in preload/pressure in a way that is different from portal vein, possibly because the pacemaker for generating electrical activity is rate sensitive but lymphatic muscle is not. The behaviour may be widely present in collecting lymphatic vessels and is probably an important mechanism for rapid adaptation of the lymphatic pump to local vascular occlusion.

Polarized intrinsic neural reflexes in response to colonic elongation

Propulsion in both small and large intestine is largely mediated by the peristaltic reflex; despite this, transit through the shorter colon is at least 10 times slower. Recently we demonstrated that elongating a segment of colon releases nitric oxide (NO) to inhibit peristalsis. The aims of this study were to determine if colonic elongation was physiologically significant, and whether elongation activated polarized intrinsic neural reflexes. Video imaging monitored fecal pellet evacuation from isolated guinea-pig colons full of pellets. Recordings were made from the circular muscle (CM) and longitudinal muscle (LM) in flat sheet preparations using either intracellular microelectrode or Ca(2+) imaging techniques. Full colons were 158.1 +/- 6.1% longer than empty colons. As each pellet was expelled, the colon shortened and pellet velocity increased exponentially (full 0.34, empty 1.01 mm s(-1)). In flat sheet preparations, maintained circumferential stretch generated ongoing peristaltic activity (oral excitatory and anal inhibitory junction potentials) and Ca(2+) waves in LM and CM. Colonic elongation (140% of its empty slack length) applied oral to the recording site abolished these activities, whereas anal elongation significantly increased the frequency and amplitude of ongoing peristaltic activity. Oral elongation inhibited the excitation produced by anal elongation; this inhibitory effect was reversed by blocking NO synthesis. Pelvic nerve stimulation elicited polarized responses that were also suppressed by NO released during colonic elongation. In conclusion, longitudinal stretch excites specific mechanosensitive ascending and descending interneurons, leading to activation of polarized reflexes. The dominance of the descending inhibitory reflex leads to slowed emptying of pellets in a naturally elongated colon.

TNBS-induced inflammation modulates the function of one class of low-threshold rectal mechanoreceptors in the guinea pig

The effects of trinitrobenzene sulfonic acid (TNBS)-induced inflammation on specialized, low-threshold, slowly adapting rectal mechanoreceptors were investigated in the guinea pig. Under isoflurane anesthesia, 300 microl saline or TNBS (15 mg/ml) in 30% ethanol was instilled 7 cm from the anal sphincter. Six or 30 days later, single unit extracellular recordings were made from rectal nerve trunks in flat-sheet in vitro preparations attached to a mechanical tissue stretcher. TNBS treatment caused macroscopic ulceration of the rectal mucosa at 6 days, which fully resolved by 30 days. Muscle contractility was unaffected by TNBS treatment. At 6 days posttreatment, responses of low-threshold rectal mechanoreceptors to circumferential stretch were increased, and the proportion of afferents responding with von Frey hair thresholds <or=0.1 mN and mechanoreceptor excitability in response to electrical stimulation were increased in TNBS-treated tissue, suggesting increased sensitivity of the mechanotransducer. Mechanoreceptor function at 30 days posttreatment was in most cases unchanged. The inflammatory mediator prostaglandin E(2) (1 microM) activated mechanoreceptors (6 days) in conjunction with contractile activity, but capsaicin (1 microM) failed to activate mechanoreceptors. Bradykinin (1 microM) activated mechanoreceptors independently of contractile activity and responses to stretch were increased in the presence of bradykinin. Both capsaicin and bradykinin activated unidentified stretch-insensitive afferents independently of contractile activity. Mechanoreceptor function is modulated at 6 days posttreatment but not at 30 days, suggesting a moderate increase in mechanoreceptor sensitivity in inflamed tissue but not after recovery. Other unclassified stretch-insensitive afferents are responsive to inflammatory mediators and capsaicin and may be involved in aspects of visceral sensation.

Characterization of arterial wall mechanical behavior and stresses from human clinical data

This paper demonstrates the feasibility of material identification and wall stress computation for human common carotid arteries based on non-invasive in vivo clinical data: dynamical intraluminal pressure measured by applanation tonometry, and medial diameter and intimal–medial thickness measured by high-resolution ultrasound echotracking. The mechanical behavior was quantified assuming an axially pre-stretched, thick-walled, cylindrical artery subjected to dynamical blood pressure and perivascular constraints. The wall was further assumed to be three-dimensional and to consist of a nonlinear, hyperelastic, anisotropic, incompressible material with smooth muscle activity and residual stresses. Mechanical contributions by individual constituents—an elastin-dominated matrix, collagen fibers, and vascular smooth muscle—were accounted for using a previously proposed microstructurally motivated constitutive relation. The in vivo boundary value problem was solved semi-analytically to compute the inner pressure during a mean cardiac cycle. Using a nonlinear least-squares method, optimal model parameters were determined by minimizing differences between computed and measured inner pressures over a mean cardiac cycle. The fit-to-data from two healthy patients was very good and the predicted radial, circumferential, and axial stretch and stress fields were sensible. Hence, the proposed approach was able to identify complex geometric and material parameters directly from non-invasive in vivo human data.

Stretch-Induced Activation of the Transcription Factor Activator Protein-1 Controls Monocyte Chemoattractant Protein-1 Expression During Arteriogenesis

Cerebral, coronary, and peripheral artery diseases combined represent the most frequent cause of death in developed nations. The underlying progressive occlusion of large conductance arteries can partially be compensated for by transformation of preexisting collateral arterioles to small artery bypasses, a process referred to as arteriogenesis. Because biomechanical forces have been implicated in the initiation of arteriogenesis, we have investigated the mechanosensitive expression of a pivotal proarteriogenic molecule, monocyte chemoattractant protein (MCP)-1, which governs the recruitment of circulating monocytes to the wall of the remodeling collateral arterioles. Using a new ear artery ligation model and the classic hindlimb ischemia model in mice, we noted that MCP-1 expression is significantly increased in collateral arterioles undergoing arteriogenesis already 24 hours after its onset. By mimicking proarteriogenic perfusion conditions in small mouse arteries, we observed that MCP-1 expression is predominantly upregulated in the smooth muscle cells, which solely sense changes in circumferential wall tension or stretch. Subsequent analyses of cultured endothelial and smooth muscle cells confirmed that cyclic stretch but not shear stress upregulates MCP-1 expression in these cells. Blockade of the mechanosensitive transcription factor activator protein-1 by using a specific decoy oligodeoxynucleotide abolished this stretch-induced MCP-1 expression. Likewise, topical administration of the decoy oligodeoxynucleotide to the mouse ear abrogated arteriogenesis through downregulation of MCP-1 expression and monocyte recruitment. Collectively, these findings point toward a stretch-induced activator protein-1-mediated rise in MCP-1 expression in vascular smooth muscle cells as a critical determinant for the initiation of arteriogenesis.

Mechanisms of Arterial Remodeling in Hypertension

Diverse data collected over the past 4 decades suggest the existence of a mechanical homeostasis across multiple length and time scales in the vasculature. For example,1 stress fibers within endothelial and vascular smooth muscle cells appear to disassemble and then reassemble in a mechanically preferred manner when perturbed from a normal value of mechanical stress or strain; focal adhesions in smooth muscle cells and fibroblasts tend to increase in area in response to local increases in mechanical loading so as to maintain the stress constant at a preferred value; fibroblasts tend to increase the tractions that they exert on the extracellular matrix when external loads are decreased from a preferred value, thus suggesting an attempt to enforce a “tensional homeostasis”; vascular smooth muscle cells tend to relengthen to their normal, preferred values when an arteriole is forced into a vasoconstricted state for an extended period; and arteries tend to decrease in caliber in response to sustained decreases in flow-induced wall shear stress, to increase in thickness in response to sustained increases in pressure-induced circumferential stress, and to lengthen in response to extension-induced increases in axial stress. Although changes in the cytoskeleton and integrins occur within minutes, changes at the cell-cell and cell-matrix levels occur over hours, and those at the vessel level occur over days to weeks or months. Hence, despite marked differences in length scales (dimensions from nanometers to centimeters) and time scales (durations from minutes to months), mechanobiological control mechanisms in the vasculature tend to restore values of stress or strain toward preferred (homeostatic) values in response to diverse perturbations from normal.2–5 Biomechanics and mechanobiology thus play key roles in vascular development, tissue maintenance in maturity, normal adaptations, aging, disease progression, and responses to injury or clinical interventions. A current challenge in hypertension research is to …

Nonlinear waves in an elastic tube with variable prestretch filled with a fluid of variable viscosity

In the present work, by employing the reductive perturbation method to the nonlinear equations of an incompressible, prestressed, homogeneous and isotropic thin elastic tube and to the exact equations of an incompressible Newtonian fluid of variable viscosity, we have studied weakly nonlinear waves in such a medium and obtained the variable coefficient Korteweg-deVries–Burgers (KdV–B) equation as the evolution equation. For this purpose, we treated the artery as an incompressible, homogeneous and isotropic elastic material subjected to variable stretches both in the axial and circumferential directions initially, and the blood as an incompressible Newtonian fluid whose viscosity changes with the radial coordinate. By seeking a travelling wave solution to this evolution equation, we observed that the wave front is not a plane anymore, it is rather a curved surface. This is the result of the variable radius of the tube. The numerical calculations indicate that the wave speed is variable in the axial coordinate and it decreases for increasing circumferential stretch (or radius). Such a result seems to be plausible from physical considerations, like Bernoulli’s law. We further observed that, the amplitude of the Burgers shock gets smaller and smaller with increasing time parameter along the tube axis. This is again due to the variable radius, but the effect of it is quite small.

Weakly non-linear waves in a fluid-filled elastic tube with variable prestretch

In the present work, by utilizing the non-linear equations of motion of an incompressible, isotropic thin elastic tube subjected to a variable prestretch both in the axial and the radial directions and the approximate equations of motion of an incompressible inviscid fluid, which is assumed to be a model for blood, we studied the propagation of weakly non-linear waves in such a medium, in the long wave approximation. Employing the reductive perturbation method we obtained the variable coefficient KdV equation as the evolution equation. By seeking a travelling wave solution to this evolution equation, we observed that the wave speed is variable in the axial coordinate and it decreases for increasing circumferential stretch (or radius). Such a result seems to be plausible from physical considerations.

691 Switching of Leptin Effects On Peripheral Vagal Afferent Mechanosensitivity with Feeding and Fasting

Background: Leptin is an important peptide involved in regulation of body weight homeostasis. In addition to secretion from adipose tissue it is also synthesized and secreted from gastric epithelial cells (Bado et al., Nature 1998; 394: 790-3). Leptin receptor is expressed in rat vagal afferents and expression of the receptor is regulated by feeding (Buyse et al., Eur. J. Neurosci. 2001; 14: 64-72). Whether this translates to a functional effect of leptin on vagal afferents is unknown. Aims: 1) To determine the effect of leptin on the response of tension and mucosal receptors to mechanical stimulation in tissue from mice fed ad libitum and mice fasted for 18 hours. 2) To determine the expression of leptin receptor in fed and fastedmice. Methods: Single fiber recordings of gastroesophageal vagal mechanoreceptors were made in mouse (J Neurophysiol, 2002: 87; 2095). mRNA from nodose ganglia was quantified by real-time RT-PCR. Results: In fasted mice, leptin (0.1-10nM) reduced by >50% the response of mouse tension receptors to circumferential stretch (0.5-5g, p<0.01, n=6). Leptin had no effect on mucosal receptor responses to mucosal stroking with calibrated von Frey hairs (10-1000mg). In fed mice, leptin (0.1-10nM) more than doubled mucosal receptor mechanosensory responses (p<0.01, n=5), but had no effect on tension receptors (n=5). There was six-fold greater expression of leptin receptor mRNA in the fed mouse nodose ganglia than those from fasted mice (p<0.001). Conclusion: Leptin has a substantial effect on the mechanosensitivity of gastroesophageal vagal afferents. This changes dramatically from fasting to feeding, to the extent that there is a switch from inhibition to potentiation. The mechanisms of these changes remain to be found, but they are consistent with a role of leptin as a regulator of food intake via vagal pathways. Supported by University of Adelaide and NHMRC Australia

Identification of capsaicin-sensitive rectal mechanoreceptors activated by rectal distension in mice

Rodents detect visceral pain in response to noxious levels of rectal distension. However, the mechanoreceptors that innervate the rectum and respond to noxious levels of rectal distension have not been identified. Here, we have identified the mechanoreceptors of capsaicin-sensitive rectal afferents and characterized their properties in response to circumferential stretch of the rectal wall. We have also used the lethal spotted (ls/ls) mouse to determine whether rectal mechanoreceptors that respond to capsaicin and stretch may also develop in an aganglionic rectum that is congenitally devoid of enteric ganglia. In wild type (C57BL/6) mice, graded increases in circumferential stretch applied to isolated rectal segments activated a graded increase in firing of slowly-adapting rectal mechanoreceptors. Identical stimuli applied to the aganglionic rectum of ls/ls mice also activated similar graded increases in firing of stretch-sensitive rectal afferents. In both wild type and aganglionic rectal preparations, focal compression of the serosal surface using von Frey hairs identified mechanosensitive “hot spots,” that were associated with brief bursts of action potentials. Spritzing capsaicin (10 μM) selectively onto each identified mechanosensitive hot spot activated an all or none discharge of action potentials in 32 of 56 identified hot spots in wild type mice and 24 of 62 mechanosensitive hot spots in the aganglionic rectum of ls/ls mice. Each single unit activated by both capsaicin and circumferential stretch responded to low mechanical thresholds (1–2 g stretch). No high threshold rectal afferents were ever recorded in response to circumferential stretch. Anterograde labeling from recorded rectal afferents revealed two populations of capsaicin-sensitive mechanoreceptor that responded to stretch: one population terminated within myenteric ganglia, the other within the circular and longitudinal smooth muscle layers. In the aganglionic rectum of ls/ls mice, only the i.m. mechanoreceptors were identified. Both myenteric and i.m. mechanoreceptors could be identified by their immunoreactivity to the anti-TRPV1 antibody and the vesicular glutamate transporter, Vglut2. Myenteric mechanoreceptors had a unique morphology, consisting of smooth bulbous nodules that ramified within myenteric ganglia. In summary, the rectum of wild type mice is innervated by at least two populations of capsaicin-sensitive rectal mechanoreceptor, both of which respond to low mechanical thresholds within the innocuous range. These findings suggest that the visceral pain pathway activated by rectal distension is likely to involve low threshold rectal mechanoreceptors that are activated within the normal physiological range.

Changes of loading tensile force–stretch relationships of rabbit mesenteric vein after 21 days of head-down rest

Changes of venous compliance may contribute to postflight orthostatic intolerance; however, direct animal studies to address the changes of venous compliance to microgravity have been rare. The purpose of this study was to determine compliance changes of mesenteric veins of rabbits after 21 days of head-down rest (HDR). Twenty-four healthy male New Zealand Rabbits were randomly divided into 21 days of HDR group, horizontal immobilization group (HIG) and control group (Ctrl), with eight in each. Loading tensile force–stretch relationships of mesenteric vein segments were constructed after 21 d HDR. With the increase of loading tensile force, both longitudinal and circumferential stretches of vein samples increased significantly. Under the same loading tensile force, mesenteric vein of the HDR showed significant increase both in circumferential stretch and longitudinal stretches compared to those of Ctrl group and HIG group. These results indicate that, a 21-day simulated weightlessness leads to increase of mesenteric venous compliance.

Mechanosignal transduction coupling between endothelial and smooth muscle cells: role of hemodynamic forces

HEMODYNAMICS play an important role in the focal nature of atherosclerosis. Mounting evidence has demonstrated that fluid shear stress is intimately involved in the biological activities of vascular endothelial cells (ECs). However, the role of neighboring smooth muscle cells (SMCs) in modulating the endothelial phenotype in the presence of shear stress remains undefined. Emerging EC and SMC coculture systems have provided the basis to elucidate the mechanosignal transduction coupling between ECs and SMCs. Hasting et al. (9) as well as Chiu et al. (2‐5) have demonstrated novel transcriptional regulation to support the notion that endothelial functional phenotypes are not only influenced by hemodynamic forces but also by neighboring SMCs. Vascular ECs in resistant arteries are constantly exposed to the dynamic changes of blood flow, namely, hemodynamic forces. These homodynamic forces can be resolved into three components: 1) shear stress, the tangential frictional force acting at the EC surface; 2) hydrostatic pressure, the perpendicular force acting on the vascular wall; and 3) cyclic strain, the circumferential stretch of the vessel wall (6, 7, 11, 13, 17). Emerging lines of evidence have supported the role of shear stress in mechanosignal transduction between vascular ECs and SMCs (3, 9). ECs are subject to fluid shear stress in the presence of neighboring SMCs (Fig. 1). The bidirectional communication between ECs and SMCs influences the homeostasis of the function and structure of the blood vessel wall. As an interface between blood and the vessel wall, ECs sense and respond to hemodynamic forces. EC and SMC coculture systems have elucidated novel transcriptional regulation between ECs and SMCs (4, 9), providing evidence that endothelial functional phenotypes are not only influenced by hemodynamic forces but also by neighboring SMCs (3, 10) (Fig. 2) . The coculture system represents a significant advance over homogeneous culture to assess the molecular mechanisms whereby shear stresses regulate EC function in the presence of SMCs (1, 14, 15). Using the perfused transcapillary coculture model, Remond et al. (15) reported that ECs protect against flow-induced SMC migration and flow-induced EC plasminogen activator inhibitor type 1. Using the parallel plate EC/SMC coculture system, Chiu et al. (4) reported that laminar shear stress significantly inhibits SMC-induced adhesion molecule gene expression. Furthermore, SMCs induce an upregulation of proinflammatory gene expression in ECs that are located in close proximity to SMCs. However, laminar shear stress acts as a negative regulator by regulating NF-B binding sites in the promoters of these inflammatory genes expressed in the presence

Selective Role for TRPV4 Ion Channels in Visceral Sensory Pathways

Although there are many candidates as molecular mechanotransducers, so far there has been no evidence for molecular specialization of visceral afferents. Here, we show that colonic afferents express a specific molecular transducer that underlies their specialized mechanosensory function: the transient receptor potential channel, vanilloid 4 (TRPV4). We found TRPV4 mRNA is highly enriched in colonic sensory neurons compared with other visceral and somatic sensory neurons. TRPV4 protein was found in colonic nerve fibers from patients with inflammatory bowel disease, and it colocalized in a subset of fibers with the sensory neuropeptide CGRP in mice. We characterized the responses of 8 subtypes of vagal, splanchnic, and pelvic mechanoreceptors. Mechanosensory responses of colonic serosal and mesenteric afferents were enhanced by a TRPV4 agonist and dramatically reduced by targeted deletion of TRPV4 or by a TRP antagonist. Other subtypes of vagal and pelvic afferents, by contrast, were unaffected by these interventions. The behavioral responses to noxious colonic distention were also substantially reduced in mice lacking TRPV4. These data indicate that TRPV4 contributes to mechanically evoked visceral pain, with relevance to human disease. In view of its distribution in favor of specific populations of visceral afferents, we propose that TRPV4 may present a selective novel target for the reduction of visceral pain, which is an important opportunity in the absence of current treatments.

Identification of functional intramuscular rectal mechanoreceptors in aganglionic rectal smooth muscle from piebald lethal mice

The mechanosensitive endings of low-threshold, slowly adapting pelvic afferents that innervate the rectum have been previously identified as rectal intraganglionic laminar endings (rIGLEs) that lie within myenteric ganglia. We tested whether the aganglionic rectum of piebald-lethal (s(l)/s(l)) mice lacks rIGLEs and whether this could explain impaired distension-evoked reflexes from this region. Extracellular recordings were made from fine rectal nerves in C57BL/6 wild-type and s(l)/s(l) mice, combined with anterograde labeling. In C57BL/6 mice, graded circumferential stretch applied to the rectum activated graded increases in firing of slowly adapting rectal mechanoreceptors. In s(l)/s(l) mice, graded stretch of the aganglionic rectum activated similar graded increases in rectal afferent firing. Stretch-sensitive afferents responded at low mechanical thresholds and fired more intensely at noxious levels of stretch. They could also be activated by probing their receptive fields with von Frey hairs and by muscle contraction. Anterograde labeling from recorded rectal nerves identified the mechanoreceptors of muscular afferents in the aganglionic rectal smooth muscle. A population of afferents were also recorded in both C57BL/6 and s(l)/s(l) mice that were activated by von Frey hair probing, but not stretch. In summary, the aganglionic rectum is innervated by a population of stretch-sensitive rectal afferent mechanoreceptor which develops and functions in the absence of any enteric ganglia. These results suggest that in patients with Hirschsprung's disease the inability to activate extrinsic distension reflexes from the aganglionic rectum is unlikely to be due to the absence of stretch-sensitive extrinsic mechanoreceptors.

Recent advances in enteric neurobiology: mechanosensitive interneurons

Until recently, it was generally assumed that the only intrinsic sensory neuron, or primary afferent neuron, in the gut was the after-hyperpolarizing AH/Type II neuron. AH neurons excited by local chemical and mechanical stimulation of the mucosa appear to be necessary for activating the peristaltic reflex (oral excitation and anal inhibition of the muscle layers) and anally propagating ring like contractions (peristaltic waves) that depend upon smooth muscle tone. However, our recent findings in the guinea-pig distal colon suggest that different neurochemical classes of interneuron in the colon are also mechanosensitive in that they respond directly to changes in muscle length, rather than muscle tone or tension. These interneurons have electrophysiological properties consistent with myenteric S-neurons. Ascending and descending interneurons respond directly to circumferential stretch by generating an ongoing polarized peristaltic reflex activity (oral excitatory and anal inhibitory junction potentials) in the muscle for as long as the stimulus is maintained. Some descending (nitric oxide synthase +ve) interneurons, on the other hand, appear to respond directly to longitudinal stretch and are involved in accommodation and slow transit of faecal pellets down the colon. This review will present recent evidence that suggests some myenteric S interneurons, in addition to AH neurons, behave as intrinsic sensory neurons.

Involvement of metabotropic glutamate 5 receptor in visceral pain

Metabotropic glutamate 5 receptor (mGluR5) antagonists are effective in animal models of inflammatory and neuropathic pain. The involvement of mGluR5 in visceral pain pathways from the gastrointestinal tract is as yet unknown. We evaluated effects of mGluR5 antagonists on the colorectal distension (CRD)-evoked visceromotor (VMR) and cardiovascular responses in conscious rats, and on mechanosensory responses of mouse colorectal afferents in vitro. Sprague–Dawley rats were subjected to repeated, isobaric CRD (12 × 80 mmHg, for 30 s with 5 min intervals). The VMR and cardiovascular responses to CRD were monitored. The mGluR5 antagonists MPEP (1–10 μmol/kg, i.v.) and MTEP (1–3 μmol/kg, i.v.) reduced the VMR to CRD dose-dependently with maximal inhibition of 52 ± 8% ( p < 0.01) and 25 ± 11% ( p < 0.05), respectively, without affecting colonic compliance. MPEP (10 μmol/kg, i.v.) reduced CRD-evoked increases in blood pressure and heart rate by 33 ± 9% ( p < 0.01) and 35 ± 8% ( p < 0.05), respectively. Single afferent recordings were made from mouse pelvic and splanchnic nerves of colorectal mechanoreceptors. Circumferential stretch (0–5 g force) elicited slowly-adapting excitation of action potentials in pelvic distension-sensitive afferents. This response was reduced 55–78% by 10 μM MTEP ( p < 0.05). Colonic probing (2 g von Frey hair) activated serosal splanchnic afferents; their responses were reduced 50% by 10 μM MTEP ( p < 0.01). We conclude that mGluR5 antagonists inhibit CRD-evoked VMR and cardiovascular changes in conscious rats, through an effect, at least in part, at peripheral afferent endings. Thus, mGluR5 participates in mediating mechanically evoked visceral nociception in the gastrointestinal tract.

Surrounding tissues affect the passive mechanics of the vessel wall: theory and experiment

The stress and strain in the vessel wall are important determinants of vascular physiology and pathophysiology. Vessels are constrained radially by the surrounding tissue. The hypothesis in this work is that the surrounding tissue takes up a considerable portion of the intravascular pressure and significantly reduces the wall strain and stress. Ten swine of either sex were used to test this hypothesis. An impedance catheter was inserted into the carotid or femoral artery, and after mechanical preconditioning pressure-cross-sectional area relations were obtained with the surrounding tissue intact and dissected away (untethered), respectively. The radial constraint of the surrounding tissue was quantified as an effective perivascular pressure on the outer surface of the vessel, which was estimated as 50% or more of the intravascular pressure. For carotid arteries at pressure of 100 mmHg, the circumferential wall stretch ratio in the intact state was approximately 20% lower than in the untethered state and the average circumferential stress was reduced by approximately 70%. For femoral arteries, the reductions were approximately 15% and 70%, respectively. These experimental data support the proposed hypothesis and suggest that in vitro and in vivo measurements of the mechanical properties of vessels must be interpreted with consideration of the constraint of the surrounding tissue.