Biomedical subjects

Jennifer Ritchie

Publications and source records attributed to Jennifer Ritchie.

10 recordsLinked to original sources

PubMed2006

Screening for pain phenotypes: analysis of three congenic mouse strains on a battery of nine nociceptive assays.

In an attempt to identify new genes responsible for variability in pain sensitivity, we tested three congenic mouse strains--in which a small portion of the genome of the MOLF/Ei strain has been placed on a C57BL/6 genetic background--on a battery of nine nociceptive assays, chosen to reflect those assays in most common use in the pain literature. Mice of both sexes were evaluated by two different testers at different points in time, allowing us to examine the relative importance of genotype, sex, tester and cohort effects on data from these assays. We find strong evidence for the existence of two quantitative trait loci (i.e., genomic regions containing variability-causing genes), one for thermal nociception on mouse chromosome (Chr) 17 (Chr 17; Tpnr3) and one for formalin test nociception on mouse Chr 12 (Nociq3). We note, however, that the nociceptive assays in this battery feature strong main effects and interactions of sex, tester, and cohort, which if not controlled or covaried can seriously confound interpretation of genetic experiments, including the comparison of transgenic knockout mice to their wild-type controls.

Animals↗

PubMed2006

The material properties of the native porcine mitral valve chordae tendineae: an in vitro investigation.

The material properties of the mitral valve chordae tendineae are important for the understanding of leaflet coaptation configuration and chordal pathology. There is limited information about the mechanical properties of the chordae during physiologic loading. Dual camera stereo photogrammetry was used to measure strains of the chordae in vitro under physiologic loading conditions. Two high-speed, high-resolution cameras captured the movement of graphite markers attached to the central section of the chordae. A uniaxial test simulating the same loading conditions was conducted on the same chordae using the same markers. The maximum strain experienced during the cardiac cycle was 4.29% +/- 3.43%. The loading rate was higher at 75.3% +/- 48.6% strain per second than the unloading rate at -54.8% +/- -56.6% strain per second. The anterior lateral strut chordae had a higher maximum strain (5.7% +/- 3.8%) and loading rate (80.5% +/- 51.9% strain per second) than the posterior medial strut chordae (5.5% +/- 2.3% strain and 68.1% +/- 48.3% strain per second). The posterior medial strut chordae had a higher unloading rate (-68.5% +/- -59.1% strain per second) than the anterior lateral strut chordae (-44.9% +/- -57.2% strain per second). Although the anterior lateral and posterior medial strut chordae have a significantly different diameter and length, they experience a similar strain, strain rate, and tension. In conclusion, a non-destructive technique was developed to measure in vitro chordal strain in the mitral valve. This technique allows the investigation of the behavior of biological tissues under physiologic loading conditions.

Animals↗

PubMed2005

Transgenic expression of a dominant-negative ASIC3 subunit leads to increased sensitivity to mechanical and inflammatory stimuli.

Molecular and behavioral evidence suggests that acid-sensing ion channels (ASICs) contribute to pain processing, but an understanding of their precise role remains elusive. Existing ASIC knock-out mouse experiments are complicated by the heteromultimerization of ASIC subunits. Therefore, we have generated transgenic mice that express a dominant-negative form of the ASIC3 subunit that inactivates all native neuronal ASIC-like currents by oligomerization. Using whole-cell patch-clamp recordings, we examined the response properties of acutely isolated dorsal root ganglion neurons to protons (pH 5.0). We found that whereas 33% of the proton-responsive neurons from wild-type mice exhibited an ASIC-like transient response, none of the neurons from the transgenic mice exhibited a transient inward current. Capsaicin-evoked responses mediated by the TRPV1 receptor were unaltered in transgenic mice. Adult male wild-type and transgenic mice were subjected to a battery of behavioral nociceptive assays, including tests of thermal, mechanical, chemical/inflammatory, and muscle pain. The two genotypes were equally sensitive to thermal pain and to thermal hypersensitivity after inflammation. Compared with wild types, however, transgenic mice were more sensitive to a number of modalities, including mechanical pain (von Frey test, tail-clip test), chemical/inflammatory pain (formalin test, 0.6% acetic acid writhing test), mechanical hypersensitivity after zymosan inflammation, and mechanical hypersensitivity after intramuscular injection of hypotonic saline. These data reinforce the hypothesis that ASICs are involved in both mechanical and inflammatory pain, although the increased sensitivity of transgenic mice renders it unlikely that they are direct transducers of nociceptive stimuli.

Acid Sensing Ion Channels↗

PubMed2005

Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene.

Heat sensitivity shows considerable functional variability in humans and laboratory animals, and is fundamental to inflammatory and possibly neuropathic pain. In the mouse, at least, much of this variability is genetic because inbred strains differ robustly in their behavioral sensitivity to noxious heat. These strain differences are shown here to reflect differential responsiveness of primary afferent thermal nociceptors to heat stimuli. We further present convergent behavioral and electrophysiological evidence that the variable responses to noxious heat are due to strain-dependence of CGRP expression and sensitivity. Strain differences in behavioral response to noxious heat could be abolished by peripheral injection of CGRP, blockade of cutaneous and spinal CGRP receptors, or long-term inactivation of CGRP with a CGRP-binding Spiegelmer. Linkage mapping supports the contention that the genetic variant determining variable heat pain sensitivity across mouse strains affects the expression of the Calca gene that codes for CGRPalpha.

Animals↗

PubMed2005

Mitral valve function and chordal force distribution using a flexible annulus model: an in vitro study.

Since variations in annular motion/shape and papillary muscle displacement have been observed in studies of dilated cardiomyopathy and ischemic mitral regurgitation, the objective of this study was to investigate the effects of annular motion/flexibility and papillary muscle displacement on chordal force and mitral valve function. Six human mitral valves were studied in a left heart simulator using a flexible annular model. Mitral flow, trans-mitral pressure and chordae tendineae tension were monitored online in normal and pathophysiologic papillary muscle positions. The flexible annulus model showed a significant increase in mitral regurgitation volume (p < 0.05) when compared to static annuli models. Furthermore, there was a significant increase of force on the basal chords compared to the force present with the static annuli models. Utilizing the flexible annulus model, papillary muscle displacement significantly increased the force on the anterior strut, posterior intermediate and commissural chords. (1) Papillary muscle displacement increases the tension on the intermediate chords inducing tenting of the leaflets and subsequent regurgitation. (2) The tension on the intermediate and marginal chords is relatively insensitive to annular motion, whereas tension on the basal chords is directly affected by annular motion.

Cadaver↗

PubMed2005

Structural characterization of the chordae tendineae in native porcine mitral valves.

BACKGROUND: This study was aimed to characterize the different mitral valve chordae tendineae to provide additional understanding of their function. METHODS: Mitral valve chordae tendineae from fresh porcine hearts were stained for collagen and elastin using either a Verhoeff and van Gieson stain or Verhoeff light green stain. Cellular distribution was determined using a hematoxylin and eosin stain. Immunohistochemistry was used to verify the findings of vasculature. Biochemical assays were performed to quantify DNA, collagen, and elastin content of each of the six different types of chordae tendineae. RESULTS: Blood vessels were observed in the longitudinal and circumferential directions of the chordae. The strut chordae on the anterior leaflet of the mitral valve showed an increased degree of vascularization compared with the other chordae. All chordae had an inner layer characterized by a high concentration of collagen and an outer layer that was mostly elastin with interwoven collagen fibers. The collagen microstructure was characterized by directional crimping. Hematoxylin and eosin staining showed fibroblasts evenly distributed throughout the inner and outer layer of the chordae tendineae. Quantitative analysis showed significantly higher levels of DNA and collagen content in the anterior and posterior marginal chordae compared with the other chordae. CONCLUSIONS: The chordae tendineae were seen to have different microstructures according to chordal type. The presence of vessels characterized the chordae tendineae as complex living components that work in coordination with the papillary muscles and mitral valve leaflets to prevent mitral valve prolapse and regurgitation. They may also function to supply nutrients to the valve leaflets.

Animals↗

PubMed2005

In vitro dynamic strain behavior of the mitral valve posterior leaflet.

Knowledge of mitral valve (MV) mechanics is essential for the understanding of normal MV function, and the design and evaluation of new surgical repair procedures. In the present study, we extended our investigation of MV dynamic strain behavior to quantify the dynamic strain on the central region of the posterior leaflet. Native porcine MVs were mounted in an in-vitro physiologic flow loop. The papillary muscle (PM) positions were set to the normal, taut, and slack states to simulate physiological and pathological PM positions. Leaflet deformation was measured by tracking the displacements of 16 small markers placed in the central region of the posterior leaflet. Local leaflet tissue strain and strain rates were calculated from the measured displacements under dynamic loading conditions. A total of 18 mitral valves were studied. Our findings indicated the following: (1) There was a rapid rise in posterior leaflet strain during valve closure followed by a plateau where no additional strain (i.e., no creep) occurred. (2) The strain field was highly anisotropic with larger stretches and stretch rates in the radial direction. There were negligible stretches, or even compression (stretch < 1) in the circumferential direction at the beginning of valve closure. (3) The areal strain curves were similar to the stretches in the trends. The posterior leaflet showed no significant differences in either peak stretches or stretch rates during valve closure between the normal, taut, and slack PM positions. (4) As compared with the anterior leaflet, the posterior leaflet demonstrated overall lower stretch rates in the normal PM position. However, the slack and taut PM positions did not demonstrate the significant difference in the stretch rates and areal strain rates between the posterior leaflet and the anterior leaflet. The MV posterior leaflet exhibited pronounced mechanically anisotropic behavior Loading rates of the MV posterior leaflet were very high. The PM positions influenced neither peak stretch nor stretch rates in the central area of the posterior leaflet. The stretch rates and areal strain rates were significantly lower in the posterior leaflet than those measured in the anterior leaflet in the normal PM position. However, the slack and taut PM positions did not demonstrate the significant differences between the posterior leaflet and the anterior leaflet. We conclude that PM positions may influence the posterior strain in a different way as compared to the anterior leaflet.

Animals↗

PubMed2005

Effects of papillary muscle position on chordal force distribution: an in-vitro study.

BACKGROUND AND AIM OF THE STUDY: Mitral insufficiency, a common and morbid pathology, has been related to topological changes in the left ventricle. These changes may affect mitral leaflet coaptation by displacing the tips of the papillary muscles (PMs), subsequently changing the tension distribution on the chordae tendineae. Therefore, further understanding of the effects of PM displacement on chordal force distribution is required. METHODS: Six human and five porcine mitral valves were studied in a physiological left heart simulator. Cardiac output and transmitral pressure were recorded online and maintained within physiological ranges. Force transducers were placed on six chordae tendineae to measure chordal force distribution. Tension on individual chordae tendineae was recorded online during the cardiac cycle. The experiment was conducted for eight different PM positions, which were constructed from 5-mm vectorial displacements from the normal PM position. RESULTS: The anterior strut chord showed significant (p <0.05) variations in peak systolic tension (PST) for those positions associated with apical motion of the PMs. The posterior intermediate chord also showed significant variations in PST for positions associated with apical displacement of the PMs, whereas posterior displacement of the PMs resulted in a reduction in tension. In contrast, both the anterior marginal and posterior marginal chords showed a relatively uniform PST for the eight different PM positions. The posterior basal and commissural chords were the most sensitive to tension variations due to PM displacement. These chords showed relatively large and significant (p <0.05) variations in PST for most of the different PM displacements. CONCLUSION: The effects of PM relocation on chordal tension depended on chordal type. Chords which insert closer to the annulus were more sensitive to PM displacement, whereas those further from the annulus, the marginal chords, were the least sensitive to PM displacement.

Animals↗

PubMed2004

Qualitative sex differences in kappa-opioid analgesia in mice are dependent on age.

The effects of aging on sex differences in analgesia from the kappa-opioid agonist, U50,488H (U50), were examined in C57BL/6J mice. U50 analgesia can be blocked by the N-methyl-d-aspartate receptor antagonist, MK-801 (MK), in male rodents and gonadectomized females, but not hormonally intact or estrogen-replaced females, suggesting the existence of alternate neurochemical mediation in females. We now report that MK antagonism of U50 analgesia is age-dependent in females. That is, reproductively senescent females display MK-sensitive U50 analgesia qualitatively similar to that displayed by males or hormonally deprived young females. Age-related reductions in U50 analgesic magnitude were also observed in females. Thus, age and gender are likely to alter the clinical efficacy of analgesic drugs active at kappa-opioid receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2003

Genotype-dependence of gabapentin and pregabalin sensitivity: the pharmacogenetic mediation of analgesia is specific to the type of pain being inhibited.

The antiepileptic drug, gabapentin, and another structurally related compound, pregabalin, are increasingly employed in the pharmacotherapy of chronic pain states, although their primary mechanism of action remains a topic of active study. A genomic approach to the study of these drugs may elucidate their potentially novel mechanisms. We examined the heritability of sensitivity to analgesia from gabapentin and pregabalin as a precursor to linkage mapping efforts. Accordingly, 11 inbred mouse strains were tested for inhibition of nociception by gabapentin or pregabalin (50-300 mg/kg, i.p.) in two different preclinical assays of inflammatory pain, the formalin test (5% formalin; 20 microl) and zymosan thermal hyperalgesia on the paw-withdrawal test (3 mg/ml zymosan; 20 microl). Significant strain-dependence of drug action was noted in each case, indicating that sensitivity to these analgesics is heritable. Furthermore, the pattern of strain sensitivities to gabapentin and pregabalin were mostly similar, supporting the notion that they act via similar genetic and physiological mechanisms. However, there was virtually no correlation between strain sensitivities to pregabalin inhibition of formalin nociception and zymosan thermal hyperalgesia. In light of previous data from our laboratory and others regarding morphine analgesia, we now establish and empirically demonstrate the general principle that pharmacogenetic mechanisms underlying analgesic sensitivity are specific to the type of pain being inhibited. This has considerable implications for ongoing pharmacogenetic investigations and, more generally, for the choices of preclinical models of pain used in drug development.

Acetates↗