Search PubMed⌕ Search

Biomedical subjects

DeWayne Townsend

Publications and source records attributed to DeWayne Townsend.

7 recordsLinked to original sources
PubMed2007

Cardiomyopathy of Duchenne muscular dystrophy: pathogenesis and prospect of membrane sealants as a new therapeutic approach.

Duchenne muscular dystrophy (DMD) is a devastating progressive disease of striated muscle deterioration. This fatal X-linked disorder results from the loss of the protein dystrophin, which in turn causes striated muscle membrane instability. Cardiac dysfunction is a growing problem in patients with DMD, but relatively little is known about the pathophysiology of the dystrophic heart. At present, there is no effective treatment for DMD and the current clinical approaches are primarily supportive in nature. This review will discuss the pathogenesis of DMD in the heart and discuss how these pathogenic processes have led to a new class of agents directed specifically at restoring membrane integrity to dystrophic myocardium. The tri-block poloxamers, specifically poloxamer 188 (P188), are able to stabilize the membranes of dystrophic myocardium in animal models and may offer a new therapeutic approach for cardiac disease in DMD.

Animals↗
PubMed2005

Mediation of neurogenic ion transport by acetylcholine, prostanoids and 5-hydroxytryptamine in porcine ileum.

Enteric neural activity modulates active transepithelial ion transport in the intestine. We investigated the neural circuits mediating neurogenic secretion in mucosal explants from porcine ileum. Transmural electrical stimulation increased short-circuit current, a measure of active ion transport, by 35+/-2 microA/cm2. The neuronal Na+ channel blocker saxitoxin, the muscarinic cholinergic receptor antagonist atropine, the 5-hydroxytryptamine3 receptor antagonist tropisetron, and the cyclooxygenase inhibitor indomethacin inhibited this response. In addition, tropisetron inhibited the atropine-resistant portion of the response, and both atropine and indomethacin attenuated the saxitoxin-resistant component. Neurogenic secretion in porcine ileum appears to be mediated by tryptaminergic and prostanoid-sensitive cholinergic pathways.

8,11,14-Eicosatrienoic Acid↗
PubMed2005

Dystrophic heart failure blocked by membrane sealant poloxamer.

Dystrophin deficiency causes Duchenne muscular dystrophy (DMD) in humans, an inherited and progressive disease of striated muscle deterioration that frequently involves pronounced cardiomyopathy. Heart failure is the second leading cause of fatalities in DMD. Progress towards defining the molecular basis of disease in DMD has mostly come from studies on skeletal muscle, with comparatively little attention directed to cardiac muscle. The pathophysiological mechanisms involved in cardiac myocytes may differ significantly from skeletal myofibres; this is underscored by the presence of significant cardiac disease in patients with truncated or reduced levels of dystrophin but without skeletal muscle disease. Here we show that intact, isolated dystrophin-deficient cardiac myocytes have reduced compliance and increased susceptibility to stretch-mediated calcium overload, leading to cell contracture and death, and that application of the membrane sealant poloxamer 188 corrects these defects in vitro. In vivo administration of poloxamer 188 to dystrophic mice instantly improved ventricular geometry and blocked the development of acute cardiac failure during a dobutamine-mediated stress protocol. Once issues relating to optimal dosing and long-term effects of poloxamer 188 in humans have been resolved, chemical-based membrane sealants could represent a new therapeutic approach for preventing or reversing the progression of cardiomyopathy and heart failure in muscular dystrophy.

Animals↗
PubMed2003

Characterization of specific delta-opioid binding sites in the distal small intestine of swine.

Delta-opioid receptors modulate neurogenic smooth muscle contractions and mucosal ion transport in the porcine distal small intestine. We compared specific delta-opioid binding sites in neuronal membranes isolated from the inner submucosal plexus and myenteric plexus of this gut region. In both preparations, the delta-opioid receptor antagonist naltrindole displaced [3H]diprenorphine from two binding sites. [3H]Naltrindole bound specifically to a single high-affinity site that was displaced by delta-opioid receptor ligands with the rank order of affinity: naltriben >7-benzylidenenaltrexone>deltorphin II>[D-Pen(2), D-Pen(5)] enkephalin. Relative decreases in delta-opioid receptor agonist affinity in the presence of Na(+) and other ions differed in submucosal and myenteric membranes. The kappa-opioid receptor antagonist norbinaltorphimine displaced [3H]naltrindole binding in myenteric membranes (K(i)=7.2 nM). Delta-opioid receptors in submucosal and myenteric plexuses of porcine ileum appear to differ in some respects.

Animals↗
PubMed2003

Characterization of specific opioid binding sites in neural membranes from the myenteric plexus of porcine small intestine.

Delta- and kappa-opioid receptors (OPRs), but not micro-OPRs, are expressed in the myenteric plexus of the porcine distal small intestine. In a subpopulation of myenteric neurons, delta- and kappa-OPRs seem to be colocalized and may functionally interact. In this study, radioligand binding was used to characterize myenteric OPR populations in detail. The nonselective OPR antagonist [3H]diprenorphine bound to a single, high-affinity site in myenteric neural membrane homogenates. Naloxone displaced 65 and 59% of [3H]diprenorphine binding from this site in Na(+)-free Tris and Krebs-HEPES buffers, respectively. Naltrexone-derived delta- and kappa-OPR antagonists, including naltriben, 7-benzylidenenaltrexone, nor-binaltorphimine, and 5'-guanidinonaltrindole, displaced [3H]diprenorphine from two distinct binding sites to levels similar to that of naloxone. The selective delta-OPR ligands Tyr-1,2,3,4-tetrahydroisoquinoline-Phe-Phe-OH (TIPP), [D-Pen2,D-Pen5]enkephalin (DPDPE), [D-Ala2, Glu4]deltorphin II, and (+)-4-[(alphaR)-alpha((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl-3-methoxybenzyl)-N,N-diethylbenzamide (SNC-80) and the kappa-OPR agonist (D-(5alpha,7alpha,8beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxoaspiro-(4,5)dec-8-yl) benzeneacetamide (U-69,593) displaced [3H]diprenorphine from three independent binding sites; these included high-affinity delta- and kappa-OPR sites, and a residual binding site. Residual [3H]diprenorphine binding was displaced by the selective kappa-OPR antagonist nor-binaltorphimine after saturation of delta and kappa sites, respectively, with DPDPE and U-69,593. The residual binding site displayed low affinity for delta- and kappa-OPR agonists and TIPP, as well as moderate affinity for naltrexone-derived ligands, properties reminiscent of delta-/kappa-OPR heterodimers.

Animals↗
PubMed2002

Predominance of delta-opioid-binding sites in the porcine enteric nervous system.

The antidiarrheal and constipating actions of opioids are mediated in part by enteric neurons, which lie within the wall of the small intestine and colon, but the differential expression of specific, high-affinity opioid-binding sites in ganglionated plexuses within functionally distinct intestinal segments has not been examined. We determined the saturation binding characteristics under Na+-free conditions of the nonselective opioid receptor (OPR) ligand [3H][(5alpha,7alpha)-17-(cyclopropylmethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-alpha, alpha-dimethyl-6,14-ethenomorphinan-7-methanol] (diprenorphine) and the respective delta-, kappa-, and mu-OPR ligands [3H]naltrindole, D-(5alpha,7alpha,8beta)-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxoaspiro-(4,5)dec-8-yl]benzeneacetamide ([3H]U-69,593), and [3H][D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) in neuronal membranes isolated from myenteric and submucosal plexuses of porcine small intestine and colon. Naloxone-displaceable [3H]diprenorphine-binding sites (KD values ranging from 0.2-0.5 nM and Bmax = 50-95 fmol/mg of protein) were found in both subregions from all gut segments examined. High-affinity [3H]naltrindole sites (KD = 60-140 pmol) were at highest densities (approximately 60 fmol/mg of protein) in submucosal plexus of the ileum and distal colon myenteric plexus and were at lowest densities (8-9 fmol/mg of protein) in the submucosal plexuses of cecum and distal colon. [3H]U-69,593 sites (KD = 0.3-4 nM) were present only in the myenteric plexuses of all segments examined, with highest densities in cecum and proximal colon (44-47 fmol/mg of protein). [3H]DAMGO-binding sites were expressed at relatively low densities in the enteric plexuses of all gut regions. These results indicate that delta-OPRs predominate in the porcine enteric nervous system with a more circumscribed expression of kappa- and mu-OPRs.

Animals↗