An increase in caffeine sensitivity of muscle cells derived from a family of related RER-affected horses was detected in vitro by use of cell culture with calcium imaging and by use of fiber bundle contractility techniques. An alteration in muscle cell calcium regulation is a primary factor in the cause of this heritable myopathy.
In the canine model, measurement of chronic intrathoracic impedance with an implantable system effectively revealed changes in thoracic congestion due to heart failure reflected by LVEDP. These data suggest that implantable device-based impedance measurement merits further investigation as a tool to monitor the fluid status of heart failure patients.
Summary The purpose of this study was to determine if chronic exertional rhabdomyolysis (ER) in Quarter Horses and Thoroughbreds represents one or several distinct myopathies. Eighteen Quarter Horses and 18 Thoroughbreds with ER were selected from cases presented to the Veterinary Hospital on the basis of a history of ER, assessment of muscle histopathology, and serum CK activity before and 4 h post exercise. In addition, 2 of 3 of the following parameters were evaluated: muscle glycogen concentrations, thyroid hormones (T3, T4), fractional excretion (FE) of sodium, potassium and chloride. The CK response to training, the metabolic response to a near maximal standardised exercise test (SET), blood glucose concentrations after an i.v. glucose challenge and a skeletal muscle in vitro caffeine contracture test were performed on 5 of the Quarter Horses, selected because of polysaccharide storage myopathy (PSSM), and 5 of the Thoroughbreds. Serum T3 and T4 were all within normal limits. Low FE of sodium and potassium were seen in <20% of Quarter Horses and Thoroughbreds. Four hours post exercise, CK was increased in 77% of Quarter Horses and 72% of Thoroughbreds with ER. Muscle glycogen concentrations in Quarter Horses with ER were significantly higher than in normal Quarter Horses and Thoroughbreds with ER. No Thoroughbreds, but 15/18 Quarter Horses with ER had abnormal polysaccharide accumulation in muscle biopsies consistent with a diagnosis of PSSM. PSSM Quarter Horses had higher CK activity during training than Thoroughbreds and higher glycogen utilisation with the SET. PSSM Quarter Horses also had significantly enhanced glucose clearance compared to normal Quarter Horses and Thoroughbreds with ER. Thoroughbreds with ER had significantly lower thresholds for caffeine‐induced contracture than normal horses and PSSM Quarter Horses. It was concluded that there are multiple causes for exertional rhabdomyolysis. In Quarter Horses, rhabdomyolysis is commonly due to a glycogen storage disorder, PSSM, and is readily expressed in untrained horses. In Thoroughbreds, ER is commonly due to an underlying abnormality of muscle contraction. Rhabdomyolysis in Thoroughbreds, however, is only expressed intermittently when key stressors are present.
A defect in the skeletal muscle sarcoplasmic reticulum (SR) calcium release channel of malignant hyperthermia-susceptible (MHS) pigs greatly enhances SR calcium release in pigs homozygous for the malignant hyperthermia (MH) gene. In pigs heterozygous at this locus, rates of calcium release from isolated SR stimulated by Ca2+, ATP, or caffeine are intermediate to those of both MHS and normal SR [Mickelson et al. Am. J. Physiol. 257 (Cell Physiol. 26): C787-C794, 1989]. In this study bundles of intact muscle cells dissected from pigs of various genotypes were used to examine the effects of the MH gene on contractile responses to caffeine (direct stimulation of the SR) or to surface membrane (sarcolemma) depolarization (i.e., stimulation by way of the steps in excitation-contraction coupling). The caffeine threshold for contractures in the heterozygous muscles (5 mM) was intermediate to both types of homozygous muscles (2 mM for MHS and 10 mM for normal) as is the case with direct stimulation of calcium release from SR vesicles [Mickelson et al. Am. J. Physiol. 257 (Cell Physiol. 26): C787-C794, 1989]. Sarcolemmal depolarization was elicited by electrical stimuli or elevated extracellular potassium. Control twitch tension for MHS and heterozygous muscles did not differ and was significantly greater in both than in homozygous normal muscles. Potassium-induced contractures were significantly larger in MHS and heterozygous than in normal muscles. Thus, in heterozygous muscles, force production via sarcolemmal depolarization (twitches and potassium contractures) was enhanced as much as in homozygous MHS muscles. This could be the result of feedback from abnormal SR calcium channels producing altered (enhanced) transverse tubule to SR signal transduction.
R ecent reports of asymptomatic cerebral lesions imaged with diffusion weighted MRI (DWI) after catheter ablation of atrial fibrillation have raised concerns about the safety of this procedure. [1][2][3][4][5] It has been speculated that these DWI lesions may be the result of cerebral microembolization, and that they could be a marker for procedure-related clinical stroke risk. 6 In addition, some speculate that the asymptomatic cerebral DWI lesions may, in fact, be associated with subtle abnormalities discernable with neuropsychiatric testing. 7,8 It has been established that thrombus, gas bubbles, and particulate debris (coagulum) can be introduced or produced with left atrial catheterization and catheter ablation in this chamber.9 New data are available on catheter ablation-related subclinical DWI lesions, often seen as punctate hyperintensities, from recent studies. However, the link between the size and characteristics of the emboli, produced with left atrial catheter ablation procedures has not been correlated to clinical stroke or subclinical DWI lesions. Clinical Perspective on p 30Considerable differences have been reported in typical lesion dimensions seen on DWI between various clinical stroke cohorts and patients with asymptomatic cerebral lesions detected on DWI after left atrial catheter ablation. There is a lack of causal data for any of the lesion types. The purpose of this canine study was to elucidate the characteristics of emboli capable of creating the DWI punctate hyperintensities seen in the clinical setting after left atrial catheter ablation procedures. We sought to differentiate the effects of embolizing pure gas microbubbles versus microparticles of smaller and larger size because smaller particles and gas microbubbles might be more likely to occlude flow in terminal cerebral vessels, and produce DWI lesions typical to those seen in asymptomatic patients after atrial fibrillation ablation. MethodsAll animal procedures were approved by and carried out in compliance with a preclinical research protocol by the Institutional Animal Care and Use Committee of the Medtronic Physiological Research Laboratories. General animal husbandry and care was supervised by a veterinary staff in accordance with the guidelines in Background-Asymptomatic cerebral lesions have been observed on diffusion weighted MRI (DWI) scans shortly after catheter ablation of atrial fibrillation, but the pathogenesis of these lesions is incompletely understood. Methods and Results-Twelve dogs underwent selective catheterization of the internal carotid or vertebral arteries. Either a microbubbled mixture of air (1.0-4.0 mL), blood, contrast, and saline (n=5), or heat-dried pulverized blood (particle size <600 μm) mixed with saline and contrast (n=6) was injected. One sham control experiment was performed. MRI scans were performed preinjection, and at 1, 2, and 4 days postinjection. Neurological tests were performed daily. Gross pathology and histopathology were performed on the brains after being euthanized on day 4. Three ...
Caffeine contractures were induced after K(+)-conditioning of skeletal muscles from pigs and mice. K(+)-conditioning is defined as the partial depolarization caused by increasing external potassium (K+0) with [K+]x[Cl-] constant. Conditioning depolarizations that rendered muscles refractory to brief electrical stimulation still enhanced the contracture tension elicited by subsequent direct caffeine stimulation of sarcoplasmic reticulum (SR) calcium release. The effects of K(+)-conditioning on caffeine-induced contractures of intact cell bundles reached a maximum at 15-30 mM K+0 and then progressively declined at higher [K+]0. Conditioning with 30 mM K+ for 5 min, which inactivates excitation-contraction (EC) coupling in response to action potentials, both increased the magnitude of caffeine contractures 2-10-fold and shifted the contracture threshold toward lower caffeine concentrations. Enhanced sensitivity to caffeine was inhibited by dantrolene (20 microM) and its watersoluble analogue azumolene (150 microM). These drugs decreased caffeine-induced contractures following depolarization with 4-15 mM K+ to 25-50% of control tension. The inorganic anion perchlorate (CIO-4), which like caffeine potentiates twitches, increased caffeine-induced contractures approximately twofold after K(+)-conditioning (> 4 mM). The results suggest that CIO-4 and dantrolene, in addition to caffeine, also influence SR calcium release either directly or by mechanism(s) subsequent to depolarization of the sarcolemma. Moreover, since CIO-4 is known to shift the voltage-dependence of intramembrane charge movement, CIO-4 may exert effects on the transverse-tubule voltage sensors as well as the SR.
The action of perchlorate (ClO4-), an agonist of the voltage sensor in excitation-contraction (EC) coupling, has been examined using bundles of intact muscle cells, isolated membrane vesicles [sarcoplasmic reticulum (SR) and transverse tubule (TT)], and cultured myotubes. The effect of ClO4- on mechanical parameters was investigated in isolated murine limb muscles. The presence of ClO4- (5 or 10 mM) greatly increased twitch tension ( > 250%), slightly enhanced tetanic tension, and increased K contracture tension. K contracture thresholds of extensor digitorum longus (EDL, 40 mM K+) and soleus (30 mM K+) muscles were not altered by ClO4-. However, in whole cell patch clamp studies of mouse myotubes, contractile activation was shifted by approximately -10 mV by 10 mM ClO4-. To further define the site of alteration of EC coupling by ClO4-, studies were conducted with isolated porcine SR and TT vesicles and with cultured mouse myotubes. The rate constant of Ca-induced 45Ca release from SR vesicles was significantly increased by ClO4-. However, neither the affinity nor level of [3H]PN200-110 binding to TT vesicles was significantly affected by ClO4- concentrations that increased twitch tension. Furthermore, slow plasmalemmal Ca currents of myotubes recorded in the whole cell patch-clamp mode were enhanced by 10 mM ClO4-, and the current-voltage relationship was shifted approximately -7mV. Thus, in enhancing EC coupling in mammalian muscle, ClO4- may act at multiple sites including the SR Ca release channel and the TT Ca channel-voltage sensor.
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