Barbiturates, which are widely used in clinical anesthesia, exert a negative inotropic effect on the myocardium. To investigate the mechanism for the negative inotropism, we studied the effect of ...sodium pentobarbital (SP) on the action potential and the slow inward current recorded from guinea pig ventricular myocytes. We found that SP at 0.6, 1.0, and 1.6 μM decreased action potential duration at 50% repolarization by 17 ± 6, 25 ± 11, and 29 ± 8%, respectively (p < 0.05, n = 4). At the concentration range of 0.6–1.6 μM, resting potential and action potential amplitude were unaffected. Voltage-clamp studies in ventricular myocytes demonstrated that SP at 0.6, 1.0, and 1.6 μM reduced the peak slow inward current by 30 ± 4, 36 ± 14, and 67 ± 5%, respectively (p < 0.005, n = 4). In conclusion, SP, a frequently used anesthetic, decreases the slow inward current in guinea pig ventricular myocytes at clinically relevant concentrations.
Spiking neural network (NN) architecture that uses Hebbian learning and reinforcement-learning schemes for adapting the synaptic weights is implemented in silicon and performs dynamic optimization ...according to hemodynamic sensor for a cardiac resynchronization therapy (CRT) device. The spiking NN architecture dynamically changes the atrioventricular (AV) delay and interventricular (VV) interval parameters according to the information provided by the intracardiac electrograms (IEGMs) and hemodynamic sensors. The spiking NN coprocessor performs the adaptive part and is controlled by a deterministic algorithm master controller. The simulated cardiac output obtained with the adaptive CRT device is 30% higher than with a nonadaptive CRT device and is likely to provide improvement in the quality of life for patients with congestive heart failure. The spiking NN architecture shows synaptic plasticity acquired during the learning process. The synaptic plasticity is manifested by a dynamic learning rate parameter that correlates patterns of hemodynamic sensor with the system outputs, i.e., the optimal AV and VV pacing intervals
Patients with obstructive jaundice are susceptible to postoperative shock. To clarify the mechanism of this phenomenon, we compared the contractile response to isoprenaline of isolated ventricular ...preparations from three groups of dogs: (a) dogs with chronic bile-duct ligation (CBDL), (b) dogs with choledochocaval anastomosis (CDCA) and (c) sham-operated dogs (SO). Isolated ventricular muscles from CBDL and CDCA dogs showed a depressed contractile response to isoprenaline as compared with SO dogs. Mechanical performance was spared in the CBDL and CDCA dogs. There were no differences in the contractile responses of SO and CBDL dogs, either to ouabain or to changes in the rates of stimulation (force-frequency relationships). These data demonstrate that, in the dog, obstructive jaundice and/or cholaemia are associated with blunted contractile response to beta-adrenoreceptor stimulation in the face of intact basic mechanical performance. Similar inotropic refractoriness to beta-adrenoreceptor stimulation could contribute to the susceptibility to postoperative shock in patients with obstructive jaundice.
Ionic Basis of Fas Receptor Effects on Ventricular Myocytes.
Introduction: Experimental evidence suggests a major role for Fas receptor activation in a wide range of myocardial pathologies. Because ...clinical situations, which are likely to be associated with Fas activation, are accompanied by a variety of ventricular arrhythmias, the major goal of this study was to investigate the ionic mechanisms responsible for these phenomena.
Methods and Results: To delineate the origin of Fas‐mediated electrophysiologic perturbations, the transient outward K+ current Ito and the L‐type Ca2+ current ICa,L were studied in murine ventricular myocytes treated with the Fas‐activating monoclonal antibody Jo2. Jo2 decreased Ito (4.36 ± 1.2 pA/pF vs 17.48 ± 2.36 pA/pF in control, VM=+50 mV; P < 0.001) and increased ICa,L (− 13.17 ± 1.38 pA/pF vs − 3.94 ± 0.78 pA/pF in control, VM= 0 mV; P < 0.001). Pretreatment of ventricular myocytes with ryanodine or thapsigargin prevented the electrophysiologic effects of Jo2, suggesting that Ca2+i elevation is important for Fas‐mediated action. In agreement with our previous studies demonstrating dependence of Fas‐based myocyte dysfunction on an intact inositol trisphosphate (1,4,5‐IP3) pathway, the effects of Jo2 on Ito and ICa,L were prevented by the phospholipase C (generates 1,4,5‐IP3) blocker U73122, and by xestospongin C (tested with Ito), a specific blocker of IP3‐operated sarcoplasmic reticulum Ca2+ release channels. Furthermore, intracellular perfusion with 1,4,5‐IP3, but not with 1,3,4‐IP3, caused electrophysiologic effects resembling those of Jo2.
Conclusion: Decreased Ito and increased ICa,L underlie Fas‐induced action potential alterations and arrhythmias in murine ventricular myocytes, effects that appear to be mediated by 1,4,5‐IP3‐induced intracellular calcium release.
In the “Na lag hypothesis” of cardiac glycoside action, Cai increases through sodium-calcium exchange following block of the sodium-calcium ATPase. This accumulation of Cai has been suggested to be ...responsible for digitalis-induced delayed afterdepolarizations and arrhythmias. We used standard microelectrode techniques to study the effects of adriamycin, 10-200 μm, on the canine Purkinje fiber transmembrane potential. Adriamycin, 10 and 50 μm, had no effect on the action potential other than inducing a 28% increase in duration at 50 μm (p < 0.01). Adriamycin, 100 and 200 μm, further prolonged action potential duration and decreased amplitude and Vmax. We then studied the effects of adriamycin, 50 μm (a concentration that purportedly blocks sodium-calcium exchange), on ouabain-induced delayed afterdepolarizations and aftercontractions in Purkinje fiber and ventricular muscle. After initially increasing delayea afterdepolarization amplitude in five of nine Purkinje fibers, adriamycin reversibly reduced their amplitude in all nine, by 78%, at a drive cycle length of 500 msec (P < 0.01). Adriamycin, 50 μm, had no effect on calcium ion-induced slow response action potentials, suggesting this concentration does not significantly reduce the slow inward current. In ventricular muscle, adriamycin, 50 μm, did not significantly reduce contraction but did depress aftercontractions (P < 0.025). In sumin concentrations that have no effect on the AP other than prolonging duration, adriamycin, 50 μm, reversibly depresses ouabain-induced delayed afterdepolarizations and aftercontractions; however, adriamycin, 50 μm, does not depress calcium ion-dependent action potentials. Although the action of adriamycin on delayed afterdepolarizations and aftercontractions is consistent with direct inhibition of the transient inward current and/or an indirect reduction via reduced activity of sodium-calcium exchange, whether either or both of these mechanisms is involved must be defined by further experimentation. (Circ Res 53655-662, 1983)
Standard techniques were used to study developmental changes in the effects of amrinone and milrinone on contractile properties of isolated canine cardiac papillary and trabecular muscle. In contrast ...to milrinone, which induced a positive inotropic effect, amrinone had a negative inotropic effect on the neonatal canine muscles studied. For both drugs there was an age-dependent increase in contractility beyond the neonatal period. The negative inotropic effect of amrinone was not related to a change in phosphodiesterase inhibition, although developmental changes in phosphodiesterase inhibition did occur. These results highlight the differences in the mechanism of action of two similar molecules. They also suggest that use of amrinone as an inotropic agent in the early neonatal period should be viewed with caution.
Ventricular arrhythmias may result from abnormalities of impulse initiation and/or impulse propagation. The former include automatic arrhythmias, which may occur at high (normal) levels of membrane ...potential or at low (abnormal) levels of membrane potential. They also include triggered activity, which may result from early (occurring before complete repolarization) or delayed (occurring after complete repolarization) afterdepolarizations. Arrhythmias resulting from abnormal impulse propagation may be reentrant, determined in part by anatomic or functional conduction block, or the result of reflection. The factors determining various arrhythmogenic mechanisms are discussed.
The present study demonstrates that in the shrew ventricular muscle the speed of tension development and relaxation, as well as twitch duration, are much shorter than in the guinea-pig. It also shows ...that ventricular myosin of the shrew has a high Ca2+-activated ATPase activity and that it is composed of alpha-type heavy chains. Namely, the native molecule is a V1 variety of myosin. These findings advance our knowledge on an as yet uncharacterized mammalian heart and further demonstrate the correlation between mechanical properties and myosin type in heart muscle.
An immunodominant epitope of myelin basic protein (MBP), VHFFKNIVTPRTP (p87-99), is a major target of T cells in brain lesions of multiple sclerosis (MS), and this peptide can trigger experimental ...autoimmune encephalomyelitis (EAE). We designed truncated peptides based on this pathogenic 13-mer that are not antigenic. These short peptides reduced production of IFN-gamma and TNF-alpha in vivo. Moreover, paraplegic rats given the 7-mer FKNIVTP in soluble form showed total reversal of paralysis in 24 h. Truncated peptides that are too small to stimulate antigenic responses to pathogenic regions of myelin basic protein are nevertheless effective tolerogens and are able to anergize autoreactive T cells. Short peptide-based tolerogens, devoid of immunogenic and pathogenic potential, may be attractive for therapy of autoimmune diseases.
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