Isolated adult rat hearts in an isovolumic nonworking Langendorff preparation were loaded with the Ca2+ indicator aequorin to investigate the effects of ischemic reperfusion on free intracellular Ca2+ concentration ([Ca2+]i) homeostasis and left ventricular (LV) contractile function. In three groups (each n = 8) that underwent 10, 20, and 30 min of ischemia, recovery of developed pressure amounted to, respectively, 63% [77 +/- 3 (SE) mmHg], 48% (56 +/- 4 mmHg), and 34% (43 +/- 4 mmHg) of preischemic control (122 +/- 5 mmHg) after 60 min of reperfusion. Diastolic pressure remained elevated at 40 +/- 4, 55 +/- 3, and 65 +/- 6 mmHg, respectively (preischemic control, 12 mmHg). During early reperfusion (0-20 min), the light transient demonstrated a prolonged time to 90% decline from peak light (t90L), which was paralleled by a delayed relaxation on the LV pressure tracing in the 10- and 20-min ischemia groups. After 60 min of reperfusion, the prolongation of t90L persisted in all groups (10-min ischemia, 89 +/- 2 ms; 20 min, 95 +/- 3 ms; 30 min, 96 +/- 2 ms; control, 82 +/- 2 ms; P < 0.05). In contrast, the LV pressure tracing was abbreviated beyond the preischemic control, indicating altered myofibrillar Ca2+ responsiveness. Diastolic [Ca2+]i was elevated after 60 min of reperfusion (10-min ischemia, 0.40 +/- 0.06 microM; 20 min, 0.48 +/- 0.04 microM; 30 min, 0.51 +/- 0.06 microM; control, 0.32 +/- 0.01 microM) and had a significant positive correlation with LV diastolic pressure (r = 0.79; P < 0.001). A positive correlation was also found for the amplitude of the Ca2+ transient and LV developed pressure (r = 0.53; P < 0.05). These findings suggest that postischemic contractile dysfunction is related to altered Ca2+ modulation with impaired [Ca2+]i homeostasis following moderate to severe reperfusion injury in the rat.
1. The inotropic and electrophysiological effects of aconitine were measured in the isolated, isometrically contracting guinea-pig papillary muscle during the prearrhythmic phase of alkaloid action. 2. In muscles stimulated continually at 1 Hz, 1 mumol/l aconitine produced a positive inotropic effect that reached 38 +/- (SEM) 9% immediately before the onset of arrhythmia (n = 3). 3. If aconitine (0.5 mumol/l) was applied to non-stimulated (resting) muscles for 30 min and 1-Hz stimulation resumed thereafter, the arrhythmia occurred after 724 +/- 101 beats. Prolongation of the rest exposure to 2 h did not significantly diminish the number of prearrhythmic beats. Thus, the onset of aconitine action is critically determined by muscle activity (rather than by time), and a 30-min aconitine application to the resting muscle suffices for complete equilibration of the tissue. 4. Using the preequilibration-at-rest procedure, the positive inotropic effect of aconitine (0.25 - 4 mumol) was found (a) to be absent in the rested-state contraction, (b) to grow with both number of subsequent beats and alkaloid concentration, and (c) to reach a similar prearrhythmic maximum at all concentrations. This maximum amounted to about 1/4 of the maximum positive inotropic effect of dihydroouabain. It was not influenced by reserpine pretreatment of the guinea pig. 5. Aconitine (1 mumol/l) delayed the repolarization phase of the action potential by establishing a secondary plateau at approximately -60 mV. This effect paralleled the positive inotropic effect and, like the positive inotropic effect, was abolished by 10 mumol/l tetrodotoxin (TTX). In partially depolarized muscles ([K]0 = 24 mmol/l) aconitine (8 mumol/l) produced a TTX-sensitive increase in amplitude and rate of rise of the rested-state contraction; this indicates a voltage-dependent effect on some resting Na channels. 6. While delaying the late repolarization phase, aconitine markedly shortened the early repolarization at levels positive to -40 mV, reduced the overshoot and decreased the maximum rat of depolarization of the action potential. Slow action potentials ([K]0 = 24 mmol/l; 10 mumol/l TTX) were insensitive to aconitine. 7. We conclude that the well known property of aconitine to prolong the Na influx during the action potential leads to a positive inotropic effect, thus confirming the importance of Na influx for the regulation of myocardial contractility. The exact mechanism of an additional effect by which aconitine reduces the overshoot and shortens the plateau phase of the action potential awaits further study.
ameliorates and epinephrine exacerbates progression of acute and chronic viral myocarditis. Am J Physiol Heart Circ Physiol 289: H1577-H1583, 2005. First published May 27, 2005 doi:10.1152/ajpheart.00258.2005.-Recent studies point to important interactions between proinflammatory cytokines and neurohumoral mediators in heart failure. Here we investigate the influence of the -adrenergic system on cytokines and neurohumoral factors and the sequelae of viral myocarditis. In an experimental model with virus-infected BALB/c mice, we studied the acute and chronic effects of epinephrine and propranolol on myocardial morphology, cytokine gene expression, and survival. BALB/c mice were inoculated with the encephalomyocarditis virus (EMCV) or sham inoculated with saline and followed for 30 days. Epinephrine increased the severity of inflammatory cell infiltration and myocardial necrosis induced by EMCV. Gene expression of TNF-␣, IL-6, and IL-10 was markedly enhanced by epinephrine in EMCV-inoculated mice. Survival rate after 30 days was reduced to 40% in epinephrine-treated EMCVinoculated mice compared with 70% in untreated EMCV-inoculated mice (P Ͻ 0.05). Treatment with the -blocker propranolol significantly decreased mortality, myocardial necrosis, and infiltration of inflammatory cells in EMCV-inoculated mice. Propranolol also suppressed gene expression of TNF-␣, IL-6, and IL-10. A single dose of epinephrine 120 days after EMCV inoculation caused sudden death in 70% of infected mice; propranolol significantly reduced incidence of death to 33%. These results indicate that acute and chronic stages of viral myocarditis are modulated by the -adrenergic system and its interactions with proinflammatory cytokines.
Our data demonstrate that intravenously infused embryonic stem cell-derived cells homed to the infarcted heart, improved cardiac function, and enhanced regional blood flow at 6 weeks after myocardial infarction. The in vitro migration assay suggested that such a homing mechanism could be associated with locally released cytokines, such as tumor necrosis factor alpha, that are upregulated in the setting of acute myocardial infarction and heart failure.
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