摘要:

A rapid deenergization procedure was used to probe the regulation of in situ adenylate deaminase and 5'-nucleotldase in isolated adult rat heart cells. In cells depleted of ATP, the rate of inosine monophosphate (IMP) production was fourfold greater in cells that had been respiring prior to deenergization than in cells that had been maintaining ATP stores through anaerobic glycolysis. This effect of respiratory inhibition was fully reversed by reaeration. When phenylephrine was present during preincubation, IMP production during a subsequent 5-minute rapid deenergization was increased by 70% in respiring cells and by 88% in those that had not been respiring. These effects of phenylephrine were abolished by prazosin. Adenosine production by cells without ATP was inversely related to that of IMP, whereas it was positively correlated with the amount of AMP remaining in cells after 5 minutes. We conclude from these data that rat heart adenylate deaminase is regulated by a product(s) of anaerobic glycolysis and by a,-adrenergic stimulation. The production of intracellular adenosine in cells without ATP, on the other hand, is governed primarily by the concentration of AMP and appears to be catalyzed by the cytosolic type I 5'-nucleotidase.

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The cellular mechanisms of Wenckebach periodicity were investigated in single, enzymatically dissociated guinea pig ventricular myocytes, as well as in computer reconstructions of transmembrane potential of the ventricular cell. When depolarizing current pulses of the appropriate magnitude were delivered repetitively to a well-polarized myocyte, rate-dependent activation failure was observed. Such behavior accurately mimicked the Wenckebach phenomenon in cardiac activation and was the consequence of variations in cell excitability during the diastolic phase of the cardiac cycle. The recovery of cell excitability during diastole was studied through the application of single test pulses of fixed amplitude and duration at variable delays with respect to a basic train of normal action potentials. The results show that recovery of excitability is a slow process that can greatly outlast action potential duration (i.e., postrepolarization refractoriness). Two distinct types of subthresbold responses were recorded when activation failure occurred: one was tetrodotoxin- and cobalt-insensitive (type 1) and the other was sensitive to sodium-channel blockade (type 2). Type 1 responses, which were commonly associated with the typical structure of the Wenckebach phenomenon (Mobitz type 1 block), were found to be the result of the nonlinear conductance properties of the inward rectifier current, IK1. Type 2 sodium-channel-mediated responses were associated with the so-called "millisecond Wenckebach." These responses may be implicated in the mechanism of Mobitz type 2 rate-dependent Mock. Single-cell voltage-clamp experiments suggest that variations in excitability during diastole are a consequence of the slow deactivation kinetics of the delayed rectifier, IK. Computer simulations of the ventricular cell response to depolarizing current pulses reproduced very closely all the response patterns obtained in the experimental preparation. It is concluded that postrepolarization refractoriness and Wenckebach periodicity are properties of normal cardiac excitable cells and can be explained in terms of the voltage dependence and slow kinetics of potassium outward currents. The conditions for the occurrence of intermittent activation failure during diastole will depend on the frequency and magnitude of the driving stimulus.

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The ionic mechanisms of slow recovery of cardiac excitability and rate-dependent activation failure were studied in single, enzyraatically dissociated guinea pig ventricular myocytes and in computer simulations using a modified version of the Beeler and Reuter model for the ventricular cell. On the basis of our results, we developed a simplified analytical model for recovery of cell excitability during diastole. This model was based on the equations for current distribution in a resistive-capacitive circuit. A critical assumption in the model is that, in the voltage domain of the subthreshoid responses, the sodium and calcium inward currents do not play a significant role, and only the two potassium outward currents, the delayed rectifier (IK) and the inward rectifier, are operative. The appropriate parameters needed to numerically solve the analytical model were measured in the guinea pig ventricular myocyte, as well as in the Beeler and Reuter cell. The curves of recovery of excitability and the rate-dependent activation patterns generated by numerical iteration of the analytical model equations closely reproduced the experimental results. Our analysis demonstrates that slow deactivation of the delayed rectifier current determines the observed variations in excitability during diastole, whereas the inward rectifier current determines the amplitude and shape of the subthreshoid response. Both currents combined are responsible for the development of Wenckebach periodicities in the ventricular cell. The overall study provides new insight into the ionic mechanisms of ratedependent conduction block processes and may have important clinical implications as well

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Recent evidence suggests that endothelium-derived relaxing factor exhibits properties of nitric oxide. Like nitric oxide, it inhibits platelet function and mediates its effects by elevating intracellular cyclic GMP. In this study we have investigated the role of reduced thiol in the mechanism of action of endothelium-derived relaxing factor on platelets. Bovine aortic endothelial cells were grown on microcarrier beads and pretreated with aspirin before use. Endothelial cells stimulated with bradykinin or exposed to stirred medium expressed a dose-dependent inhibition of platelet aggregation that was potentiated by the reduced thiol, /V-acetykysteine. Endothelial cell-mediated platelet inhibition was attenuated by methylene blue. Inhibition of platelet aggregation by endothelial cells was associated with a rise in platelet intracellular cyclic GMP, an effect that was enhanced by JV-acetylcysteine. These data show that 1) the reduced thiol N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor and 2) this effect is associated with increasing intracellular platelet cyclic GMP levels.

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Endothelial cells produce at least three substances that can attenuate the platelet aggregation response: tissue-type plasminogen activator; the platelet inhibitory prostaglandins I2 and E,; and endothelium-derived relaxing factor, one form of which exhibits properties of nitric oxide. Since platelet aggregates formed in vivo are involved in the initiation of many clinically important occlusive vascular syndromes, we tested the hypothesis that these endothelial products act synergistically to disperse platelet aggregates. Our data reveal that tissue-type plasminogen activator, prostaglandin E, and nitroglycerin (an organic nitrate activator of guanylate cyclase analogous to endothelium-derived relaxing factor) act synergistically to disaggregate platelets and do so in part by modulation of platelet cyclic nucleotides. These data suggest a potential mechanism by which the endothelium protects against the formation of platelet aggregates in vivo and offer a potential strategy for improving the efficacy of thrombolytic therapy.

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

We present a new approach for estimation of transmural distributions of stress and strain in the equatorial region of a passive left ventricle. We employ a thick-walled cylindrical geometry, assume that myocardium is incompressible, and use a three-dimensional constitutive relation that yields a material symmetry consistent with observed transmural variations in muscle fiber orientations. Moreover, we consider finite deformations including inflation, extension, twist, and transmural shearing and suggest a new method for determination of the requisite deformation parameters directly from experimental strain data. We show representative transmural distributions of stress and strain, and perform a parametric study to illustrate differing predictions of stress induced by varying boundary conditions, muscle fiber orientations, or modes of deformation. Our analysis can be used to guide and check future predictions of cardiac stresses, and to guide experimentalists by suggesting the accuracy of measurements essential for stress analysis in the heart.

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Several laboratories have reported that Na+-Li+ countertransport activities are increased in red blood cells from patients with essential hypertension. It has been proposed that the activity of this red blood cell transport system might reflect the activity of a similar system in vascular smooth muscle. We previously demonstrated Na+-Ii+ exchange in sarcolemmal vesicles from canine artery and proposed that this transport function might be mediated by the Na+-H+ exchanger. In the present studies, however, we were unable to demonstrate Na+-Ii+ countertransport in canine red blood cells. Since bovine red blood cells have a vigorous Na+-Li+ exchanger and we previously demonstrated Na+-H+ exchange in sarcolemmal vesicles from bovine artery, we wished to determine whether bovine sarcolemmal vesicles mediate Na+-Li+ exchange and whether this transport function is mediated via the Na+-H+ exchanger. We found that an outwardly directed proton or Li+ gradient stimulated "Na+ uptake in sarcolemmal vesicles from bovine superior mesenteric artery. Li+ gradient-stimulated Na+ uptake was not due to electrical coupling between the two ions, was not affected by a change in membrane potential, and could not be explained by the parallel operation of IJ+-H+ and Na+-H+ exchange. External U+ inhibited proton gradient-stimulated Na+ uptake, and external protons inhibited LJ+ gradient-stimulated Na+ uptake. Na+ efflux from vesicles was stimulated by inwardly directed gradients for Li+ or protons, and these effects were not additive. Proton efflux from vesicles was stimulated by inwardly directed gradients for Na+ or Li+, and these effects were not additive. Finally, Na+-H+ exchange and Na+-U+ exchange in sarcolemmal vesicles were inhibited by 5-(yV-ethyl-/Y-isopropyl)aniiloride in an identical dose-dependent manner. In conclusion, Na+-Ii+ countertransport could not be demonstrated in canine red blood cells, but as is the case with bovine red blood cells, sarcolemmal vesicles from bovine artery mediate Na+-Li+ countertransport. This transport function and sarcolemmal Na+-H+ exchange are mediated via a single 5-(Ar-ethyl-Ar-isopropyl)amiloride-sensitive cation exchanger with affinity for Na+, Ll+, and protons. The cow, as opposed to the dog, may be a good animal model to test whether the activity of red blood cell Na+-LJ+ countertransport is predictive of the activity of Na+-Ii+ (and Na+-H+) exchange in vascular smooth muscle.

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The effects of halothane and ethrane on gap junction-mediated intercellular communication and on membrane excitability were examined in cultured neonatal rat cardiac myocytes using whole-cell voltage-clamp and current-clamp techniques. Excitability was maintained at doses of both anesthetics that reversibly abolished current flow through junctional membranes. The degree of reduction of junctional conductance was a steep function of the dose of anesthetic; complete block occurred at lower aqueous concentrations of halothane than ethrane. The time course for loss of communication was rapid; 90% reduction of initial junctional conductance occurred in less than 15 seconds after exposure to 2 mM halothane or 4 mM ethrane. Recovery of junctional conductance and junctional permeability to intracellularly injected Lucifer yellow was rapid and complete on washout of the anesthetics. As junctional conductance was reduced by halothane or ethrane exposure, unitary conductance of the gap junctional channels remained constant at about 50 pS. Uncoupling by these anesthetics is thus attributable to a decrease in the number of conducting channels rather than to reduction of the channel's unitary conductance. The data are discussed with regard to the possible role of this intercellular communication pathway in the arrhythmias and alterations of conduction velocity and contractility produced by volatile anesthetics.

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The calcium-channel inhibiting agent, diltiazem, has been shown to enhance salvage of reperfused myocardium independent of effects on coronary blood flow or myocardial work. Because lipid peroxidation may be a mediator of reperfusion injury and modifiable by calcium-sensitive pathways, we evaluated the effects of diltiazem on the formation of malondialdehyde (MDA), a product of lipid peroxidation, in isolated rabbit hearts perfused with buffer under control conditions or after 60 minutes of ischemia with or without 3 minutes of reperfusion. Diltiazem (5xl0∼7 M) reduced tissue MDA content in seven reperfused hearts compared with levels measured in 14 hearts reperfused without drug (1.54 ± 1.09 [SD] compared with 3.57 ± 1.88 nmol/g, p<0.05). Superoxide dismutase and catalase were ineffective in reducing tissue MDA content in reperfused hearts (n=8; MDA concentration, 3.88 ± 2.82 nmol/g) although they were effective in preventing lipid peroxidation in separate studies in which oxygen-centered free radicals were generated directly by an infusion of xanthine oxidase and hypoxanthine. These results suggest that the salutary effects of diltiazem in the setting of reperfusion may be mediated by reduction of lipid peroxidation at a locus not accessible to scavengers of oxygen-centered free radicals or by a mechanism not mediated by free radical pathways.

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Complement is activated, and C3a and C5a anaphylatoxins are generated during hypersensitivity reactions clinically associated with cardlopulmonary collapse. The administration of C3a or C5a to nonsensitized isolated guinea pig hearts mimics the events caused by antigen challenge of sensitized hearts (i.e., cardiac anaphylaxis) in the absence of complement. Thus, complementderived anaphylatoxins may participate in immediate hypersensitivity reactions in which the heart is a target organ. To assess the contribution of complement activation and anaphylatoxin generation to cardiac dysfunction, we have elicited anaphylaxis in isolated guinea pig hearts in the presence of complement and found that the ensuing dysfunction is markedly enhanced. This amplification is most likely attributable to anaphylatoxin formation because 1) inactivation of C3 or selective C3 depletion, i.e., the loss of the component responsible for the formation of the anaphylatoxins C3a and C5a, prevents complement-induced exacerbation of cardiac anaphylaxis, whereas reconstitution with C3 and C5, or even only C3, restores it; in fact, the greater the C3 content at the time of antigen challenge, the more intense the anaphylactic crisis; and 2) the severity of cardiac anaphylaxis is markedly reduced by preexposure to C3a, and this redaction is directly related to the dose of C3a injected and to the amount of endogenous cardiac histamine depleted by C3a before antigen challenge. Complement-derived anaphylatoxins appear to promote the same mediator release that has been initiated by the antigen-antibody reaction; thus, complement activation functions as an amplification system in cardiac anaphylaxis.

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID