摘要:

Quinidine is the most commonly used drug for the chronic treatment of ventricular arrhythmias, but it may be arrhythmogenic. Much information exists concerning quinidine's effects on active properties in cardiac tissues, but virtually nothing is known of its effects on passive properties. We studied the effects of quinidine, in a clinically relevant concentration, on the balance among active and passive cellular properties that comprise the electrophysiologic matrix that determines cardiac excitability. The multiple microelectrode method of intracellular-current application and transmembrane voltage recording was used in sheep Purkinje fibers to determine strength-duration and constant current- voltage relations as well as cable properties. A rapid, on-line computerized data analysis system tracked in time the alterations in the active and passive properties relevant to excitability. In normal fibers at [K+]0= 5.4 mM, quinidine increased cardiac excitability as manifested by a decrease in the current required to attain threshold and/or a downward shift in strength- and charge-duration relations by altering passive properties despite a depressed sodium system and a slowed conduction velocity. During washout, excitability and passive properties remained altered despite a return of descriptive action potential parameters such as the resting potential, the maximum rate of rise of phase 0, overshoot, and the action potential duration to or nearly to normal. At [K+]0= 8.0 mM, quinidine could either increase or decrease excitability; net excitability depends on the balance between altered passive properties and the depressed sodium system. The results explain, in part, the antiarrhythmic actions and arrhythmogenic potential of quinidine. The data for quinidine and other antiarrhythmic drugs are interpreted in terms of the electrophysiologic matrix, which we believe has important advantages over traditional hierarchical classifications.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

To test the ability of regenerated endothelium to evoke endothelium-dependent relaxations, male Yorkshire pigs underwent balloon endothelial denudation of the proximal left anterior descending coronary artery. Endothelium-dependent responses were examined in vitro, in rings of coronary segments taken from the denuded area or from the proximal left circumflex coronary artery. The experiments were performed 8 days or 4 weeks after the denudation. Endothelial regrowth was confirmed by histologic examination 8 days after the denudation and by demonstrating the presence of endothelium-dependent relaxations to bradykinin; at that time aggregating platelets evoked normal endothelium-dependent responses. However, 4 weeks after the denudation, the relaxations to aggregating platelets were markedly depressed although continuous endothelial lining was present, and the endothelium-dependent responses to bradykinin, adenosine diphosphate, the Ca2+-ionophore A23187, platelet activating factor, and thrombin were unaltered. Four weeks after denudation, endothelium-dependent relaxations to serotonin were depressed. Higher concentration of serotonin induced endothelium-dependent contractions in quiescent rings with regenerated endothelium, suggesting that regenerated endothelial cells may produce endothelium-derived constricting factor(s) and release less endothelium-derived relaxing factor(s) when exposed to the monoamine. The endothelium-dependent relaxation to serotonin was not reduced by the S2-serotonergic antagonist ketanserin but prevented by the combined S,- and S2-serotonergic blocker methiothepin. The platelet-induced relaxation was due to released serotonin and adenine nucleotides in control left circumflex coronary arteries, but in left anterior descending coronary artery with regenerated endothelium, it was due solely to the latter. The platelet-induced contractions were due to activation of receptors on the smooth muscle cells. Four weeks after denudation, regenerated endothelial cells were morphologically different from native cells; they were elongated and cuboidal, and the number of the cells had increased twofold. At this state, eccentric myointimal thickening was present in the previously denuded portion. These experiments indicate that the protective role of endothelial cells against the vasoconstriction induced by aggregating platelets is depressed in the chronic regenerated state. A lack of responsiveness to serotonin appears to be the cause for the endothelial dysfunction.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Extracellular and intracellular longitudinal resistances (r0and r1), transmembrane potentials, and conduction velocity were determined in arterially blood-perfused rabbit papillary muscles. Cable analysis was made possible by placing the muscle in a H2O-saturated gaseous environment, which acted as an electrical insulator. Ischemia was produced by exchanging the O2in the atmosphere by N2(94% N2-6% CO2) in addition to arresting coronary flow. The first 10–15 minutes of ischemia were characterized by an increase in r0, while r1remained constant. The early part of the increase in r0coincided with the drop in perfusion pressure and was probably due to the diminution of intravascular volume. Rapid electrical uncoupling, reflected by an increase in r1(threefold within 5 minutes), occurred thereafter. The dissociation between the early increase in r0and the delayed increase in r, produced an initial increase in the ratio r0:r1, which subsequently decreased. The decrease in conduction velocity was less than observed in intact hearts with ischemia. This difference is explained by the relatively small changes in resting membrane potential and action potential amplitude in the preparation used. Our results suggest that in the early, reversible phase of ischemia, the increase in r0contributes to a small but significant extent to the slowing of conduction. After 15–20 minutes, the rapid cellular uncoupling, which was most likely coincident with breakdown of cellular homeostasis, may contribute to the occurrence of arrhythmias during this phase of ischemia. Moreover, the early change in the ratio r0: r1will influence the amplitude of the extracellular electrograms following coronary occlusion (TQ-segment and ST-segment shifts).

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Helical strips of human coronary arteries contracted in response to histamine concentration dependently, they relaxed with low concentrations and contracted with high concentrations. Treatment with cimetidine potentiated contraction in the strips with intact and damaged endothelium to a similar extent and attenuated relaxation. Removal of endothelium abolished relaxation and potentiated contraction in the cimetidine-treated strips. Methylene blue increased the contractile response to histamine in the strips with endothelium but did not alter the response in the damaged-endothelium strips. Histamine-induced relaxations in the intact strips were suppressed or abolished by treatment with ETYA, AA861, a lipoxygenase inhibitor, and by chlorpheniramine but were unaffected by indomethacin. Chlorpheniramine also abolished amine-induced contraction. It may be concluded that histamine-induced contraction in human coronary arteries is mediated by H1receptors in smooth muscle, and relaxation is mediated by H2receptors in smooth muscle and H1receptors in endothelium. Also, stimulation of the endothelial H1receptor liberates vasodilator substance and possibly activates smooth muscle guanylate cyclase to accumulate cellular cyclic guanosine monophosphate.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

The expression of different isoforms of the contractile protein myosin plays a major role in determining contractile characteristics in both cardiac and skeletal muscle in the adult. There is little evidence pertaining to putative changes in myosin phenotype during cardiac embryogenesis or if such changes could play a role in modulating the contractile characteristics of the developing heart. We examined Isomyosin expression during cardiogenesis in the chick by indirect immunofluorescence microscopy with monoclonal antibodies to adult ventricular and atrial myosin heavy chains. Antibody specificity' was characterized in the adult on the basis of immunofluorescence localization, ELISA, and protein blot immunoassay. Results show that the early embryonic chick heart has a different myosin phenotype than the later embryonic or adult heart. Both the embryonic ventricular and atrial myocardia initially expressed a myosin heavy chain that was recognized by antibody specific (in the adult) for ventricular myosin heavy chain. The ventricles remained reactive throughout life with the ventricular antibody, but reactivity of the atrial myocardium was confined to the initial 6 days of embryonic development. On the other hand, reactivity of the embryonic heart with multiple antibodies specific (in the adult) for atrial myosin was confined to the atrial myocardium throughout development. Thus, the distribution of myosin isoforms became similar to that of the adult myocardium by the time the embryonic heart achieved a 4-chambered configuration at 6 days in ovo.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Smooth muscle cell (SMC) proliferation in injured arteries is inhibited by heparin, but the mechanism of inhibition is unknown. In particular, it is not clear whether heparin prevents exit of quiescent SMC from the resting state, inhibits progression through the prereplicative (G1) sequence, or acts during DNA synthesis itself. In this study, induction of ornithine decarboxylase (ODC) activity was used as a marker of SMC entry into the cell cycle in an attempt to localize the site of heparin action during the initial hours after rat carotid injury. Rapid and transient induction of ODC activity was observed that reached a maximum (twenty-three-fold) 6 hours after wounding. Heparin failed to prevent ODC induction but greatly reduced frequencies of [3H]thymidine-labelled SMC nuclei 33 hours after injury. Moreover, heparin infusion could be delayed for up to 18 hours after the injury event with no significant loss of antiproliferative effect. Further delays resulted in marked loss of growth inhibition. The results of these studies show that SMC rapidly and synchronously leave the resting state after injury and suggest that heparin acts late in the prereplicative (G1) sequence or early in S phase to inhibit SMC proliferation in damaged arteries.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Pretreatment of the ischemic myocardium with verapamil protects against mitochondrial respiratory depression observed during ischemic arrest as well as during reperfusion. Since ischemic mitochondrial function appears not to be altered further by reperfusion, the purpose of this study is to identify a biochemical event affecting mitochondria that is specifically associated with reperfusion injury. It has been proposed that increased cellular Ca2+ influx and oxygen toxicity may result from reintroduction of coronary flow. Increased cytosolic Ca2+ Is transmitted to the mitochondria with subsequent activation of Ca2* -dependent events, including phospholipase A2. Net production of lysophospholipids (and loss of total diacylphospholipids from the mitochondria) will proceed when reacylation mechanisms are inhibited. Since acyl-CoA: lysophospholipid acyltransferase is a sulfhydryl-sensitive enzyme and since increased activity of glutathione peroxidase shifts the levels of the mitochondrial sulfhydryl buffer, glutathione, towards oxidation, levels of glutathione and its oxidation state were measured during reperfusion in the absence or presence of verapamil pretreatment. Ischemia lowers total glutathione and reduces the redox ratio (reduced glutathione: oxidized glutathione) by 85%. Reperfusion partially returns the redox ratio to control by causing oxidized glutathione to disappear from the matrix. Verapamil maintains both the concentration and the redox potential of glutathione at control levels. Concomitant with alterations in reduced glutathione: oxidized glutathione is a decrease in ischemic mitochondria! phospholipid content. During reperfusion, phosphatidylethanolamine and its major constituent fatty acids (C 18:0 and C 20:4) are specifically lost from the mitochondrial membrane. Accompanying the significant loss of arachidonic acid during reperfusion is the decreased content of 11-OH, 12-OH, and 15-OH arachidate. These lipid peroxidation products are not increased in ischemia. It is proposed that oxidation of matrix glutathione to glutathione disulfide during ischemia results in formation of glutathione-protein mixed disulfides and inhibition of sulfhydryl-sensitive proteins, including acyl-CoA lysophosphatide acyltransferase. Thus, metabolic events occurring within the ischemic period set the stage for prolonged dysfunction during reperfusion.

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID