摘要:

Frequency- and voltage-dependent modification of drug-induced inhibition of maximal upstroke velocity of the action potential (Vmax) by the combined administration of two class antiarrhythmic drugs was studied in canine Purkinje fibers, taking depression of upstroke velocity as an indicator of sodium channel blockade. The kinetics of onset of drug-induced Vmax depression and the time course of Vmax recovery were studied after exposure to therapeutic concentrations of tocainide (50, uM) and quinidine (5, uM) both singly and in combination. The rate constant for onset of block during a drive train at a cycle length of 600 msec was 0.95 ± 0.32 pulses in the presence of tocainide and 5.61 ± 0.50 pulses in the presence of quinidine. The magnitude of block was three times greater with quinidine than with tocainide. The magnitude of block produced by the combination was no greater than that produced by quinidine alone and may be partly due to abbreviation of action potential duration by tocainide. Onset of block in the presence of the combination was best fitted by a double exponential with rate constants of 0.88 ± 0.19 and 6.47 ± 1.36 pulses. Vmax recovery after termination of a rapid train of impulses was delayed by both drugs. Poststimulation recovery from either tocainide- or quinidine-induced block was characterized by a single time constant (1.04 ± 0.49 and 4.81 ± 0.76 sec, respectively), while that of the combination was characterized by two time constants (0.43 ± 0.22 and 5.94 ± 0.56 sec), presumably corresponding to dissociation of each drug from the sodium channel receptor. The mixture of the two drugs produced a large depression of Vmax of early diastolic premature responses without producing much further depression of Vmax than that produced by quinidine alone at longer coupling intervals. The time constant of recovery from tocainideinduced block was greatly dependent upon membrane potential. After steady-state changes in frequency, the combination produced a greater depression of Vmax at rapid heart rates compared with that produced by quinidine alone, but abbreviated action potential duration more at slower heart rates. Addition of tocainide to fibers equilibrated with quinidine shifted the Vmax-membrane potential relationship to more hyperpolarized potentials, resulting in greater depression of Vmax at more depolarized membrane potentials with little or no additional depression of Vmax at more negative membrane potentials. The results provide a rationale for a possible enhanced antiarrhythmic efficacy of a combination of two class I drugs that have different kinetics of interaction with the sodium channel.

ISSN:0009-7322    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

The purpose of these experiments was to determine the frequency dependence of the effects of amiodarone and its active desethyl metabolite on slow-channel tissues. Intravenous amiodarone and desethylamiodarone (10 or 25 mg/kg) increased atrioventricular conduction time (AVCT) and refractory period (AVERP) in open-chest, chloralose-anesthetized dogs. Drug effects on AVCT and AVERP were greatly augmented by increasing atrial stimulation frequency. The frequency dependence of drug effects was quantified by studying the response of atrioventricular (AV) conduction to changes in coupling interval. Under control conditions, premature atrial stimulation increased AVCT with a time constant of 70 msec. In the presence of amiodarone and desethylamiodarone, a biexponential relationship between AVCT and coupling interval was observed. One component had a time constant similar to control, and a slower component with a time constant of about 1 sec appeared. Slow-channel action potentials produced in canine cardiac false tendons by elevated potassium (25 mM) and isoproterenol in vitro showed interval-dependent changes in Vmax with a time constant averaging 74 msec in the absence of amiodarone. In the presence of amiodarone, a slower recovery phase of Vmax with a time constant averaging 0.94 sec was observed. These results indicate that amiodarone and its metabolite produce heart rate-dependent changes in AV nodal function in vivo and suggest use-dependent calcium-channel blockade as a mechanism of this action. Amiodarone's rate-related effects on slowchannel properties should produce selective depression of supraventricular tachyarrhythmias involving rapid activation of the AV node.

ISSN:0009-7322    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

We studied the acute and chronic biological reaction to balloon-expandable intracoronary stents in the adult dog. Twenty stainless steel stents were placed, by standard angioplasty techniques, into the left anterior descending, left main, or circumflex coronary arteries of 20 dogs. Angiography was performed at 1, 3, 6, and 12 months and animals were killed in groups of three at 1, 3, 8, and 32 weeks, for gross, light, and electronmicroscopic analysis. All dogs survived, all stents were patent, and there was no evidence of myocardial infarction, spasm, rupture, or aneurysm formation during follow-up (longest 18 months; average, 12 months). The stent was initially covered by a thin layer of thrombus that was replaced later by neointimal muscular proliferation that reached its maximal thickness by 8 weeks (p < .01). This neointima gradually thinned as it became more sclerotic and less cellular. The stents were covered completely by immature endothelium by 1 week without loss of side branches. We conclude that balloon-expandable intraluminal stents can be safely placed percutaneously into normal canine coronary arteries. Because of rapid endothelialization high patency rates can be expected, thus offering promise for clinical applications in man.

ISSN:0009-7322    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

The mechanism for the prolonged contractile dysfunction observed in myocardium reperfused after reversible regional ischemia ("stunned" myocardium) is unclear. Recent studies suggest that myocardial stunning may be mediated by oxygen-derived free radicals, but the precise molecular species involved remain unknown. Thus we explored the role of the highly cytotoxic hydroxyl radical in regional postischemic dysfunction by using dimethylthiourea (DMTU), an effective and highly permeable hydroxyl radical scavenger. Open-chest dogs undergoing a 15 min occlusion of the left anterior descending coronary artery followed by 4 hr of reperfusion received either DMTU (0. 5 g/kg iv over 45 min starting 30 min before occlusion, n = 14) or saline (n = 15). Control and treated dogs were comparable with respect to variables that may affect postischemic dysfunction, including heart rate, aortic pressure, left atrial pressure, arterial blood gases and hemoglobin concentration, size of the occluded bed (determined by postmortem perfusion), and collateral blood flow (determined by radioactive microspheres). Regional myocardial function was assessed by measuring wall thickening with an epicardial Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions and similar degrees of dyskinesis during ischemia. After reperfusion, however, wall thickening (expressed as percent of baseline) was considerably greater in treated as compared with control dogs: 53 + 9% (mean -+- SEM) vs 9 ± 14% (p < .03) at 1 hr, 55 ± 9% vs 23 ± 13% (p < .05) at 2hr, 60 + 9%vs28 ± 14% (p < .05) at 3hr, and67 ± 5%vs36 + 13% (p < .05) at 4hr. Thus DMTU produced a significant and sustained improvement in recovery of contractile function. In concentrations greater than the plasma levels attained in vivo, DMTU did not scavenge either hydrogen peroxide or superoxide anion in vitro. These results suggest that the myocardial dysfunction occurring after a brief episode of regional ischemia is mediated in part by the hydroxyl radical.

ISSN:0009-7322    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

To determine the effect of intracoronary perfluorochemical on endothelial cell structure and function, 16 dogs were randomized to receive either low-dose (15 ml/kg) intracoronary perfluorochemical (Fluosol-DA) or saline after 90 min of proximal occlusion of the left anterior descending coronary artery (LAD). The animals underwent reperfusion for 60 min with the introduction of perfluorochemical or saline 5 to 10 min after the onset of reperfusion. Endothelium-dependent coronary vasodilatory reserve was determined in vivo both at baseline and 1 hr after reperfusion by infusion of acetylcholine and then serotonin into the distal LAD bed in 12 animals (six in each group). Both agonists significantly increased regional flow measured by 133Xe washout in the two groups before occlusion, but at 1 hr after reperfusion only animals given perfluorochemical demonstrated a significant increase in flow. Vasodilatory reserve was assessed in vitro with cumulative dose-reponse curves to acetylcholine on LAD rings proximal and distal to the snare in all animals. These studies demonstrated a significant reduction in endothelial cell-mediated relaxation of epicardial arterial segments in the ischemic segment of control but not treated animals. Light microscopy revealed the presence of neutrophils within vessels in the ischemic zones in control animals only. Electron microscopy showed capillary obstruction by endothelial cell protrusions and neutrophil and red cell plugging in control animals in the ischemic region but an intact endothelium and predominantly unobstructed capillaries in treated animals. These findings suggest that the structural and functional endothelial damage after reperfusion may be prevented by the administration of intracoronary perfluorochemical after the onset of reperfusion.

ISSN:0009-7322    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

Effects of leukotriene (LT) C4 and LTD4 on coronary artery spasm in atherosclerotic miniature pigs were examined angiographically. Endothelial balloon denudation of the left circumflex coronary artery was performed in 15 Gottingen miniature pigs; 11 were fed a 2% cholesterol diet and four were fed a regular diet for 3 months. Three months after this denudation, the area of the coronary artery was reduced by 94 ± 2% and 43 + 5% (p < .01) in the denuded and nondenuded areas by the intracoronary administration of 10, g/kg histamine after pretreatment with 60 mg/kg iv cimetidine. The effects of LTC4 and LTD4 on coronary diameter and the preventive effects of FPL-557 12, a LTC4 and LTD4-receptor blocker, or diphenhydramine, a histamine HI-receptor blocker, on histamineinduced coronary spasm were then examined angiographically. Administration of LTC4 or LTD4 in doses of 1 and 10, ug into the left coronary artery, or selectively into the left circumflex and left anterior descending coronary arteries in a dose of 5, ug, led to the elevations in the ST segment on the electrocardiogram and there was delayed filling of the contrast medium in the peripheral coronary artery. However, these LTs provoked no augmented constrictions at any site on the epicardial coronary arteries (n = 15). Diphenhydramine, 1 mg/kg (n = 6), abolished the histamine-induced coronary spasm. FPL-55712, 0.1 mg/kg, with which the LT-induced myocardial ischemia was abolished, did not prevent the histamine-induced coronary artery spasm. Hence, in a swine preparation of coronary artery spasm, LTC4 and LTD4 constricted the coronary arteries at the level of small vessels and rendered the perfused myocardium ischemic. These compounds do not seem to play a primary role in the provocation of epicardial coronary artery spasm induced by histamine in this atherosclerotic swine preparation.

ISSN:0009-7322    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

The purpose of the present study was to evaluate potential diurnal changes in resting coronary blood flow under conditions of comparable myocardial oxygen requirements. We studied 21 conscious, resting dogs instrumented for the measurement of coronary flow, left ventricular pressure, and regional myocardial segment length. Recordings were taken in the early morning and late afternoon. In the afternoon, left circumflex coronary blood flow was 12.8% higher than in the morning, without detectable changes in the major hemodynamic determinants of myocardial oxygen consumption, i.e., heart rate, left ventricular pressure, peak positive dP/dt, end-diastolic regional myocardial dimension, and regional myocardial stroke work. These results are consistent with a circadian variation of coronary vascular tone accompanied by compensatory alteration in myocardial oxygen extraction and may have clinical relevance, since the coronary vascular tone may change dynamically in patients with critical coronary stenosis.

ISSN:0009-7322    

出版商:OVID    

年代:1987

数据来源: OVID