摘要:

Background Acute inflammation may play a role in injury during reperfusion following myocardial ischemia. Studies in vitro suggest that intracellular adhesion molecule-1 (ICAM-1) mediates neutrophil adherence to cardiac myocytes and neutrophil-mediated injury. We have shown cytokine activity in postischemic cardiac lymph sufficient to maximally express ICAM-1 on myocytes and that ICAM-1 mRNA is found in the previously ischemic myocardium early in reperfusion.Methods and Results In the present study, we used in situ hybridization techniques to detect ICAM-1 mRNA and examine the cells of origin, relation to cell injury, and relation to inflammatory infiltration after 1 hour of ischemia and varying times of reperfusion. By 1 hour of reperfusion, ICAM-1 mRNA was detected in much of the ischemic myocardium, except in areas of contraction band necrosis. At 2 and 3 hours, a clear demarcation of necrotic areas surrounding ischemic areas of viable myocardium with ICAM-1 mRNA staining was present, and ICAM-1 mRNA staining increased with time. Nonischemic areas had no visible ICAM-1 mRNA staining in the first 3 hours. By 24 hours of reperfusion, ICAM-1 mRNA was present in both control and ischemic segments (excluding the necrotic areas) compatible with a generalized circulation of cytokines persistent at 24 hours. In the absence of reperfusion, ICAM-1 mRNA staining was not seen in the first 3 hours and was markedly reduced at 24 hours. The interface of viable and necrotic cells also contained the most extensive inflammatory infiltration.Conclusions Evidence is presented that induction of ICAM-1 mRNA has highly specific localization to ischemic but viable myocardium. Induction of ICAM-1 mRNA transcription in early reperfusion may render the viable "border zone" susceptible to neutrophil-induced injury. (Circulation. 1994;89:2736-2746.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background The abnormal transmembrane action potentials of subendocardial Purkinje fibers that survive 24 to 48 hours after coronary artery occlusion can be a source of the multiform ventricular tachycardias that occur during this time. A change in the density or function of either or both the T-type and L-type cardiac Ca2+ channels may contribute to the altered electrical activity of these Purkinje myocytes.Methods and Results The purpose of this study was to determine the function of the T- and L-type Ca2+ currents (iCatand iCaL, respectively) in Purkinje myocytes dispersed from the subendocardium of the left ventricle 24 and 48 hours after coronary artery occlusion (IZPC24and IZPC48, respectively). To do this we compared whole-cell Ca2+ currents from Purkinje myocytes enzymatically dispersed from free-running fiber bundles (SPCs), from the subendocardium of the noninfarcted canine heart (NZPCs), and from IZPC24and IZPC48. ICaLand iCatwere recorded with Cs sup + - and EGTA-rich pipettes and in Na sup + -K sup + -free external solutions to eliminate overlapping currents. ICaLdensity was significantly reduced in IZPC48compared with NZPC or IZPC sub 24. This was not accompanied by a shift in the current-voltage relation or by a change in the time course of decay of iCaL. Replacement of Ca sup 2+ with equimolar Ba2+ increased iCaLdensity in all cell types, but peak iBaLof IZPC48remained reduced compared with control iBaLvalues. T-type Ca2+ currents were recorded in all SPCs and NZPCs. In IZPC24and IZPC48there was a reduction in peak iCatamplitudes and densities. This was not accompanied by a shift in the current-voltage relation or by a change in the time course of decay of peak iCat. However, there was a hyperpolarizing shift in the steady-state availability relations in both IZPC24and IZPC48. In addition, the maximally available iCatin IZPC24was not different from control, whereas it was significantly reduced in IZPC48.Conclusions The L-type ICadensity in subendocardial Purkinje myocytes that survive in the infarcted heart is significantly decreased by 48 hours after the time of coronary artery occlusion. The peak T-type ICadensity is decreased in subendocardial Purkinje myocytes that survive in the infarcted heart at 24 hours, but further reduction occurs in these myocytes by 48 hours. This loss in Ca2+ channel function could contribute to the abnormal transmembrane potentials of these myocytes surviving in the infarcted heart. (Circulation. 1994;89: 2747-2759.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Autoantibodies against the beta sub 1 -adrenoceptor have been detected in the sera of patients with idiopathic dilated cardiomyopathy (DCM). The mechanisms by which these autoantibodies can alter normal receptor function are investigated, and the results are interpreted in the light of the beneficial effects of beta1-blockade in some of these patients.Methods and Results Autoantibodies against the beta sub 1 -adrenoceptor, affinity purified from sera of patients with idiopathic DCM, were analyzed in a functional test system of spontaneously beating neonatal rat heart myocytes. Antibodies from rabbits immunized with peptides derived from the amino acid sequence of this receptor were also analyzed. Autoantibodies against the second extracellular loop increased the beating frequency of isolated myocytes in a concentration-dependent manner, to approximately 80% of maximal isoproterenol stimulation. Rabbit anti-peptide antibodies against the second extracellular loop increased the beating frequency correspondingly. Autoantibodies and rabbit anti-peptide antibodies against the second extracellular loop were able to immunoprecipitate the unliganded receptor but not the antagonist-occupied receptor. In contrast, rabbit antibodies against the extracellular N-terminal sequence 34-57 of the beta1-adrenoceptor were able to immunoprecipitate both the unliganded and the antagonist-occupied receptor although with no effect on the beating frequency of myocytes. The positive chronotropic effect of the antibodies was completely neutralized both by the addition of increasing concentrations of the beta1-selective antagonist bisoprolol and by preincubation with the peptide corresponding to the second extracellular loop. The antibody-induced increase in beating frequency remained unchanged for more than 6 hours. This should be compared with the isoproterenol-stimulated beating frequency, which undergoes desensitization within 60 minutes. Addition of isoproterenol to autoantibody-stimulated myocytes resulted in only a small increase in beating frequency and did not cause desensitization. Antibodies had only a marginal effect on cyclic AMP production of stimulated cardiomyocytes compared with the 10-fold increase obtained after stimulation with isoproterenol.Conclusions The second extracellular loop of the beta sub 1 - adrenoceptor is a specific target for antibodies with stimulatory activity detected in patients with idiopathic DCM. The antibodies have a positive chronotropic effect on isolated rat heart myocytes. Autoantibody stimulation does not cause the normal agonist-induced desensitization phenomena of the effector system. These findings could contribute to our understanding of the pathophysiological mechanisms of the autoantibodies and of the beneficial effect of beta1-blocking agents in the treatment of patients with idiopathic DCM. (Circulation. 1994;89:2760-2767.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background The renin-angiotensin system and endothelium-derived nitric oxide (EDNO) are important regulators of vascular tone. This study was designed to investigate endothelial and vascular smooth muscle function in coronary arteries of Ren-2 transgenic rats.Methods and Results Left anterior descending coronary arteries and aortas were isolated from transgenic rats and Sprague-Dawley control rats at 6 (young) and 12 (adult) weeks of age and examined in myographs or organ chambers for isometric tension recording. Systolic blood pressure was significantly higher in transgenic rats (young, 229+-6 mm Hg; adult, 239+-8 mm Hg) than in control rats (young, 126+-2 mm Hg; adult, 118+-3 mm Hg; P<.005). Nomega-Nitro-l-arginine methyl ester (L-NAME, 10 sup -7 to 10 sup -4 mol/L) evoked marked endothelium-dependent contractions in coronary arteries (young, 52+-8% of the contraction to 100 mmol/L KCl; adult, 40+-8%) but not aortas (young, 3+-1%; adult, 2+-1%). In coronary arteries, this response was significantly smaller in adult (n=9) than in young (n=8, P<.05) control rats. Young transgenic rats (56+-9%, n=8) showed slightly stronger contractions in response to L-NAME than young control rats (NS), which almost totally disappeared in adult transgenic rats (6+-3%, n=7; P<.05 versus adult control rats; P<.01 versus young transgenic rats). Endothelium-dependent relaxations in response to acetylcholine (10 sup -9 to 10 sup -4 mol/L) were totally blocked by L-NAME (10 sup -4 mol/L) but were unaffected by the thromboxane receptor antagonist SQ30741 (10 sup -7 mol/L). This stimulated release of EDNO, endothelium-independent relaxations in response to the nitrovasodilator linsidomine (10 sup -9 to 10 sup -5 mol/L), and contractions in response to KCl (100 mmol/L) were comparable in all groups of rats.Conclusions Ren-2 transgenic rats develop fulminant hypertension that is associated with a selective decrease in endothelium-dependent contractions in response to L-NAME, whereas endothelium-dependent relaxations in response to acetylcholine as well as smooth muscle function remain unaffected. (Circulation. 1994;89:2780-2786.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Experiments were carried out using the new Na sup + -H sup + exchange inhibitor (3-methylsulfonyl-4-piperidinobenzoyl)guanidine methanesulfonate (HOE 694) to assess the role of Na sup + -H sup + exchange in myocardial ischemic and reperfusion injury.Methods and Results Three groups of rabbit hearts (n=5 in each) were perfused with blood and were subjected to 45 minutes of global normothermic (37 degrees C) ischemia, followed by 1 hour of reperfusion. Group 1 was the control group (vehicle only); in group 2, HOE 694 (1 micromole/L) was administered before ischemia (pretreatment group); and in group 3, HOE 694 was given only during reperfusion to separate actions exerted during ischemia from those specifically obtained during reperfusion. End-diastolic pressure rise at 1 hour of reperfusion was reduced by administration of HOE 694 starting before ischemia (from 52.2+-8.5 mm Hg in group 1 to 17.6+-4.5 mm Hg in group 2, P<.01) or starting on reperfusion (28.8+-5.4 mm Hg in group 3, P<.05 versus group 1). Left ventricular developed pressure (LVDP) and its derivative (dP/dt) recovered better in HOE 694-pretreated hearts (LVDP, 79+-9.9 mm Hg in group 2 versus 24.8+-10 mm Hg in group 1; dP/dt, 1580+-198 mm Hg/s versus 340+-221 mm Hg/s, P<.01). In hearts treated only on reperfusion, some improvement was observed, which, however, did not reach statistical significance. Coronary flow on reperfusion was higher in groups 2 and 3 compared with controls, and no "no-reflow" was observed. Two additional groups of hearts were perfused with phosphate-free Krebs-Henseleit solution to enable studies with Phosphorus-31 nuclear magnetic resonance (NMR). ATP was better preserved in HOE 694-pretreated (62+-4.9% of preischemic value) than in control hearts (44+-3.3%) at the end of 30 minutes of reperfusion, and phosphocreatine resynthesis was higher (109+-3.7% versus 86+-5.4%). HOE 694 did not affect the time course of intracellular acidosis during ischemia but suppressed a small alkaline overshoot occurring early in reperfusion (pH 6.96+-0.02 in HOE 694-pretreated hearts versus 7.14+-0.05 in control hearts). Electron microscopy with Ca2+ staining of the blood-perfused hearts showed that clumping of Ca2+ aggregates in mitochondria was prevented by HOE 694.Conclusions Postischemic dysfunction was associated with a rise in end-diastolic pressure. This rise was effectively blocked by HOE 694. The drug was most effective when hearts were treated before ischemia, although partial protection was observed when administration was started on reperfusion. The action of HOE 694 strengthens the idea that Na sup + -H sup + exchange during both ischemia and reperfusion contributes to contractile dysfunction. (Circulation. 1994;89:2787-2798.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background The role of vascular endothelium in the control of epicardial coronary artery vasomotion during treadmill exercise remains unclear. Therefore, we examined the consequences of in vivo balloon endothelial denudation on external coronary diameter of the left circumflex artery during exercise in conscious dogs.Methods and Results Seven dogs instrumented for the measurement of arterial blood pressure, external coronary artery diameter, and coronary blood flow were studied during exercise before and up to 21 days after balloon endothelial denudation of the proximal left circumflex artery. Endothelial denudation was confirmed by abolition of the epicardial coronary artery dilation induced by acetylcholine (0.3 micrograms/kg IV) and reactive hyperemia. Epicardial coronary vasodilation was observed in the control state during treadmill exercise (+5.2+-1.0%). In contrast, a marked vasoconstriction was observed 3 (-4.6+-0.6%) and up to 6 days after endothelial denudation. Complete epicardial coronary artery dilation in response to acetylcholine and exercise was restored 9 days after endothelial denudation. In addition, epicardial coronary artery vasomotor responses to acetylcholine and treadmill exercise were closely correlated (r=.82, P<.001). Reactive dilation was not completely restored 21 days after endothelial denudation, but reactive hyperemia and exercise vasomotor responses during the 21 days follow-up were correlated (r=.70, P<.001). Vasodilation induced by nitroglycerin (1 micrograms/kg IV) was reduced by 25% (P<.01) 3 days after endothelial denudation and returned to its corresponding control level 3 days later. Prazosin (50 micrograms/kg IV) significantly attenuated the exercise-induced coronary artery constriction after endothelial denudation (+1.5+-1.4% versus -4.6+-1.0%).Conclusions These data demonstrate that endothelium is essential for the mediation of epicardial coronary dilation during exercise and may protect these vessels against the vasoconstrictor effect of endogenous catecholamines. (Circulation. 1994;89:2799-2808.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background In de novo human atherosclerosis, compensatory vessel enlargement limits the effect of intimal plaque formation on lumen narrowing. We hypothesized that arterial remodeling may also play an important role in determining the chronic lumen size after angioplasty and tested this hypothesis using the hypercholesterolemic rabbit iliac artery angioplasty model.Methods and Results Morphometric analysis of histological cross-sectional areas of vessels from animals killed immediately after angioplasty (acute group, n=11) were compared with the same areas from animals killed 4 weeks after the procedure (chronic group, n=37), when restenosis occurs in this model. The area circumscribed by the internal elastic lamina (IEL) increased by 20% from acute to 4 week follow-up after angioplasty (acute group, 2.36+-0.45 mm2; chronic group, 2.84+-0.89 mm sup 2). Over the same time period, intimal area increased by 0.82 mm2. Despite this increase in intimal area, lumen area decreased by only 0.34 mm sup 2 because of the compensatory enlargement of the IEL area. In the chronic group, polynomial regression analysis revealed a quadratic relation between intimal area and lumen area (R2=.35, P<.001). A lumen area of 0.45 mm2(the nadir of the quadratic relation) was used to divide the chronic group into two subgroups: restenotic (n=21; lumen area, <0.45 mm20.45 mm2). By definition, there was a significant difference in lumen area between the two subgroups (0.15+-0.15 mm2for restenotic; 0.73+-0.18 mm2for nonrestenotic). Surprisingly, the intimal areas in the two subgroups were virtually identical (2.41+-0.92 mm2for restenotic, 2.49+-0.69 mm2for nonrestenotic, P=NS). The difference in the lumen area between restenotic and nonrestenotic vessels was a result of the significantly greater IEL area in the nonrestenotic subgroup (3.22+-0.83 mm2for nonrestenotic, 2.56+-0.84 mm21, limiting the effect of intimal plaque on luminal narrowing.Conclusions These data indicate that the iliac artery in an atherosclerotic rabbit model compensates for intimal formation after angioplasty by vessel enlargement. Furthermore, the degree of vessel enlargement is more important than intimal area in determining the chronic lumen size. (Circulation. 1994;89:2809-2815.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Although arterial renarrowing after angioplasty has been attributed largely to intimal hyperplasia, there has been no systematic effort to correlate the actual hyperplastic tissue mass with angiographic lumen reduction. Using balloon angioplasty in various animal restenosis models, we quantitatively assessed the separate contributions of intimal hyperplasia and arterial remodeling to angiographic late lumen loss.Methods and Results Data used for this study were obtained from experiments of conventional and thermal (37 degrees C or 55 degrees to 90 degrees C) balloon angioplasty-treated femoral and iliac arteries in normal rabbits and conventional balloon angioplasty-treated iliac arteries in Yucatan micropigs fed either a normal or an atherogenic diet. Quantitative angiography was performed immediately before and after intervention and at 3 or 8 weeks thereafter, and late loss in lumen diameter was taken as the difference between arterial diameter immediately after treatment and at 3 or 8 weeks of follow-up. Intimal hyperplasia was quantified histologically as the area of tissue mass within the internal elastic lamina. We observed a consistent discrepancy between the actual late loss seen with angiography and the diameter reduction that could be explained by histological intimal thickness alone in both animal models. This discrepancy ranged from 86+-3% of the late loss in the 8 weeks/37 degrees C group to 77+-22% in the conventional group for rabbits and 52+-23% in an atherogenic diet group (n=10) to 89+-11% in a normal diet group (n=6) for pigs. This discrepancy appeared to be due predominantly to reduction of the area circumscribed by the internal elastic membrane, a process that is tentatively designated as arterial remodeling. In both the rabbit femoral artery and in the Yucatan iliac artery, remodeling, not intimal hyperplasia, correlated with angiographic late loss.Conclusions In both the normal rabbit and the normal and atherosclerotic pig, restenosis after angioplasty results from both intimal hyperplasia and arterial remodeling. The exact etiology of arterial renarrowing after angioplasty has important implications on the design of antirestenosis drugs and new coronary devices. (Circulation. 1994;89:2816-2821.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Von Willebrand factor and platelet membrane glycoprotein Ib receptors interact to mediate platelet adhesion and thrombogenesis in stenosed and endothelium-injured arteries. We wished to determine whether blocking glycoprotein Ib receptors with a recombinant von Willebrand factor binding domain (VCL) increases the time required for thrombus formation after injury to the coronary arteries. We also wished to determine whether, after thrombolysis with tissue plasminogen activator (TPA), VCL delays or protects against coronary artery reocclusion. Twenty-seven dogs were treated with either saline, VCL, or aspirin before thrombosis was induced in their coronary arteries by electrical injury. The time from injury to the formation of occlusive thrombi was significantly greater with VCL (70+-10 minutes) and aspirin (69+-20 minutes) than with saline (18+-3 minutes, P<.001 and P<.05). Thrombosis was induced in 30 other dogs that then received thrombolytic treatment in four groups. Our major finding was that coronary artery reocclusion occurred in 72+-11 minutes after treatment with TPA (80 micrograms/kg+8 micrograms x kg sup -1 x min sup -1) and heparin (200 U/kg) (n=7); in 142+-24 minutes after TPA, heparin, and VCL (4 mg/kg+2 mg x kg sup -1 x h sup -1) (n=7) (compared with TPA and heparin, P<.05); in 74+-13 minutes after TPA, heparin, and aspirin (5 mg/kg) (n=8); and in 173+-8 minutes after TPA, heparin, VCL, and aspirin (n=8) (compared with TPA and heparin, P<.001). Thus, VCL increases the length of time required for thrombus formation in coronary arteries, and, when given with TPA and heparin, delays coronary artery reocclusion more effectively than aspirin. (Circulation. 1994;89:2822-2828.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background The potential usefulness of adriamycin (ADR) is restricted because of its cardiotoxic side effects. Since free radicals and lipid peroxidation are suggested to be involved in ADR cardiomyopathy, we examined the beneficial effects of probucol, a lipid-lowering drug with strong antioxidant properties.Methods and Results ADR was administered to rats in six equal intraperitoneal injections over a period of 2 weeks (cumulative dose of 15 mg/kg). After a 3-week posttreatment period, cardiomyopathy and congestive heart failure were characterized by ascites, congested liver, depressed cardiac function, elevated left ventricular end-diastolic pressure, and myocardial cell damage. Myocardial glutathione peroxidase (GSHPx) activity was decreased, and lipid peroxidation was increased. Probucol (cumulative dose, 60 mg/kg IP) was administered in six equal injections over a 2-week period on days alternating with ADR treatment. Probucol significantly attenuated the myocardial effects of ADR, improved left ventricular function, and lowered mortality as well as the amount of ascites. Treatment with probucol was also accompanied by an increase in myocardial GSHPx and superoxide dismutase activities, with a concomitant decrease in lipid peroxidation.Conclusions These data provide evidence that ADR cardiomyopathy is associated with an antioxidant deficit. Improved cardiac function resulting from treatment with probucol may be related to the maintenance of the antioxidant status of the heart. The study suggests potential usefulness of antioxidant (probucol) therapy in ADR cardiomyopathy. (Circulation. 1994;89:2829-2835.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID