摘要:

BackgroundSmooth muscle cell proliferation and extracellular matrix accumulation are the principal mechanisms leading to vascular restenosis. We have previously demonstrated the growth-inhibitory effect of antisense oligomers targeting the c-mycproto-oncogene in human smooth muscle cells. The goal of this study was to investigate whether c-mycantisense oligomers reduce neointimal formation in balloon-denuded porcine coronary arteries.Methods and ResultsFirst, type I collagen synthesis, which reflects synthetic function, was markedly reduced following c-mycantisense oligomers in porcine vascular smooth muscle cells independent of the growth inhibition. These effects in vitro provided the rationale for assessing c-mycantisense oligomers in the prevention of neointima in vivo. Second, the efficiency of single transcatheter delivery of oligomers into denuded porcine coronary arteries was determined. Despite rapid plasma clearance following local delivery, oligomers persisted at the site of injection for at least 3 days, exceeding by severalfold their concentration in peripheral organs. Third, morphometric analyses were carried out in balloon-denuded coronary arteries at 1 month after transcatheter c-mycan-V tisense oligomer administration. Maximal neointimal area was reduced from 0.80±0.17 mm2in the control group (n=12) to 0.24±0.06 mm2in the antisense-treated group (n= 13,P<.01). Likewise, a significant reduction in maximal neointimal thickness was observed in the antisense-treated group (P<.01). These changes in vascular remodeling following denuding injury resulted in an increase in residual lumen from 64±6% in the control group to 81±5% in the antisense-treated group (P<.05).Conclusions(1) Single transcatheter administration al-lowed for endoluminal delivery of oligomers to the site of coronary arterial injury. (2) C-mycantisense oligomers reduced the formation of neointima in denuded coronary arteries, implying a therapeutic potential of this approach for the prevention of coronary restenosis. (3) It is postulated that the c-mycproto-oncogene is involved in the process of vascular remodeling, regulating smooth muscle cell proliferation and extracellular matrix synthesis.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

PurposeExperiments were designed to determine whether or not leukocytes activated by acute pulmonary rejection cause contractions of isolated pulmonary arteries.Methods and ResultsSeparate suspensions of (a) polymor-phonuclear cells (>95%) and (b) mononuclear cells (85% lymphocytes/10% monocytes/5% polymorphonuclear cells), respectively, were obtained from the arterial blood of four groups of adult male mongrel dogs: unoperated dogs (controls), dogs with single-lung autotransplants, dogs with rejecting single-lung allotransplants, and unoperated dogs treated with the same immunosuppressants as allotransplanted dogs. These suspensions were added to rings of control intralobar pulmonary arteries suspended in organ chambers for measurement of isometric force. The endothelium was removed mechanically from selected rings. No significant change in basal tension of pulmonary arterial rings occurred by adding suspensions of polymorphonuclear cells from any of the four groups of dogs. Significant cell-number-dependent increases in tension occurred with suspensions of mononuclear cells from unoperated dogs, autotransplanted dogs, and unoperated, medicated dogs. These increases in tension were less in rings with compared to those without endothelium. Addition of a synthetic analogue of L-arginine abolished this difference. Suspensions of mononuclear cells from rejecting allotrans-planted dogs caused significantly greater contractions in rings with endothelium than those observed with suspended cells from either unoperated, autotransplanted dogs or unoperated, medicated dogs. Addition of superoxide dismutase plus catalase or an antagonist of endothelin-A receptors (BQ-123) reduced contractions in rings with endothelium but not in those without endothelium to suspensions of mononuclear cells from rejecting allotransplanted dogs.ConclusionsThe results of this study suggest that mononuclear cells cause contraction of pulmonary arteries, which can be partially inhibited by endothelium-derived nitric oxide. However, if the mononuclear cells are activated by acute pulmonary rejection, contractions are no longer inhibited by the endothelium. Under conditions of rejection, contractions are mediated in part by oxygen radicals and endothelin(s).

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundMyocardial stunning is characterized not only by a decreased regional postischemic function but also by a relatively high oxygen consumption (ie, decreased mechanical efficiency). Several lines of evidence suggest that the underlying mechanism may involve a decreased sensitivity of the myofibrils to calcium, but in vivo evidence is lacking. We therefore evaluated this hypothesis in vivo using EMD 60263, a calcium-sensitizing agent, which is devoid of any phospho-diesterase- inhibiting properties.Methods and ResultsWe first established the effect of two consecutive doses of EMD 60263 (0.75 and 1.5 mg/kg IV, n=7), administered at 15-minute intervals, on segment length shortening (SLS), external work index (EW; the area inside the left ventricular pressure-segment length loop), myocardial oxygen consumption (MVo2), and mechanical efficiency (EW/ MVo2) in anesthetized pigs with normal myocardium. After the highest dose of EMD 60263, SLS in the distribution area of the left anterior descending coronary artery (LADCA) increased from 13± 1% at baseline to 17± 1% (P<.05). However, EW, MVo2, and EW/MVo2were not significantly affected (123±10%, 98±9%, and 85±13% of baseline, respectively). In 14 other anesthetized pigs, myocardial stunning was induced by two sequences of 10 minutes of LADCA occlusion and 30 minutes of myocardial reperfusion. After induction of stunning, the two doses of EMD 60263 (n=7) or saline (3 and 6 mL, n=7) were infused. In the distribution area of the LADCA, the stunning protocol caused decreases in SLS from 16±1% to 8±1% (P<.05) and in EW to 49±5% of baseline (P<.05), whereas MVo2was only minimally affected (P<.05). Consequently, mechanical efficiency decreased to 59±8% of baseline (P<.05). Saline infusion did not affect any of these regional myocardial variables, but after administration of EMD 60263 SLS recovered dose-dependently to 15±2% after the highest dose of the drug. EW and mechanical efficiency also recovered dose-dependently to 89±4% (P<.05 versus stunning) and to 88±7% (NS versus baseline) of baseline, respectively. In the not-stunned segment, SLS increased from 15±2% (at baseline) to 18±2% (after the highest dose), and EW per beat was not changed significantly. An adrenergic mode of action of EMD 60263 was excluded by blocking the α-and β-adrenergic receptors with phentolamine and proprano-lol, respectively, 15 minutes before administration of EMD 60263 (ie, 15 minutes into the second reperfusion period) in five additional experiments. In these experiments the EMD 60263-induced increases in SLS and EW were not attenuated. Because EMD 60263 decreased heart rate from 106±4 to 76±3 beats per minute (P<.05) in the animals with stunned myocardium, we performed five experiments with the specific negative chronotropic compound zatebradine (UL-FS 49, 0.1 to 0.5 mg/kg) to rule out bradycardia as a factor contributing to the effects of EMD 60263. These zatebradine doses lowered heart rate from 116±5 to 55±1 beats per minute (P<.05) but had no effect on SLS of stunned and not-stunned myocardium.ConclusionsCalcium sensitization affects function and mechanical efficiency of stunned myocardium more profoundly than of not-stunned myocardium, lending support to the hypothesis that Ca2+desensitization of the myofibrils is involved in myocardial stunning.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundPhysical activity can reduce sympathetic tone and may be beneficial to human health. Whether the vascular responses to norepinephrine (NE), an adrenergic vasocon-strictor, could be altered by chronic exercise was unclear. We therefore conducted this study to investigate the effects of endurance exercise training on NE-induced vasoconstrictive response in healthy rabbits. Possible mechanisms were also studied.Methods and ResultsTwenty-four male New Zealand White rabbits were used for this study. They were divided into two groups: control and training. The training group was trained on a treadmill with running speed of 0.88 km/h at a 0° grade for 10 to 60 minutes per day, for 5 days a week for a total of 8 weeks. At the end of the experiments, thoracic aortae (3 mm long) were isolated. The vascular tension was measured with a force transducer. The dose-response relation of NE-induced vasoconstriction was determined and compared for control (n=5) and trained (n=6) groups. To verify the possible involvement of endothelium-derived relaxing factor (EDRF) in the alteration of NE-induced vasoconstriction after exercise training, we compared the vascular responses to NE in endo-thelium- intact,Nω-nitro-L-arginine (L-NNA, 10−4mol/L)-pre-treated, or denuded vessel segments (n=4 for each experiment of each group). EDRF release in the presence or absence of NE was also evaluated by the increased tension induced by hemoglobin (10−5mol/L), an EDRF scavenger (n=6 for the control group and n=8 for the trained group). In addition, vascular responses to some specific adrenergic agonists (ie, phenylephrine, an α1-agonist, and clonidine, an α2-agonist) were also studied to see if a specific adrenergic receptor was involved (n=4 for each experiment of each group). Our results indicated that (1) [NE]ED50of the thoracic aorta was elevated by exercise training; (2) in the presence of NE, EDRF release from the thoracic aorta, assessed by addition of hemoglobin or L-NNA, was higher in the trained group than in the control group; (3) both phenylephrine (10−8mol/L) and clonidine (10−6mol/L) could evoke vasorelaxation that would be inhibited by L-NNA; and (4) in addition to causing vasoconstriction, NE could stimulate EDRF release, possibly via α1- and α2-receptors of endothelial cells.ConclusionsOur data suggest that exercise training may decrease NE-induced vasoconstrictive response and may increase NE-stimulated EDRF release.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundHeart rate (HR) variability is a marker of tonic cardiac autonomic activity and contributes in assessing risk for sudden death after myocardial infarction. Recent clinical observations have indicated that attenuation of HR variability, which occurs after myocardial infarction, may be transient. This study addresses the issue of whether autonomic control of heart rate recovers at different rates after myocardial infarction in subjects at high and low risk for ventricular fibrillation (VF).Methods and ResultsThirty dogs, 22 with myocardial infarction and 8 sham-prepared animals, completed the study. Changes and recovery in cardiac autonomic activity after myocardial infarction were examined by measuring HR variability before and at defined intervals during the first 30 days after infarction. Each HR variability measurement was made before and after β-blockade in dogs at high (n=10) and low (n=12) risk for VF. Arrhythmia risk was determined on the basis of development of VF during exercise and transient myocardial ischemia 30 days after infarction. No sham-pre-pared animals developed VF. Preinfarction measurements of HR variability were not different between the groups before 3-blockade, but HR variability increased much more in response to β-blockade in animals destined to be resistant compared with susceptible animals (289±26 to 369±35 msec, Δ27.7%, versus 270±36 to 283±34 milliseconds, Δ4.8%, respectively,P<.01). Immediately after infarction, HR variability was significantly attenuated in all dogs, but in the resistant dogs it recovered to pre-myocardial infarction levels within 10 days. After the infarction, β-blockade did not increase HR variability in either group of animals. Postoperative increases in HR variability from β-blockade were preserved in the sham group. Susceptible animals were characterized by a persistent attenuation of HR variability throughout the 30 days.ConclusionsThe depression in HR variability produced by myocardial infarction has a clearly different temporal recovery pattern between low- and high-risk animals. After myocardial infarction, β-adrenergic blockade does not alter HR variability, thus preserving its predictive value. Before myocardial infarction, however, β-blockade increases HR variability only in the animals destined to be at low risk for lethal arrhythmias after the infarction. The recovery pattern of HR variability after myocardial infarction may contribute to the early recognition of individuals at high risk for sudden death.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundThe purpose of this study was to identify determinants of coronary artery reactivity among premeno-pausal female monkeys. Estrogen replacement therapy in postmenopausal females modulates reactivity of atherosclerotic coronary arteries. However, no studies have evaluated the factors that modulate coronary artery reactivity among premenopausal females.Methods and ResultsTwenty-five adult premenopausal female monkeys were fed an atherogenic diet for 32 months. During this time, monkeys were housed in small social groups and determined to be socially dominant (associated with normal ovarian function) or subordinate (associated with impaired ovarian function). After 32 months, coronary artery vasomotor responses to intracoronary acetylcholine, nitroglycerin, and serotonin were assessed by computer-assisted quantitative coronary angiography. Coronary arteries of dominant monkeys dilated (+9±2%), whereas those of subordinate monkeys constricted (−6±2%) in response to acetylcholine (P<.05). There was no effect of social status on vascular response to nitroglycerin or serotonin (P>.10). Vascular responses to acetylcholine were independent of social status effects on plasma lipids, blood pressure, and atherosclerosis extent. The correlation between acetylcholine responses and plasma estradiol concentration measured on the day of angiography wasr=.7 (P= <.01). Furthermore, dilation occurred only if plasma estradiol concentrations were greater than 60 pg/mL.ConclusionsPsychosocial factors and endogenous estrogen production are important modulators of acetylcholine-mediated dilation of atherosclerotic coronary arteries among pre-menopausal female monkeys.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundCoronary thrombosis is a dynamic process dependent on the pathological substrate, the local shear forces, and blood factors.Methods and ResultsWe investigated the effect of a severe (80%) eccentric stenosis on fibrin(ogen) interaction with a deeply damaged vessel wall, its relation to platelet deposition in thrombus formation, and the influence of time on thrombus growth. Porcine125I-fibrinogen and autologous111In-platelets were injected into pigs instrumented for extracorporeal circulation and treated with low-dose heparin (aPTT ratio < 1.5) that has been previously shown and herein confirmed not to affect platelet and/or fibrin(ogen) attachment. Tunica media, as a model of severely injured vessel wall, was mounted in a tubular perfusion chamber containing an eccentric axisymmetric sinusoidal stenosis obstructing the lumen and exposed for 1, 5, and 10 minutes to perfusing blood. A shear rate of 424 s−1at the laminar, parallel parabolic local flow perfused segments one to two orders of magnitude greater at the apex of the stenosis. Fibrin(ogen) deposition, its axial distribution with respect to the apex, and its relation to platelet deposition were determined by an ex vivo analysis of the test substrates. Fibrin(ogen) and platelet deposition were both significantly higher at the apex of the stenosis than at either the prestenotic or poststenotic area at all the studied perfusion times (P<.02). However, fibrin(ogen) deposition demonstrated a significantly smaller degree of increase from the prestenotic area to the apex as well as a smaller degree of decrease from the latter to the poststenotic region, compared with platelet deposition (P<.05). Although both fibrin(ogen) and platelet deposition increased over time, the ratio of fibrin(ogen) to platelets showed a progressive decrease that became significant from 5 to 10 minutes (P<.03) at either low or high shear rate. The rate of platelet deposition was relatively constant; however, fibrin(ogen) deposition progressively decreased, especially at the apex.ConclusionsOn severely damaged vessel wall, fibrin(ogen) and platelet deposition is maximal at the apex of the stenosis where shear rate is extremely high and parallel streamlines are deformed. Nevertheless, fibrin(ogen) deposition is significantly less dependent on high shear rate than is platelet deposition, and the pattern is not influenced by time. Finally, fibrin(ogen) deposition appears to be predominant in the thrombus layers adjacent to a severely damaged vessel wall regardless of the local shear stress levels and flow conditions.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundExperimental studies in vitro suggest that neutrophils can modulate platelet function and vasomotor responses. In the present study, the interactions among neutrophils, platelets, and arterial responses to injury in vivo were assessed.Methods and ResultsThe acute thrombotic and vasomotor responses of porcine carotid arteries to balloon injury in vivo were evaluated in three groups of animals: neutropenic pigs treated (n= 11) or not treated (n= 12) with aspirin and healthy untreated control pigs (n= 15). Neutropenia was achieved by treatment with cyclophosphamide (50 mg/kg, 4 days before the experiment), which decreased circulating leukocyte count by 92% and almost abolished neutrophil aggregation toN-formyl-methionyl- leucyl-phenylalanine without affecting blood platelet count, hematocrit, hemoglobin concentration, or whole blood platelet aggregation to ADP.51Cr platelet deposition on deeply injured and uninjured arterial segments was not statistically influenced by neutrophil depletion, whereas the angio-graphic vasoconstrictive response at the site of endothelial injury distally was significantly reduced by 41% from 46.3±2.9% in the control group to 27.2±4.1% in the neutropenic group (P<.05). Aspirin treatment in combination with neutropenia produced a 50% reduction in whole blood platelet aggregation, resulted in a significant inhibition of platelet deposition to deeply injured arteries, and decreased vasocon-striction by 66% to 15.6±3.0% (P<.05 versus control and neutropenic).ConclusionsNeutrophils can influence the vasoconstrictive response at the site of endothelial injury in vivo. In addition to platelets, neutrophil interaction with the injured vessel wall may be implicated in the pathophysiological response to arterial injury in vivo.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundCoronary stenting is associated with two major complications: subacute thrombosis and neointimal proliferation resulting in restenosis. Our hypothesis is that the biocom-patibility of metallic stents can be improved by coating with a polymer membrane that delivers agents that favorably modify the local arterial microenvironment. This study evaluates the kinetics, distribution, and bioactivity of the model drug for-skolin delivered to the local arterial wall by a polyurethane-coated removable metallic stent.Methods and ResultsStents were used in rabbit carotid arteries (n=20) for as long as 24 hours. The quantity of forskolin bound to the stent decreased exponentially with a half-life of 5.8 hours. Blood concentrations peaked at 140±39 pg/μL at 4 hours. The adjacent arterial media contained 60±39 ng/mg, which was 380- and 460-fold greater than the contralateral carotid media and the systemic blood, respectively (P<.0001). Media forskolin concentrations declined exponentially over time with a tissue half-life of 5.0 hours. Drug distributed throughout the vessel wall with decreasing gradients in the radial and axial dimensions consistent with a diffusion process. Removal of the stent was associated with a 100-fold decline in media forskolin concentration within 2 hours. Forskolin release was associated with a sustained 92% increase in carotid blood flow and a 60% decrease in local arterial resistance compared with coated control stents (P<.005). In another set of rabbits (n=14) using a carotid crush injury, flow-reduction model, forskolin prolonged the time to flow variation and occlusion by 12-fold compared with the use of bare metal stents and 5-fold compared with the use of polyurethane-coated stents (P<.0001).ConclusionsA polymer-coated metallic stent can deliver forskolin to the local arterial wall in high concentrations relative to the blood or other tissues. High local drug concentrations are dependent on maintaining stent-to-tissue gradients. The delivered drug is biologically active, demonstrating vasodilating and antiplatelet properties.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundDouble-wave reentry (DWR) can be a mechanism for acceleration of ventricular tachycardia (VT) with a large excitable gap (EG). The purpose of this study was to determine the effects of heptanol, class Ic, and class III drugs on the inducibility of DWR.Methods and ResultsIn 11 Langendorff-perfused rabbit hearts, a thin ring of anisotropic left ventricular epicardium was created by a cryoprocedure. VTwith a revolution time of 180±26 milliseconds and an EG of 106±8 milliseconds was induced by incremental pacing. During control, entrainment with 10 stimuli at a 99±15-millisecond interval terminated VT in seven hearts. In four hearts VT was accelerated from 205±24 to 115±14 milliseconds by introduction of a second circulating wave in the ring. In the seven VTs that could not be accelerated, 0.5 μmol/L Org7797 (class Ic) and 1.0 mmol/L heptanol (uncoupling agent) prolonged the cycle ength of VT by 32% and 37%, respectively. Because the refractory period (RP) only increased by 11%, the EG prolonged by 71% and the ratio between EG and RP was increased from 0.66 to 1.00. Under these conditions, DWR could be induced in all seven hearts. In the four VTs that could be accelerated during control, administration of the class III drug D-sotalol (35 μmol/L) only slightly slowed VT by 6%. Because the RP was prolonged by 15%, the ratio between the EG and the RP decreased from 0.76 to 0.63. Entrainment now failed to accelerate VT in two of four hearts, whereas in the two other hearts, double-wave reentry self-terminated within eight cycles.ConclusionsDrugs that increase the ratio of EG and RP enhance the susceptibility to acceleration of VT, whereas drugs that decrease this ratio prevent induction of sustained double-wave reentry.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID