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1. |
Antibodies to the ADP/ATP Carrier, an Autoantigen in Myocarditis and Dilated Cardiomyopathy, Penetrate Into Myocardial Cells and Disturb Energy Metabolism In Vivo |
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Circulation Research,
Volume 64,
Issue 2,
1989,
Page 179-192
Karsten Schulze,
Bernhard Becker,
Heinz Schultheiss,
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摘要:
We identified the ADP/ATP carrier, located within the inner mitochondrial membrane, to be an organ- and conformation-specific autoantigen in myocarditis and dilated cardiomyopathy. We also showed that autoantibodies to the ADP/ATP carrier inhibit the nucleotide transport in vitro. Specific binding of the autoantibodies to the carrier was demonstrated by radioimmunoassay and the immunoblot technique; the inhibition of the nucleotide transport was determined by the inhibitor stop method. To establish if these autoantibodies might also affect cardiac energy metabolism in vivo, we measured whether they are capable of penetrating into myocytes and whether subcellular ATP/ADP ratios and phosphorylation potentials of ATP change in hearts of guinea pigs that have been immunized with the isolated ADP/ATP carrier. An intracellular deposition of autoantibodies was observed by direct immunofluorescence and by immunoperoxldase staining on cryosections of the myocardial tissue of animals immunized with the ADP/ATP carrier. Furthermore, binding of autoantibodies to mitochondrial membrane structures was shown by immunoelectron-microscopic methods. The cytosolic and intramitochondrial distribution of adenine nucleotides in stimulated, isolated perfused hearts of guinea pigs immunized with the ADP/ATP carrier was measured by nonaqueous fractionation. Compared with controls performing equal external heart work, the cytosolic ATP decreased in the immunized animals, whereas the mitochondria! ATP increased strongly; ADP concentrations showed an opposite change. Thus, a resultant cytosolic decrease and a marked mitochondrial increase of the ATP/ADP ratio was established. As a consequence, the cytosolic-mitochondrial phosphorylation potential of ATP was diminished. These findings demonstrate that antibodies against intracellular antigens are able to penetrate into living cells, and that antoimmunity to the ADP/ATP carrier may contribute to the pathophysiology of myocarditis and dilated cardiomyopathy by causing an autoantibody-mediated imbalance between intracellular energy delivery and demand.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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2. |
Regional Differences in the In Vivo Synthesis and Degradation of Myosin Subunits in Rabbit Ventricular Myocardium |
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Circulation Research,
Volume 64,
Issue 2,
1989,
Page 193-202
Allen Samarel,
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摘要:
To test for regional differences in the rates of synthesis and degradation of contractile proteins during normal physiological growth of the heart in vivo, fractional rates of protein accumulation and synthesis were assessed for total protein, myosin heavy chain, myosin light chain, phosphorylatable myosin light chain, and actin in the right and left ventricular free walls of growing, New Zealand White rabbits. Fractional rates of protein accumulation were determined from regional protein content growth curves of total and individual myofibrillar proteins measured in 82 animals ranging from 1 day to 9 weeks of age. In vivo right and left ventricular fractional rates of protein synthesis were determined by the [3H]leucine constant infusion method in 9-week-old rabbits. At this age, right and left ventricular fractional accumulation rates for total protein, myosin subunits, and actin were found to be identical, thus allowing for the comparison of the effect of regional hemodynamic load on protein degradation independent of its effect on growth. Total protein and individual myofibrillar protein fractional degradative rates were then derived as the difference between fractional rates of synthesis and accumulation. The results indicate increased fractional synthesis and degradation of myosin heavy chain and light chains, but not actin, in the left compared to the right ventricular free wall. Accelerated left ventricular replacement of myosin subunits may be related to regional differences in hemodynamic load. These results help explain the apparent increase in the in vivo rate of myocardial protein degradation observed in several experimental models of ventricular hypertrophy.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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3. |
Electrophysiological Properties of Cultured Dog Myocytes Obtained by Endomyocardial Biopsy |
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Circulation Research,
Volume 64,
Issue 2,
1989,
Page 203-212
Sunao Sakai,
Takayuki Tokimasa,
Masatoshi Nohara,
Yoshinori Koga,
Takashi Akasu,
Hironori Toshima,
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摘要:
Right ventricular cardiac tissue (10-20 mg wet weight) was obtained from anesthetized adult dogs by endomyocardial biopsy. The biopsy could be repeated in one dog every 2 weeks for up to 3 months. Fifty to 200 cardiomyocytes, dispersed with collagenase and trypsin, were collected by centrifugation of the cells with 50percent; polysucrose-sodium diatrizoate solution (Ficoll-Paque). Single cardiomyocytes were suspended in a minimum essential medium containing 20percent; fetal bovine serum and 8-bromoadenosine 3': 5'-cyclic monophosphate (0.1 mM) for up to 3 weeks. Approximately 70-80percent; of the cultured cardiomyocytes were rod shaped after 24 hours (10-20percent; after 7 days). Cytoplasmlc organelles of the cultured cells, examined with a transmission electron microscope, were within the normal range of canine heart morphology in vivo. Resting membrane potential of the cells was about -80 mV when superfused with a Krebs' solution containing 4.7 mM potassium ions. The action potential lasted for 300 msec and had a peak amplitude of about 120 mV. Voltage-clamp experiments demonstrated the presence of an inward calcium current (±0.9 nA at +9 mV), which was facilitated by isoproterenol (0.1-1 μM). The background potassium current showed typical inward rectification at potentials more negative than -80 mV. The results indicate that morphological, electrophysiological, and pharmacological properties of the cultured cardiomyocytes were intact. We propose that the culture techniques we have developed can be useful for repeated investigation on functional aspects of cardiac muscles in myocardial disease.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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4. |
Vagally Induced Block and Delayed Conduction as a Mechanism for Circus Movement Tachycardia in Frog Atria |
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Circulation Research,
Volume 64,
Issue 2,
1989,
Page 213-226
Leonid Rosenshtraukh,
Alexey Zaitsev,
Vladimir Fast,
Arcady Pertsov,
Valentin Krinsky,
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摘要:
Episodes of tachycardia induced by strong vagal stimulation in spontaneously beating isolated atria of frog (Rana temporaria) were studied with multielectrode mapping technique. These episodes were inducible in 19 of 39 preparations. The arrhythmia started several seconds after cessation of vagal stimulation strong enough to cause sinus arrest, without electrical stimulation of the myocardium. The arrhythmia consisted of two to 20 beats (6±4, mean±SD, n=42) with a cycle length of 100-500 msec. Recording from 32 sites with spatial resolution of 1-2 mm showed that the arrhythmia was due to intra-atrial circus movement. The estimated perimeter of the reentrant circuit ranged from 6 to 20 mm. In circuits of the minimal size, the average conduction velocity along the circuit was as low as 2-3 cm/sec. Paroxysms of the tachycardia were always preceded by vagally induced nonuniform depression of conduction, with some areas of atria being completely blocked. As the vagal influence decreased, the blocked areas recovered in an inhomogeneous manner, their unblocking being significantly (p<0.05) delayed after inhibition of tissue cholinesterase by proserine. The reentrant tachycardia was initiated when a sinus impulse arrived during certain phase of the unblocking. Unlike the well-known mechanism of reentrant excitation, which is based on inhomogeneous refractoriness and critically timed extrabeat(s), the circus movement in our model depended on vagally induced conduction block and could be launched by a single sinus impulse.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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5. |
Pharmacokinetics and Distribution of Heparin‐Binding Growth Factor I (Endothelial Cell Growth Factor) in the Rat |
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Circulation Research,
Volume 64,
Issue 2,
1989,
Page 227-234
Todd Rosengart,
John Kuperschmid,
Thomas Maciag,
Richard Clark,
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摘要:
Heparin-binding growth factor I (HBGF I), previously designated as endothelial cell growth factor, is a potent mitogen for endothelial cells in vitro, which may prove useful for promoting endothelial regeneration in vivo. Analysis of the pharmacokinetics and organ distribution of HBGF I is necessary before use of HBGF I as a pharmacological agent. Consequently, pharmacological studies were carried out with [125I]HBGF I in the rat. Intravenous injections of HBGF I were given with or without heparin (2.5 units/ng HBGF I). Blood concentrations of HBGF I decreased by one half 17 seconds after HBGF I bolus. This time was prolonged to 60 seconds when HBGF I was injected with heparin. The elimination half-life of HBGF I was 14 minutes in the presence of heparin. The highest concentrations of HBGF I following intravenous bolus were found in kidney, liver, and spleen, and the lowest in fat and brain. Heparin increased HBGF I concentrations in blood and all organs measured except kidney, which was significantly decreased (p
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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6. |
Anti‐inflammatory Actions of Enprofylline, a Modified Xanthine, in the Canine Forelimb |
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Circulation Research,
Volume 64,
Issue 2,
1989,
Page 235-242
David Dobbins,
Connie Soika,
Molly Buehn,
Joe Dabney,
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摘要:
It has been previously reported that enprofylline (3-propyl xanthine) prevents histamine-mediated edema formation in the guinea pig lung. To further assess the potential anti- inflammatory effects of enprofylline, we infused it intra-arterlally into the canine forelimb before and during a local intra-arterial infusion of histamine (4 μg/min) while monitoring forelimb skin lymph parameters. Infusion of enprofylline at 2 mg/min significantly decreased forelimb arterial pressures and increased heart rate and pulse pressure. Subsequent infusion of histamine caused a further reduction in forelimb arterial pressures and an increase in lymph flow, protein concentration, and protein transport similar to that seen with the infusion of histamine alone. Infusion of enprofylline at 5 mg/min decreased forelimb arterial pressures and systemic pressure. Subsequent histamine infusion further reduced forelimb arterial pressures, but the increase in lymph parameters was markedly attenuated. Enprofylline infused at 10 mg/rain also decreased forelimb arterial and systemic pressures, but subsequent histamine infusion was essentially without effect on lymph parameters. To assess the role of catecholamines in enprofylline-mediated attenuation of histamine edema formation, we infused enprofylline at 5 mg/min in the presence of a β2-receptor blockade produced by the intra-arterial infusion of ICI 118551. The effects of enprofylline and histamine on vascular pressures were similar to those seen in the absence of β2-receptor blockade, but lymph flow, protein concentration, and protein transport increased similar to that seen with histamine alone. These data indicate that enprofylline is capable of attenuating histamine-induced increases in microvascular permeability, but this action of enprofylline is of an indirect nature, mediated through the release of catecholamines.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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7. |
Effect of Reduced Energy Metabolism and Reperfusion on the Permeability and Morphology of the Capillaries of an Isolated Rete Mirabile |
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Circulation Research,
Volume 64,
Issue 2,
1989,
Page 243-254
Eugenio Rasio,
Moise Bendayan,
Carl Goresky,
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摘要:
The effects of reduction in energy metabolism were explored in the eel rete mirabile, an organ composed predominantly of capillaries. In vitro experiments showed that glycolysis is the major pathway of energy production in this capillary tissue, and that iodoacetate, KCN, and low PO2in combination markedly reduce its ATP generation. When in situ energy generation was inhibited by this combination during countercurrent perfusion of the arterial and venous capillaries of the rete, an approximate doubling of the intercapillary barrier permeability for human [125I]albumin, [14C]sucrose, and22Na was found. Structural damage was evident, but the intercellular junctions remained intact. The effect of cessation of flow for 30 minutes, followed by re perfusion, was then explored. Stasis alone altered the structure, chiefly of the venous capillary endothelium, but not the permeability of the intercapillary barrier. Stasis with a hypoxic medium containing the inhibitors of energy generation, followed by reperfusion with oxygenated control medium, resulted in a progressive breakdown of the intercapillary barrier, with a threefold to fourfold increase in solute (labeled albumin, sucrose, and sodium) permeability, evolving during early reperfusion, but no change for labeled water permeability. Morphologically, the endothelial cells, especially those in venous capillaries, showed substantial damage; they appeared vacuolated, then cytoplasm was extracted, and cytoplasmic and membrane debris were found in the lumen; intercellular junctions remained intact. Local pericyte detachment with interstitial edema also appeared. Thus, stasis and reperfusion amplified the effects of reduction in energy generation and hypoxia on both permeability and morphological change.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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8. |
Long‐term Versus Intrabeat History of Ejection As Determinants of Canine Ventricular End‐Systolic Pressure |
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Circulation Research,
Volume 64,
Issue 2,
1989,
Page 255-264
Seiryo Sugiura,
William Hunter,
Kiichi Sagawa,
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摘要:
We studied the effect of ejection on end-systolic pressure in isolated heart preparations. Ejecting beats were compared with isovolumic beats having the same volume as at end systole. While holding end-systolic volume constant, various stroke volumes, including negative stroke volumes (volume injected during systole), were imposed using a predetermined volume command. After switching contraction mode between ejecting and isovolumic, we measured the immediate and steady changes in end-systolic pressure. In the first isovolumic beat after switching from steady-state ejecting beats, the change in end-systolic pressure was variable, depending on the stroke volume. The end-systolic pressure of the ejecting beat exceeded that of the isovolumic beat on average by up to 18 mm Hg with small stroke volume, but the ejecting end-systolic pressure became lower than isovolumic with either large stroke volume (stroke volume/end-systolic volume <0.96) or with negative stroke volume. During the transient phase following a switch from ejecting to isovolumic, the end-systolic pressure gradually decreased to a steady state. Consequently, even in steady state, ejecting end-systolic pressure exceeded isovolumic pressure over a significant range of stroke volume (stroke volume/end-systolic volume <1.18). After returning contraction mode from isovolumic back to ejecting, we observed responses that were a mirror image. These results indicated that in addition to negative uncoupling effect, ejection exerts positive effects on ventricular end-systolic pressure that are manifest both quickly and gradually. We hypothesized that the mechanism responsible for the positive effect is length-dependent activation via the larger volume (both at the initiation of contraction and averaged over a cardiac cycle) of a beat that ejects compared to one held isovolumic at end-systolic volume. The results with volume injection were consonant with this concept.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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9. |
End‐Systolic Pressure As a Balance Between Opposing Effects of Ejection |
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Circulation Research,
Volume 64,
Issue 2,
1989,
Page 265-275
William Hunter,
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摘要:
Ejection has previously been thought to exert only negative effects on end-systolic left ventricular pressure, via mechanisms like shortening deactivation and the force-velocity relation. Whether ejection also exerted a positive influence on pressure generation was tested by comparing two successive beats: 1) the last beat of steady-state ejection versus 2) a totally isovolumic contraction at the end-systolic volume. In 12 isolated, blood-perfused canine hearts loaded with a simulated arterial system, ejecting end-systolic pressure exceeded isovolumic pressure by approximately 10 mm Hg when ejection fraction was 0.3. With both higher and lower ejection fractions, the excess of ejecting end-systolic pressure was smaller; beyond an ejection fraction of roughly 0.5, the trend reversed so that ejecting end-systolic pressure fell below isovolumic pressure. The maximum excess in ejecting end-systolic pressure was quite variable (1-17 mm Hg), but the pattern of its variation with ejection fraction was consistent. A correlate of the positive effect of ejection on ventricular pressure was found in the timing of end systole. For an ejection fraction of 0.4, the systolic duration of ejecting beats was approximately 45percent; longer than in isovolumic beats (range, 23-67percent;). Potentially, a positive effect of ejection might be due to a residual influence of the stronger activation of cardiac myofilaments early in ejecting systole during which the sarcomeres were at longer lengths than in the isovolumic beat at end-systolic volume (length-dependent activation). A hypothetical model based on this mechanism reproduced both of the positive effects of ejection that were observed: excess end-systolic pressure and prolonged duration of systole. Thus, the approximate load independence of end-systolic pressure could result from the counter balance between opposing influences of ejection.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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10. |
Effects of Calcium Channel Antagonists on Carotid Sinus Baroreflex Control of Arterial Pressure and Heart Rate in Anesthetized Dogs |
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Circulation Research,
Volume 64,
Issue 2,
1989,
Page 276-286
Dean Rigel,
Ronald Millard,
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摘要:
Our study was designed to determine whether the calcium channel antagonists verapamil, diltiazem, and nifedipine and the nitrate vasodilator sodium nitroprusside modulate carotid sinus (CS) baroreflex control of mean arterial pressure (MAP) and heart rate (HR). Pentobarbital-anesthetized, vagotomized dogs were surgically prepared for reversible vascular isolation of the CS regions. Open-loop performance of the CS baroreflex was determined under control conditions and after intravenous infusion of each agent for 20 minutes at four rates (nitroprusside: 0.3-10 μg/kg/min; verapamil and diltiazem: 1-30 μg/kg/min; nifedipine: 0.1-3 μg/kg/min). With the CS baroreflex loop dosed, each vasodilator decreased MAP from control (nitroprusside: 127±3 to 69±5 mm Hg; verapamil: 137±7 to 86±5 mm Hg; diltiazem: 137±9 to 100±5 mm Hg; nifedipine: 140±6 to 109±7 mm Hg). Each compound also caused a dose-dependent downward shift in the open-loop CSP-MAP relations. The higher doses of each vasodilator also depressed the total range of control of MAP (i.e., maximum MAP minus minimum MAP) by the baroreflex and significantly attenuated the peak open-loop MAP/CSP gains (nitroprusside: 1.21±0.19 to 0.56±0.12; verapamil: 1.36±0.16 to 0.64±0.10; diltiazem: 1.52±0.34 to 0.89±0.11; nifedipine: 1.35±0.20 to 0.83±0.14) but did not alter the CSP at which the peak gain was manifest. Only verapamil and diltiazem significantly shifted downward the CSP-HR relations, whereas none of the drugs affected the total range of baroreflex control of HR (i.e., maximum HR minus minimum HR) or the peak open-loop HR/CSP gains. Our results suggest that 1) it is unlikely that calcium channel antagonists act directly on the baroreceptors or the neural components of the baroreflex loop (i.e., afferent, central and efferent nerves) because they impair CS baroreflex control of MAP but not HR and 2) the impairment of MAP control is predominantly due to a nonspecific blunting of adrenergic vasoconstriction.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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