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1. |
Metabolism of Adenine Nucleotides in Human Blood |
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Circulation Research,
Volume 65,
Issue 3,
1989,
Page 531-537
Stephen Coade,
Jeremy Pearson,
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摘要:
Biologically active concentrations of potently vasoactivc and platelet-active adenine nucleotides are generated in plasma by a variety of pathophysiological mechanisms. Although there is evidence that ATP and ADP are inactivated by endothelial ectonucleotidases, there has been little attempt to study the metabolic routes of their catabolism in blood or to assess the contribution of this process to their clearance in vivo. Therefore, we have studied the rates and patterns of catabolism of ATP, ADP, and AMP in whole blood, plasma, and isolated blood cells. Rates of degradation of each nucleotide in cell-free plasma ranged from 0.07–032 nmol/min/ml with 1 μM substrates to 1.1–3.6 nmol/min/ml with 100 μM substrates. The pattern of catabolism indicated that sequential dephosphorylation from ATP → ADP → AMP → adenosine occurs. In whole blood, the pattern was similar although ATP and ADP (but not AMP) breakdown was more rapid. This was due to leukocyte ectonucleotidase activity. The use of selective inhibitors demonstrated that catabolism was not due to nonspecific phosphatase activity and that plasma 5-nucleotidase is distinct from ATPase or ADPase. In leukocytes, ATPase and ADPase activities were distinguishable, and each contributed substantially to the rates of catabolism in whole blood. Leukocyte 5-nucleotidase did not measurably contribute to AMP dephosphorylation in blood. By comparison, ecto-ATPase and ecto-ADPase activities on cultured human umbilical vein endothelial cells were similar to those on leukocytes while endothelial S'-nucleotidase per 10* cells was equivalent to the soluble activity in 1 ml of blood or plasma. We conclude that in microvascular beds, endothelial catabolism of circulating nucleotides predominates (as expected from the short half-lives of added nucleotides in vivo), but in larger blood vessels or at sites of impaired blood flow such as within a forming thrombus, leukocyte ecto-ATPase and ecto-ADPase and soluble 5'-nucleotidase may be important regulators of the concentrations of vasoactive nucleotides.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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2. |
Prostaglandin E Receptors in Cardiac Sarcolemma Identification and Coupling to Adenylate Cyclase |
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Circulation Research,
Volume 65,
Issue 3,
1989,
Page 538-545
Gary Lopaschuk,
Marek Michalak,
Elayne Wandler,
Richard Lerner,
Tino Piscione,
Flavio Coceani,
Peter Olley,
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摘要:
Purified cardiac sarcolemmal membrane vesicles were used to determine if specific prostaglandin (PG) receptors are present on the myocyte. Two binding sites for PGE2were identified in isolated bovine sarcolemmal membranes: a high-affinity site with a dissociation constant (K4) of 032 nM and a maximum binding (Bmaxof 376 fmol/mg of protein and a lower-affinity site with a K4of 3.41 nM and a Bmaxof 2,112 fmol/mg of protein. In competition experiments, unlabeled PGE1displaced3H]PGE2from its membrane receptor at concentrations similar to those of unlabeled PGE2. Both PGF2μ and PGD2displaced [3H]PGE2from the membrane, but only at high concentrations (> 10−6M and > 10−5M, respectively). Digestion of sarcolemmal membrane with trypsin resulted in a threefold decrease in specific [3H]PGE2binding. Phosphorylation of the membrane with protein kinase A also decreased specific [3HJPGE2binding. At concentrations of PGE2} that occupy the high-affinity site, sarcolemmal adenylate cyclase activity was inhibited in the presence of 5'-guanylylimidodiphosphate [Gpp(NH)p]. We conclude that the isolated cardiac sarcolemmal membrane contains a high-affinity binding site for PGEj that is functionally coupled to adenylate cyclase. The binding site is stereospecific and probably recognizes the 9-keto, ll-hydroxyl portion of the ring structure of these prostaglandins.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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3. |
Intracoronary Injections of Salbutamol Demonstrate the Presence of Functional ft-Adrenoceptors in the Human Heart |
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Circulation Research,
Volume 65,
Issue 3,
1989,
Page 546-553
J. Hall,
M. Petch,
M. Brown,
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摘要:
To demonstrate the presence of functional cardiac β2-adrenoceptors in man, we studied the responses to intracoronary injections of salbutamol in three groups of six patients. We injected salbutamol, a selective β2-adrenoceptor agonist, into the right coronary artery to avoid peripheral vasodilator action and to stimulate the sinoatrial node directly. Salbutamol injections caused a sinus tachycardia. The same doses of salbutamol injected into the aortic root caused no change in heart rate, ruling out a systemic effect. The mean dose required to cause an increase in heart rate of 30 beats/min (IHR30) was 2.6 μg in the first group of six patients. In 12 other patients salbutamol was given after β-blockade to confirm the β2-selectivity of the responses. Doses of practolol (β1,-selective blockade) and of propranolol (β1- and β2-blockade) that had equal β1-blocking activity were used. In six patients who were given practolol, the mean IHR30dose was 2.1 μg. In six patients who were given propranolol, the mean IHR30dose was significantly greater at 64 μg (p<0.001, practolol vs. propranolol). This study demonstrates that direct cardiac β2-adrenoceptor stimulation in man has a positive chronotropic effect.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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4. |
Intracellular pH of Canine Subendocardial Purkinje Cells Surviving in 1-Day-Old Myocardial Infarcts |
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Circulation Research,
Volume 65,
Issue 3,
1989,
Page 554-565
Karl Drcsdner,
Richard Kline,
Andrew Wit,
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摘要:
A large reduction of intracellular potassium activity in depolarized subendocardial Purkinje fibers 24 hours after coronary artery ligation is accompanied by a much smaller increase in intracellular sodium activity. Similar intracellular ionic changes also occur during acute ischemia in ventricular muscle and are consistent with mechanisms based on intracellular acidification, which is known to occur in acutely ischemic muscle. To determine if canine subendocardial Purkinje cells 24 hours after myocardial infarction are also acidic, their intracellular pH, surfacepH, and maximum diastolic potential (MDP) were measured with double-barrelpH-sensitive microelectrodes and compared with control fibers in noninfarcted hearts. In 12 mM bicarbonate Tyrode's solution (5% CO2-95% O2), the average intracellular pH was not significantly different (p>Q.25) for normal tissue (6.83 ± 0.08, SD, MDP= −83.5 ± 3.2 mV), for depolarized Purkinje fibers in in fa ret preparations during the first hour of superfusion (6.88 ± 0.11, MDP=−47.8 ± 11.8 mV), and for partially recovered Purkinje fibers in infarcts averaged over the third to sixth hours of superfusion (6.85 ± 0.12, MDP=−74.S ± 9.6 mV). In 24 mM bicarbonate Tyrode's solution, infarct intracellular pH during both the first hour of superfusion (7.08 ± 0.13, MDP=−57.6 ± 15.7 mV) and during the third to sixth hours of superfusion (7.06 ± 0.15, MDP=−76.5 ± 9.6 raV) was significantly alkaline (p<0.0005) compared with average control pH (6.92 ± 0.12, MDP=82.1 ± 3.7 mV). In 24 mM bicarbonate Tyrode's solution, the intracellular pH did vary with MDP (0.0032 pH units/mV). During superfusion of normal Purkinje fibers with hypoxic Tyrode's solution, intracellular pH acidified by 0.22 pH units as they depolarized. Therefore, intracellular acidification does not seem to be a cause of the depolarization of subendocardial Purkinje cells 24 hours after myocardial infarction.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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5. |
Determinants of Sensitization of Carotid Baroreceptors by Pulsatile Pressure in Dogs |
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Circulation Research,
Volume 65,
Issue 3,
1989,
Page 566-577
Mark Chapleau,
Francois Abboud,
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摘要:
The threshold pressure of single baroreceptor units is decreased after compared with before exposure to pulsatile pressure according to previous studies in our laboratory. The purpose of the present study is to characterize the determinants of sensitization of arterial baroreceptors by pulsatile pressure. Carotid sinus nerve activity was recorded in dogs anesthetized with chloralose. Two indexes of baroreceptor "sensitivity" were obtained by comparing nerve activity before and immediately after exposure of the isolated carotid sinus to pulsatile pressure for periods up to 10 minutes. Sensitization occurred 1) when the threshold pressure of single baroreceptor units determined with a slow nonpulsatile ramp decreased after as compared with before pulsing and 2) when multiple unit activity increased after as compared with before pulsing at various mean levels of static pressure. Sensitization was evident after pulsing at mean pressures of 50 and 100 mm Hg, but not at 150 and 200 mm Hg, and was caused by the pulsatile change in diameter or deformation and not by the pulsatile change in wall tension. The magnitude of the effect was directly related to the duration of the pulsing period and to the frequency and amplitude of the pressure pulses. The sensitization could not be explained by increased diameter (sonomicrometers) or strain of the carotid sinus at the same pressure after pulsing; thus, there was an increase in "strain sensitivity" that outlasted the period of pulsing by up to several minutes. In most experiments the shift from static to pulsatile pressure at 50 and 100 mm Hg caused an increase in nerve activity, yet sensitization occurred after pulsing when one would have expected postexcitatory hyperpolarization or depression of activity upon return to static pressure. The sensitization was not caused by the release of prostacyclin from the endothelium since it was not reduced after endothelial denudation or inhibition of cyclooxygenase with indomethacin (30–80 μM) or ibuprofen (250 μM}. We speculate that sensitization of baroreceptors by pulsatile pressure may contribute to the decreased sympathetic activity after periods of elevated pulse pressure (e.g., after exercise). We also propose that the decreased sensitivity of baroreceptors after acute elevation of arterial pressure (acute resetting) may be offset in part by the sensitizing effect of increased pulsatile stretch.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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6. |
Fractal Nature of Regional Myocardial Blood Flow Heterogeneity |
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Circulation Research,
Volume 65,
Issue 3,
1989,
Page 578-590
James Bassingthwaighte,
Richard King,
Stephen Roger,
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摘要:
Spatial variation in regional flows within the heart, skeletal muscle, and in other organs, and temporal variations in local arteriolar velocities and flows is measurable even with low resolution techniques. A problem in the assessment of the importance of such variations has been that the observed variance increases with increasing spatial or temporal resolution in the measurements. This resolution-dependent variance is now shown to be described by the fractal dimension, D. For example, the relative dispersion (RD=SD/mean) of the spatial distribution of flows for a given spatial resolution, is given by: RD(m)=RD(mref)·[m/mref]1-D, where m is the mass of the pieces of tissue in grams, and the reference level of dispersion, RD(mref), is taken arbitrarily to be the RD found using pieces of mass mref, which is chosen to be 1 g. Thus, the variation in regional flow within an organ can be described with two parameters, RD(mref) and the slope of the logarithmic relationship denned by the spatial fractal dimension D5. In the heart, this relation has been found to hold over a wide range of piece sizes, the fractal D5being about 1.2 and the correlation coefficient 0.99. A D, of 1.2 suggests moderately strong correlation between local flows; a D5,=1.0 indicates uniform flow and a D5,= 1.5 indicates complete randomness.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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7. |
Effect of Phalloidin on Structure and Permeability of Rete Capillaries in the Normal and Hypoxic State |
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Circulation Research,
Volume 65,
Issue 3,
1989,
Page 591-599
Eugenio Rasio,
Moise Bendayan,
Carl Goresky,
J. Alexander,
David Shepro,
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摘要:
The effects of 10−6M phalloidin on reperfusion-injured blood capillary structure and permeability were studied in the countercurrent perfused rete mirabile of the eel swim bladder. In the normal rete, the addition of phalloidin to the perfuston medium did not induce morphological or functional changes. When flow was arrested for 30 minutes, during which time the capillaries were exposed to inhibitors of ATP generation, and flow was then resumed with an oxygenated medium, cell membrane blebs and vacuolization, mitochondria! swelling, pericyte shrinkage, and interstitial space edema were observed. The permeability coefficients for labeled albumin, sucrose, and sodium increased to three to four times baseline values, whereas the permeability to water was not significantly modified. When the same protocol was repeated with phalloidin present in the medium throughout the experiment, the structural integrity of the endotbelial cells was completely preserved and pericyte shrinkage was abolished, but interstitial space edema still occurred. The permeability to albumin, sucrose, and sodium increased only to 1.5 times baseline values, a significantly decreased increment in comparison with the experiments performed without phalloidin. We concluded that although phalloidin does not improve the capillary barrier of the normal rete, it provides protection against the structural and functional damage induced by hypoxia and reperfusion.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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8. |
Calcium, Its Role in Isoproterenol-Stimulated Atrial Natriuretic Peptide Secretion by Superfused Rat Atria |
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Circulation Research,
Volume 65,
Issue 3,
1989,
Page 600-606
Rick Schiebinger,
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摘要:
The β-adrenergic agonist isoproterenol stimulates immunoreactive atrial natriuretic peptide (IR-ANP) secretion by superfused rat atria in vitro. β-Adrenergic agonists alter the cellular handling of calcium, which culminates in a rise in the systolic calcium concentration. This is achieved by increasing calcium influx through voltage-dependent calcium channels and by increasing the storage pool of calcium in the sarcoplasmic retlculum (SR). We therefore asked the question whether isoproterenol-stimulated IR-ANP secretion was dependent on the protein kinase A-induced rise in systolic calcium or was due to a direct effect of protein kinase A activation. Isolated rat left atria paced at 3 Hz were superfused in vitro. IR-ANP secretion was determined by radioimmunoassay of timed collections of the superfusate. Superfusion with 0.1 μM isoproterenol or 0.5 mM dibutyryl cyclic AMP increased IR-ANP secretion twofold. Stimulated IR-ANP secretion was lowered to near baseline by lowering the buffer calcium concentration from 1.8 to 0.2 mM or by adding to the superfusate 10 μM nitrendipine (a calcium-channel blocker) or 1 μM ryanodine (an inhibitor of SR calcium release). Superfusion of nonbeating, electrically quiescent left atria with 0.1 μM isoproterenol failed to stimulate IR-ANP secretion. We conclude: 1) Isoproterenol-stimulated IR-ANP secretion is dependent on calcium influx through voltage-dependent calcium channels and on the release of calcium from the SR. 2) Enhanced calcium influx alone is not adequate to maintain isoproterenol-stimulated IR-ANP secretion. 3) The SR appears to be the primary source of calcium for isoproterenolstimulated IR-ANP secretion. 4) The stimulatory effect of isoproterenol on IR-ANP secretion is dependent on electrical membrane activity. 5) Thus, protein kinase A activation does not appear to have a direct effect on IR-ANP secretion. Its effect appears to be mediated by protein kinase A-directed changes in the handling of calcium by atrial cardiocytes. These results suggest that calcium-channel blockers may lower plasma ANP levels in man when sympathetic tone is high. Lowering plasma ANP may be responsible, in part, for fluid retention in patients treated with calcium-channel blockers.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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9. |
Marked Reduction of Free Radical Generation and Contractile Dysfunction by Antioxidant Therapy Begun at the Time of Reperfusion Evidence That Myocardial "Stunning" Is a Manifestation of Reperfusion Injury |
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Circulation Research,
Volume 65,
Issue 3,
1989,
Page 607-622
Roberto Bolli,
Mohamed Jeroudi,
Bharat Patel,
Okezie Aruoma,
Barry Halliwell,
Edward Lai,
Paul McCay,
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摘要:
Recent evidence suggests that postischemic myocardial dysfunction (“stunning”) may be mediated by oxygen free radicals, but the exact time window during which the critical radical-mediated damage develops remains unknown. Furthermore, the evidence for the oxyradical hypothesis is indirect and, therefore, inconclusive. Thus, the potent and cellpermeable antioxidant JV-(2-mercaptopropionyl)-glycine (MPG) was administered as an intracoronary infusion (8 mg/kg/hr) to three groups of open-chest dogs undergoing a 15-mlnute coronary occlusion followed by 4 hours of reperfusion. In group I (n=8), the infusion of MPG was started 15 minutes before occlusion and ended 2 hours after reperfusion; in group II (n=9), MPG was started 1 minute before reperfusion and ended 2 hours thereafter; in group III (n= 10), MPG was started 1 minute after reperfusion and ended 2 hours and 15 minutes thereafter. Control dogs (group IV) (n= 10) received vehicle. Recovery of contractile function (assessed as systolic wall thickening) was equivalent in groups I and II, and in both groups it was substantially greater than in controls (p<0.005 at 4 hours). In contrast, in group III recovery of function was indistinguishable from controls. To determine whether the protection afforded by MPG was due to inhibition of free radical reactions, myocardial production of free radicals was directly assessed by intracoronary infusion of the spin trap o-phenyl JV-tert-butyl nitrone (PBN). In control dogs (group VII,n=6), radical adducts of PBN were released in the coronary venous blood after reperfusion, with a burst occurring in the first 5 minutes. MPG given as in group II (group V,n-5) markedly suppressed myocardial production of PBN adducts (Δ = − 98% over 3 hours,p<0.01 vs. controls); this effect was evident immediately after reperfusion. MPG given as in group III (group VI,n=5) also suppressed PBN adduct production (Δ =−83% over 3 hours,p<0.025 vs. controls), but this effect was delayed. Hence, the radicals important in myocardial stunning appear to be those generated immediately after reperfusion. In vitro studies demonstrated that MPG is an exceptionally powerful scavenger of • OH (rate constant=8.1x109M−1sec−1by pulse radiolysis) but has no significant effect on • O2(rate constant < 103M−1sec−1), H2O2(rate constant=1.6 M−1sec−1), or non- • OH-initiated lipid peroxidation, suggesting that removal of • OH is the major mechanism of the beneficial effects of MPG. These results demonstrate that a substantial portion (apparently most) of the damage responsible for myocardial stunning develops in the initial seconds of reperfusion and can be prevented by antioxidant therapy started just before reftow. The results further demonstrate that attenuation of this reperfusion-induced damage is associated with attenuation of free radical reactions in vivo, thereby providing direct evidence for a causal role of reactive oxygen species. It is proposed that myocardial stunning is, at least in part, a form of oxyradicalmediated "reperfusion injury."
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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10. |
Effect of Left Ventricular Volume on Right Ventricular End-Systolic Pressure-Volume Relation Resetting of Regional Preload in Right Ventricular Free Wall |
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Circulation Research,
Volume 65,
Issue 3,
1989,
Page 623-631
Seiji Yamaguchi,
Kai Tsuiki,
Hiroshi Miyawaki,
Yoshiaki Tamada,
Ikuro Ohta,
Hiroyasu Sukekawa,
Masayuki Watanabe,
Tadashi Kobayashi,
Shoji Yasui,
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摘要:
Effect of left ventricular (LV) volume on right ventricular (RV) end-systolic pressure-volume relation (ESPVR) was investigated, and the mechanism was examined from a standpoint of the alteration of RV free wall mean fiber length. Twelve cross-circulated isovolumically contracting canine hearts in which both ventricular volumes were controlled independently were used, and RV-ESPVR was determined at three different LV volume levels. At small (10.2 ± 0.6 ml), middle (IS J ± 1.0 ml), and large (20.5 ± 1.4 ml) LV volume, the slope of the RV-ESPVR was 2.63 ± 0.13, 2.74 ± 0.13, and 2.89 ± 0.12 mm Hg/ml, respectively, and each value was significantly different from the others (p<0.01). The volume intercept (V0) of the relation (RV-V0) was significantly decreased with the increment of LV volume (RV-V0 in small, middle, and large LV volume; 3.92 ± 0.68, 3.39 ± 0.67, and 2.87 ± 0.71 ml, respectively;p<0.01). In nine hearts, RV free wall lengths in latitudinal and meridional direction were measured at three LV volume levels when RV volume was held constant (16.1 ± 1.1 ml). RV latitudinal end-diastolic length was significantly augmented with increasing LV volume (latitudinal length in small, middle, and large LV volume; 9.68 ± 0.55, 9.81 ± 0.56, and 9.92 ± 0.55 mm, respectively). RV meridional end-diastolic length also increased significantly with increasing LV volume. We concluded that RV-ESPVR showed upward-leftward shift with increasing LV volume and that this shift could be, at least in part, explained by the alteration of end-diastolic length in RV free wall that occurred with constant RV volume (resetting of regional preload), probably due to the deformation of RV becoming more crescent.
ISSN:0009-7330
出版商:OVID
年代:1989
数据来源: OVID
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