摘要:

&NA;Repolarization during phase 1 of cardiac action potential is important in that it may influence both impulse conduction in partially depolarized tissue and action potential duration. Thus, it is important to know the properties and regulation of the underlying currents. In about 50% of canine ventricular myoeytes, the action potential displays a phase 1 of fast repolarization and a prominent notch between phase 1 and the plateau. A transient outward current is responsible for both. This current is composed of two components: one (Ito1) blocked by 4‐aminopyridine and the other (Ito2) blocked by manganese. In the present study, we characterized each of the components in isolation from the other. Both had an activation threshold between ‐30 and ‐20 mV. At the same voltage, Ito1was larger than Ito2and had a shorter time to peak. The peak current‐voltage relationship for Ito1was almost linear, but that for Ito2was bell‐shaped. Ito1decayed during sustained depolarization with a single exponential time course: &tgr;<30 msec at all voltages. It recovered from inactivation with a voltage‐dependent time course: &tgr;=70 msec at ‐90 mV and 720 msec at ‐40 mV. Ito2was augmented by elevating [Ca2+]. or by isoproterenol. It was inhibited by caffeine, ryanodine, or a preceding transient inward current, suggesting that it was activated by intracellular calcium released from sarcoplasmic reticulum. We conclude that Ito1and Ito2in canine ventricle are similar to those described for many other cardiac tissues, but the kinetics of Ito1are significantly faster than in other tissues. (Circulation Research1989;64:633‐647)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;Intracellular recordings were made from eustachian ridge of cat right atrium to determine mechanisms responsible for subsidiary pacemaker automaticity. Pacemaker action potentials exhibited two phases of diastolic depolarization: an initial steeper slope (D1) followed by a more gradual slope (D2). Cesium (1 mM) decreased D1(‐45.6%) to a significantly greater extent than D2(‐33.6%) and increased spontaneous cycle length (SCL) (+37.7%). Tetrodotoxin (10‐6M) had no effect on maximum rate of rise of upstroke, although it increased SCL (+23.9%). Verapamil (0.4‐1.0 &mgr;M) progressively increased SCL by decreasing late diastolic slope, resulting in oscillatory potentials and eventual quiescence. Both norepinephrine (2×10‐9M) and Bay K 8644 (10‐7M) elicited a significantly greater increase in D2than in D1, resulting in a decrease in SCL. Ryanodine (10‐6M) caused a small but significant initial decrease (−3.7%) followed by a progressive increase in SCL (+172%). Ryanodine decreased D2without changing D1, increased maximum rate of rise and overshoot potential, and abolished tension. In the presence of ryanodine, Bay K 8644 progressively increased D1amplitude, resulting in a cyclic pattern of dysrhythmic activity. In the presence of ryanodine, cesium significantly decreased D1(‐39.3%), shifted the late diastolic potential more negative, and increased SCL (+25.7%). These results indicated that multiple mechanisms participate in subsidiary pacemaker automaticity. They include 1) a cesium‐sensitive component that contributes to a greater extent during the initial phase of diastolic depolarization, 2) a component mediated via calcium released from the sarcoplasmic reticulum that contributes primarily during the latter half of diastolic depolarization, and 3) possibly a direct contribution by the slow inward calcium current. (Circulation Research1989;64:648‐657)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;Acute hypertension disrupts the blood‐brain barrier and may neutralize the negative charge on cerebral endothelium. The goal of this study was to determine the effects of molecular charge on permeability of the blood‐brain barrier during acute hypertension. Intravital fluorescent microscopy and fluorescein‐labeled dextrans were used to evaluate disruption of the blood‐brain barrier during acute hypertension in rats. Disruption of the blood‐brain barrier was quantitated by calculating clearance of neutral dextran and of anionic dextran sulfate in two groups of rats. Pressure in pial venules, which are the primary site of disruption of the blood‐brain barrier during acute hypertension, was measured using a servo‐null device. When systemic arterial pressure was increased from 87±5 (mean±SEM) to 188±5 mm Hg, clearance of neutral dextran increased from 0.04±0.01 to 4.38±0.72 ml/sec×10−6. When systemic arterial pressure was increased from 91±4 to 181±3 mm Hg, clearance of anionic dextran sulfate increased from 0.02±0.01 to only 0.70±0.23 ml/sec × 10−6. Increases in pial venular pressure were similar in the two groups. Thus, similar increases in systemic arterial pressure and pial venular pressure during acute hypertension produce less disruption of the blood‐brain barrier to anionic dextran sulfate than neutral dextran. The findings suggest that 1) the net negative charge of cerebral vessels may be preserved during acute hypertension, and 2) molecular charge is an important determinant of the severity of disruption of the blood‐brain barrier during acute hypertension. (Circulation Research1989;64:658‐664)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;Available data demonstrate that oxygen free radicals and derived reactive species of oxygen are produced during myocardial ischemia as well as upon reperfusion of the ischemic tissue. The present study was designed to determine if polyethylene glycol‐conjugated superoxide dismutase (PEG‐SOD), with its extended plasma half‐life in excess of 30 hours in contrast to the native form of the enzyme (Native‐SOD), could provide protection to the ischemic myocardium subjected to a 6‐hour regional ischemia followed by reperfusion for 24 hours. We hypothesized that myocardial injury due to an ischemic interval is a dynamic process involving the sustained production of cytotoxic oxygen radicals that may continue beyond the ischemic interval. The ability to demonstrate a protective effect of the free radical scavenger enzyme superoxide dismutase would require the continued presence of the antioxidant during the ischemic interval and especially during reperfusion. To test this hypothesis, 22 anesthetized, open‐chest dogs underwent 6 hours of circumflex coronary artery occlusion followed by reperfusion for 24 hours. Rapid administration of either Native‐SOD (1,000 U/kg), PEG‐SOD (1,000 U/kg), PEG‐albumin (PEG‐ALB), or 0.9% sodium chloride solution for injection (saline) was administered via the left atrium 15 minutes before occlusion of the vessel. A continuous infusion of an additional 1,000 U/kg of the respective enzyme interventions or an equivalent volume of PEG‐ALB or saline was given during the 6‐hour coronary artery occlusion and terminated 15 minutes after reperfusion. The animals were euthanized 24 hours after reperfusion, and the myocardial region at risk and the infarct region were quantitated by the tetrazolium method. The area of myocardium at risk of infarction, expressed as a percent of the left ventricle, did not differ among the groups: Native‐SOD (n=8), 46.2±1.8%; PEG‐SOD (n=6), 45.7±2.1%; PEG‐ALB, 38.4±2.3% (n=4); and saline 46.0±2.1% (n=4). Hemodynamic parameters, the calculated rate‐pressure‐product, as well as regional myocardial blood flow (radiolabeled microsphere method) in the endocardial, midmyocardial, and epicardial segments of the risk and the nonrisk regions were comparable for all groups. Mean infarct size, determined 24 hours after reperfusion, in the group treated with PEG‐SOD was 47.1±2.9% of the area at risk (n=6), significantly smaller than that observed in each of the other treatment groups: Native‐SOD, 63.5±2.2% (n=8); PEG‐ALB, 64.6±2.4% (n=4); saline, 70.8±2.2% (n=4). The present studies provide support for the concept that superoxide dismutase can prevent myocardial necrosis due to oxygen radicals produced during the ischemic interval as well as the period of reperfusion. Because PEG‐SOD was more effective than Native‐SOD, the results suggest that the sustained presence of oxygen radical scavenger activity is necessary to prevent rather than delay myocardial necrosis. (Circulation Research1989;64:665‐675)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;We investigated the mechanisms by which spontaneously beating cultured rat ventricular cells regulate intracellular pH (pHi). Specifically, the relative contributions of the Na+/H+antiport, Cl−/HCO3−exchange, ATP, and calmodulin‐dependent processes in regulating the pHiof cells loaded with the intracellular fluorescent pH indicator BCECF were investigated. The pHiof ventricular cells bathed in HEPES‐buffered medium averaged 7.30±0.02. Subsequent exposure of the cells to CO2‐HCO3−‐buffered medium resulted in intracellular acidification followed by recovery to pHilevels approximately 0.1 pH units lower than in controls. Recovery was inhibited by the Na+/H+antiport inhibitor 5‐(N‐ethyl‐N‐isopropyl) amiloride (EIPA). The recovery from intracellular acidification, induced by a 15‐mM ammonium chloride prepulse, was also dependent solely upon activation of the Na+/H+antiport. Recovery was dependent upon extracellular sodium, was completely inhibited by EIPA, and could be modulated by changes in extracellular pH (pHo). At low pHovalues (6.3) the recovery of pHiwas greatly attenuated, while at high pHo(8.0) the recovery process was accelerated. The final pHito which the cells recovered was also dependent upon pHo. Preincubation of the cells with 2‐deoxy‐D‐glucose to deplete cellular ATP levels reduced pHiby approximately 0.2 pH units and greatly impaired the cells' ability to recover from 15‐mM ammonium chloride‐induced acid load. Similarly, preincubation of cells with the calmodulin inhibitors W‐7 and trifluoperazine also impaired their ability to recover from the acid load. The Cl−‐HCO3−exchange played no role in the cells' ability to recover from intracellular acidosis. However, the presence of HCO3−significantly increased the resistance of myocardial cells to changes in pHiby approximately doubling their buffer capacity. These results demonstrated that a Na+/H+antiport is the major pHi‐regulating system in spontaneously beating rat ventricular cells. The ability of the Na+/H+antiport to regulate myocardial pHiis dependent upon the cells' ability to maintain adequate levels of ATP. The antiport's dependency on ATP, in conjunction with its dependency on calmodulin, suggests that activation of the antiport in ventricular cells involves phosphorylation processes. (Circulation Research1989;64:676‐685)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;The reflex mechanisms that produce the neurocirculatory adjustments to hemorrhagic hypotension are incompletely understood. The goal of this study was to determine if hemorrhagic hypotension in rats produces differential effects on sympathetic outflow to the adrenal gland and kidney and if the two sympathetic nerve responses are governed by different reflex mechanisms. We performed simultaneous multifiber recordings of adrenal and renal sympathetic nerve activity (SNA) during 8 minutes of sustained hemorrhagic hypotension to a mean arterial pressure of 50 mm Hg in chloralose‐anesthetized Sprague‐Dawley rats with a) baroreceptors intact, b) cervical vagotomy, c) sinoaortic baroreceptor denervation, and d) combined vagotomy plus sinoaortic denervation. During hemorrhagic hypotension in rats with intact baroreceptors, renal SNA decreased by 31±10% (mean±SEM,p<0.05 vs. control) and heart rate decreased from 384±13 to 365±16 beats per minute (p<0.05), but adrenal SNA increased by 69±10% over control (p<0.05). The decreases in renal SNA and heart rate were reversed by cervical vagotomy but not by atropine, which indicates vagal afferent mediation. In contrast, the increases in adrenal SNA during hemorrhage were not affected by vagotomy alone or by sinoaortic denervation alone but were markedly attenuated by combined sinoaortic denervation and vagotomy, which indicates redundancy in the baroreflex control of adrenal SNA. The major new conclusions from this study are 1) that hemorrhagic hypotension in rats produces directionally opposite reflex changes in renal and adrenal SNA with sympathoinhibition in the kidney but sympathoexcitation in the adrenal gland, and 2) that both of these reflex responses are mediated by vagal afferents. Differential reflex control of regional sympathetic outflow by vagal afferents is an important factor in producing a complex and highly differentiated pattern of autonomic response to this form of hypotension. (Circulation Research1989;64:686‐694)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;Dahl Salt Sensitive (DS) rats rapidly develop high blood pressure when exposed to a high‐salt diet. Recent studies suggest that DS rats have poorly functioning baroreceptor afferents and baroreflexes even when salt intake is restricted. This study examines baroreceptor pressure‐ and mechano‐transduction in DS, Dahl Resistant (DR), and Sprague‐Dawley (SD) rats during low‐and high‐salt conditions. Single unit, regularly discharging baroreceptors were studied using an in vitro aortic arch‐aortic nerve preparation. Pressure thresholds and suprathreshold pressure sensitivities were determined from responses to slow ramps of pressure. Pressure‐diameter relations measured in each rat were used to transform pressure threshold and pressure sensitivity values to their mechanical equivalents in terms of aortic wall strain. A total of 407 unit baroreceptors were studied from 49 rats. Tail systolic blood pressures were significantly higher only in DS during high salt. Pressure threshold was similar for all groups on low salt. Exposure to a high‐salt diet increased the mean pressure threshold for all three groups. Pressure threshold for high‐salt diet was highest in DS and lowest in DR. Pressure sensitivities were lowest in DS and highest in DR on low salt. High salt had no significant effect on pressure sensitivity. The differences in threshold apparent when expressed in terms of pressure were eliminated by conversion to their mechanical equivalents (strain threshold and strain sensitivity). The results suggest that baroreceptors in the two Dahl rat strains represent two extremes from normal baroreceptor function. DS tend to be less pressure responsive than normal (SD), and DR tend to be somewhat more responsive to pressure. High salt altered baroreceptor properties in all three rat strains. The elevation of pressure threshold in DR and SD occurred without increases in systolic blood pressure suggesting that high dietary salt can alter baroreceptor function independent of blood pressure effects. The mechanism of this effect appears to be related to the local mechanical properties of the vessel wall or the way in which the receptor is coupled to the vessel wall. (Circulation Research1989;64:695‐702)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;The hemodynamic effects of phasic variations in intrathoracic pressure (ITP) timed to the cardiac cycle were predicted by a mathematical model and were compared with data from canine experimental studies. The model was used to predict the hemodynamic effects of changing the onset of the ITP rise relative to the start of cardiac systole, as well as the hemodynamic effects of changes in the duration and amplitude of the ITP rise. The predictions of the model were compared with hemodynamic data from seven anesthetized dogs. Cardiac function was depressed with large doses of verapamil and propranolol, and the hearts were atrioventricular sequentially paced at a rate of 72 beats/min. Phasic ITP variations were generated by a perithoracic vest and were electronically timed to the cardiac cycle. The model predicted, and the experimental data confirmed, that phasic intrathoracic pressure variations generated by vest inflation, timed to the cardiac cycle, can augment both peak and mean aortic flow. The following predictions of the model were also confirmed by the experimental data: 1) Maximum flow augmentation occurs when the onset of the ITP rise is simultaneous with the onset of left ventricular isovolumic contraction, and the ITP rise has a duration of 400 msec. 2) The magnitude of the flow augmentation is a function of the amplitude of the ITP rise. The experimental data showed that there was little further flow augmentation when the ITP rise was greater than 30‐40 mm Hg. 3) The magnitude of flow augmentation was inversely proportional to the peak left ventricular elastance (Emax). The best fit between the measured and predicted flow augmentations was obtained for an assumed Emaxof 0.5 mm Hg/ml, while Emaxmeasurements in three dogs, using a volume conductance catheter and transient vena caval occlusion, yielded values of 0.4‐1.6 mm Hg/ml. Thus, both the mathematical model and canine experiments showed that relatively low‐amplitude ITP variations, rising synchronously with the onset of cardiac systole and having an optimal duration, assist the failing heart by augmentation of aortic flow. The degree of cardiac assistance decreases if the ITP variations do not rise synchronously with the onset of systole, or if their duration is not optimal. Thus, properly applied ITP variations may be used as an efficient, noninvasive method to temporarily assist the failing heart. (Circulation Research1989;64:703‐720)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;Epicardial wall motion was measured on the left ventricular free wall in six isolated potassium‐arrested dog hearts using a biplane video technique. Significant regional variations in epicardial deformations were recorded during static ventricular filling. Epicardial stretches varied linearly with cavity volume, sometimes exceeding 20% at physiological left ventricular end‐diastolic pressures. The maximum component of epicardial stretch and the derived wall thinning increased substantially from the base to the apex on both the anterior and the posterior free walls of the left ventricle. In five hearts, the direction of greatest epicardial stretch at moderate and high filling pressures coincided closely with the local epicardial fiber direction, suggesting that the left‐handed epicardial fiber helices stretch preferentially during passive filling to maximize end‐diastolic fiber lengths. Epicardial rotation was always counterclockwise, consistent with a reduction in the pitch of the fiber helix during filling. These results suggest that, on the epicardial surface, the passive myocardium is anisotropic with respect to the local fiber direction. We suggest that the resulting torsional shear acts to minimize transmural gradients of fiber stretch. (Circulation Research1989;64:721‐733)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;We examined the longitudinal propagation of contraction in isolated human and pig coronary arteries. Epicardial coronary arteries of about 2 cm were cut open longitudinally, and the tension development of circular muscles was measured simultaneously at three sites (both cut ends and the midportion of the segment). Cyclic tension changes arising at one site of human coronary artery propagated smoothly to the other sites, and the whole length of segment worked as a single unit. Contraction induced by locally applied prostaglandin F2&agr;or histamine also propagated in four of seven preparations. The remaining three human and all seven pig coronary arteries showed propagation of such drug‐induced contraction after treatment with 10 mM tetraethylammonium (TEA). In pig coronary arteries treated with TEA, electrical stimulation evoked a reproducible local contraction and its propagation. Propagation velocity was 9.0±0.7 at 0.8 mM calcium concentration and increased to 11.1±0.9 and 13.1±1.4 mm/sec as calcium concentration rose to 1.8 mM and 7.2 mM, respectively. Local contraction did not propagate at calcium concentrations of 0.2 mM or less. The calcium antagonist diltiazem decreased the propagation velocity dose dependently and blocked propagation of contraction at 0.3 &mgr;M without significant effects on the magnitude of local contraction. We conclude that smooth propagation of contraction develops in epicardial coronary arteries of humans and pigs and that the propagation may depend on calcium influx. (Circulation Research1989;64:734‐741)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID