Showing papers in "Circulation Research in 1979"

Myocardial infarct size and ventricular function in rats.

Abstract: To define the relationship between infarct size and ventricular performance, we performed hemodynamic studies in rats 21 days after left coronary artery occlusion. Ventricular performance was assessed under ether anesthesia by measurements of baseline hemodynamics and stressed performance as determined by the peak cardiac output and stroke volume obtained during intravenous volume loading and by the peak left ventricular developed pressure obtained during occlusion of the ascending aorta. Infarct size was determined by planimetry of the endocardial circumference of each of four histological slices of the left ventricle. Rats with small (4-30%) myocardial infarctions had no discernible impairment in either baseline hemodynamics or peak indices of pumping and pressure-generating ability when compared to the sham-operated, noninfarcted rats. Rats with moderate (31-46%) infarctions had normal baseline hemodynamics but reduced peak flow indices and developed pressure. Rats with infarctions greater than 46% had congestive heart failure, with elevated filling pressures, reduced cardiac output, and a minimal capacity to respond to pre- and after load stresses. The entire spectrum of postinfarction ventricular function was observed, from no detectable impairment to congestive failure. In this model of histologically healed myocardial infarction, the impairment of left ventricular function was directly related to the loss of myocardium.

The [18F]fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man.

Abstract: A method has been developed to measure local glucose consumption in the various structures of the brain in man with three-dimensional resolution. [18F]-2-deoxy-2-fluoro-D-glucose is used as a tracer for the exchange of glucose between plasma and brain and its phosphorylation by hexokinase in the tissue. A mathematical model and derived operational equation are used which enable local cerebral glucose consumption to be calculated in terms of the following measurable variables. An intravenous bolus of [18F]-2-deoxy-2-fluoro-D-glucose is given and the arterial specific activity monitored for a predetermined period of from 30 to 120 minutes. Starting at 30 minutes, the activity in a series of sections through the brain is determined with three-dimensional resolution by an emission tomographic scanner. The method was used to measure local cerebral glucose consumption in two normal volunteers. The values in gray matter structures range from 5.79 mg/100 g per minute in the cerebellar cortex to 10.27 in the visual cortex, whereas, in white matter structures, the values range from 3.64 mg/100 g per minute in the corpus callosum to 4.22 in the occipital lobe. Average values for gray matter, white matter, and whole brain metabolic rates, calculated as a weighted average based on the approximate volume of each structure, are 8.05, 3.80, and 5.90 mg/100 g per minute, respectively. The value of 5.9 mg/100 g per minute compares favorably with values previously reported.

Influence of cardiac fiber orientation on wavefront voltage, conduction velocity, and tissue resistivity in the dog.

Abstract: When the canine epicardium is stimulated, the spread of epicardial excitation is 2.4 times faster parallel to the long axes of the cardiac fibers than perpendicular to them. Likewise, gross tissue resistivity is lower parallel to fibers by a factor of 3.2, and the voltage across the depolarization wave is approximately three times as great in the longitudinal direction. Equations are presented which relate these variables. Theoretical considerations confirm the experimental finding that the potentials around a wave of depolarization cannot be accounted for by the conventional hypothesis that the wavefront is a uniform double-layer current source.

Increased sheep lung vascular permeability caused by Escherichia coli endotoxin.

Abstract: We infused Escherichia coli endotoxin, 0.07-1.33 microgram/kg, intravenously into chronically instrumented unanesthetized sheep and measured pulmonary arterial and left atrial pressures, lung lymph flow, lymph and blood plasma protein concentrations, and arterial blood gases. Endotoxin caused a biphasic reaction: an early phase of pulmonary hypertension and a long late phase of steady state increased pulmonary vascular permeability during which pulmonary arterial and left atrial pressures were not increased significantly and lung lymph flow was 5 times the baseline value. Lymph: plasma total protein concentration ratio during the late phase (0.76 +/- 0.04) was significantly (P less than 0.05) higher than during baseline (0.66 +/- 0.03). The lymph response was reproducible. Lung lymph clearance of endogenous proteins with molecular radii (r) 35.5 to 96 A was increased during the steady state late phase of the reaction, but, as during baseline, clearance decreased as r increased. The endotoxin reaction was similar to the reaction to infusing whole Pseudomonas bacteria, except that endotoxin had less effect on pressures during the steady state response and caused a relatively larger increase in lymph clearance of large proteins. We conclude that E. coli endotoxin in sheep causes a long period of increased lung vascular permeability and may have a greater effect on large solute pathways across microvessels than do Pseudomonas bacteria.

Extracellular potentials related to intracellular action potentials during impulse conduction in anisotropic canine cardiac muscle.

Abstract: This paper considers a quantitative description of intracellular and transmembrane currents in anisotropic muscle, with emphasis on the factors that determine the extracellular potentials. Although Vmax of the intracellular action potential had no relation to changes in conduction velocity in anisotropic tissue with constant membrane properties, the extracellular waveforms were quite sensitive to velocity changes. Large amplitude biphasic deflection occurred in the fast areas, and in the slow areas the waveforms were of lower amplitude and triphasic in shape; i.e., negative potentials preceded the biphasic positive-negative deflection. The extracellular potentials were simulated on the bases of a model of intracellular currents, and the theoretical and measured results showed good agreement. In tissue with anisotropic conductivity, the relationship between the spatial intracellualr potential gradient and the magnitude of the extracellular potential of the excitation wave was opposite to the classical relationship in isotropic tissue. Due to the influence of the effective intracellular conductivity on the spread of intracellular currents and on conduction velocity, in anisotropic tissue the extracellular potential decreased as the intracellular potential gradient increased. The peak values of the positive and negative potentials and the spatial distribution of the potential gradients varied considerably along the activation front. These findings were accounted for by differences in the distribution and spatial extent of the transmembrane currents, which were determined by the intracellular currents. The theoretical analysis showed that intracellular and transmembrane currents were proportional to the local conduction velocities of the wavefront. Thereby, it was not possible to have a "uniform layer" of current when there were differences in conduction velocity along the length of the excitation wave. The implications of the analysis are considerable, since the gratifying agreement between the theoretical and measured results indicates that the details of the extracellular waveforms can be explained on the basis of the distribution of intracellular currents; i.e., extracellular potentials provide a sensitive index of intracellular current flow.

Control of maximum rates of glycolysis in rat cardiac muscle.

Abstract: The maximum rate of glucose utilization by isolated rat hearts was approximately 16 /unol/g dry weight per minute. This rate was observed in aerobic hearts that were developing high levels of ventricular pressure. This same rate has been reported for anoxic hearts. In both conditions, stimulation of glycolysis resulted in increased cytosolic NADH/NAD ratios and the rate of disposal of glycolytically produced NADH appeared to limit the maximum glycolytic rate. In aerobic hearts, oxidation of glucose and lactate increased linearly as developed ventricular pressure was raised from 60 to 160 mm Hg, but then plateaued. Oxygen consumption and pyruvate oxidation, on the other hand, continued to increase linearly over a wide range of cardiac work. The observation that substrates that produce NADH in the cytosol (glucose and lactate) showed limited rates of utilization, whereas pyruvate oxidation was linearly related to oxygen consumption, indicates that disposal of cytosolic NADH limits maximum stimulation of glycolysis. With maximum stimulation, the rate of glyceraldehyde-3-phosphate dehydrogenase appeared to determine the overall rate of the glycolytic pathway. The rate of this enzyme was probably restricted by an increased cytosolic NADH/NAD ratio. Glycolytic production of pyruvate was not fast enough to match the rate of its utilization by the citric acid cycle under any condition studied, and with glucose as the only exogenous substrate, synthesis of citrate was limited by availability of acetyl-CoA. Anaerobic production of ATP from glycolysis never accounted for more than 7% of the normal aerobic requirements for energy. We conclude that glycolytic rate in cardiac muscle is not sufficient to support high rates of oxidative metabolism. Circ Res 44:166-176, 1979

Instantaneous pressure-volume relationship of the canine right ventricle.

Abstract: SUMMARY The instantaneous isovolumic and ejecting pressure-volume relationship of the right ventricle was studied in 11 cross-circulated, isolated canine hearts to characterize the right ventricular contractile state. Accurate measurement of volume was achieved by the use of a water-filled, thin latex balloon in the right ventricle connected to a special volume loading and transducing chamber. Pressure was measured with a miniature pressure transducer mounted within the balloon. Wide variations in loading conditions were achieved by changing the volume of air above the volumetric chamber. The pressure and volume data were collected from multiple beats under a constant contractile state in the same mode of contraction while the left ventricle was vented to air. Linear regression analysis applied to each of the isochronal pressure-volume data sets at 20-msec intervals from the onset of contraction showed a highly linear correlation between the pressure and the volume. Both the slope and the volume intercept of the regression lines changed with time throughout the cardiac cycle. The maximal slope of the regression line (E,,,,) averaged 2.50 ± 0.49 mm Hg/ml (mean ± SD) for ejecting beats and 2.68 ± 0.55 mm Hg/ml for isovolumic beats. Epinephrine infusions of 12.5 fig/min and 25.0 /ig/min increased E^u by 31% and 82%, respectively (P < 0.005). We conclude that: (1) The instantaneous pressure-volume relationships of the right ventricle in the isovolumic and ejecting modes can be regarded as linear, at least within the physiological range; however, these two modes of contraction did not yield an identical relationship. (2) The slope of these pressure-volume relationship curves changes with a change in the contractile state. Ore Res 44: 309-315, 1979 IT IS WELL KNOWN that there are major anatomical and physiological differences between the right and left ventricles. Compared with the left ventricle, the right ventricle has a greater regional variation in wall thickness and a more complex geometric shape. The developed pressure in systole is much smaller, and intraventricular pressure falls considerably while ejection proceeds. Much recent research has been focussed on left ventricular function, yet there is little quantitative information concerning the right ventricle, particularly with respect to the question of how to characterize contractile state and pumping ability. Those indices of contractile state used in characterizing left ventricular function have not been quantified in and shown to be valid for the right ventricle. Since there are major differences between left and right ventricles, we investigated whether right ventricular contractile state could be described in a similar fashion as left ventricular contractile state. In this study we determined the time-varying ratio of instantaneous pressure to volume, which has been shown to be sensitive to changes in left ventricular contractile state and nearly independent of

The cardiac hypertrophy process. Analyses of factors determining pathological vs. physiological development.

Abstract: COMPLICATED and even contradictory concepts concerning the biochemical and physiological aspects of cardiac hypertrophy are less enigmatic if we first discern whether the type of hypertrophy analyzed is physiological or pathological; i.e., whether factors secondary to the process of hypertrophy have induced the heart to augment or depress its mechanical function. In this review physiological hypertrophy is defined as hypertrophy accompanied by a normal or augmented contractile state in which the maximum rate at which myosin hydrolyzes ATP and the maximum velocity of muscle shortening are either normal or elevated. Pathological hypertrophy, on the other hand, is associated with depressed contractility without necessarily concordant heart failure, in which case the rate of myosin ATPase activity and the velocity of muscle shortening are decreased. Both types of hypertrophy may be considered compensatory in that the heart biochemically and physiologically adjusts to cellular alterations that occur according to the severity of the workload. Thus, our definition is not the same as that provided by Meerson (1976), since he did not distinguish between the two types of hypertrophy described here.

Cardiotonic activity of amrinone--Win 40680 [5-amino-3,4'-bipyridine-6(1H)-one].

Abstract: The cardiotonic activity of a new, noncatechol, nonglycoside agent, amrinone, was investigated in vitro and in anesthestized and unanesthetized dogs. Amrinone (3-100 microgram/ml) caused a dose-dependent increase in papillary muscle developed tension and df/dt without significant changes in duration of the contractile cycle or time-to-peak tension. Amrinone induced slight increases in right atrial rate with no changes in electrophysiological properties of the cat papillary muscle or dog Purkinje fibers. In anesthetized dogs, intravenous bolus injections of amrinone at doses ranging from 1 to 10 mg/kg caused increases in cardiac contractile force and left ventricular dp/dt max with relatively small changes in heart rate and blood pressure. No significant changes in lead II ECG were observed. In unanesthetized dogs, intravenous infusion of amrinone (10-100 microgram/kg per min) caused increases in left ventricular dp/dt max and only small changes in heart rate and blood pressure. Amrinone, tested orally in this model at doses of 2-10 mg/kg, produced a positive inotropic effect with a rapid onset and long duration of action. The inotropic response to amrinone was not blocked by propranolol, dibenzyline, chlorisondamine, atropine, metiamide, or reserpine. Amrinone's inotropic response was not associated with significant alterations in cardiac norepinephrine, phosphodiesterase, cyclic AMP, or Na+, K+-activated ATPase.

The renal kallikrein-kinin system.

Abstract: THE KIDNEY contains several hormonal systems—kallikrein-kinin, renin-angiotensin, prostaglandin—which serve as renal self-regulatory mechanisms and may have extrarenal effects as well. Although the functions of the kallikrein-kinin system are incompletely defined, there is evidence that it may regulate renal blood flow, modulate tubular salt and water transport, and participate in the pathogenesis of a number of human diseases, such as hypertension. Unfortunately, many components of the renal kallikrein-kinin system are not adequately characterized and many current assays are of uncertain specificity. Hence, at present we must be cautious in interpreting available observations. Greater awareness of the potential physiological and clinical importance of the renal kallikrein-kinin system has led to increased research in this area. Recent progress in purification of components and in development of more specific assays should lead to important insights in the near future. Because this is a rapidly evolving field, it is important to note that this review was completed in July, 1978. To limit the reference list within the compass of a Brief Review, only relatively recent references are cited in most cases, even if original or older investigations are more extensive.

Brain adenosine production in the rat during 60 seconds of ischemia.

Abstract: In rats, cerebral perfusion pressure were altered abruptly by aortic transection to determine the production by ischemic brain of adenosine and its metabolites, inosine and hypoxanthine. Brain samples were obtained after 0, 5, 10, 15, 30, and 60 seconds of ischemia. Also measured were ATP, ADP, AMP, phosphocreatine (PCr), lactate, and pyruvate. Blood pressure was monitored continuously, and arterial PO2, PCO2, and pH were measured just prior to induction of ischemia. Adenosine was elevated t 2.30 +/- 0.31 (SE) nmol/g at 5 seconds from a control value of 0.96 +/- 0.07. A significant elevation of adenosine continued to 60 seconds (5.50 +/- 1.24). Furthermore, inosine showed a progressive upward trend during the entire 60 seconds of ischemia, whereas no change in hypoxanthine occurred between the moment of transection (31.81 +/- 2.01 nmol/g) and 60 seconds of ischemia (34.72 +/- 2.93). PCr decreased by 1.24 mumol/g within the first 5 seconds. After the onset of hypotension, significant changes did not occur in AMP and ADP until 30 seconds, and in ATP and pyruvate until 60 seconds after aortic transection; lactate was elevated by 10 seconds. The rapid rise of cerebral adenosine within 5 seconds after the onset of ischemia supports a role for adenosine in the regulation of cerebral blood flow.

The "border zone" in myocardial ischemia. An electrophysiological, metabolic, and histochemical correlation in the pig heart.

Abstract: Regional ischemia was produced in isolated perfused pig hearts and in hearts in situ, by clamping the left descending coronary artery. Intramural and epicardial DC electrograms were recorded from multiple, regularly spaced sites in the central ischemic and border zones and in the normal myocardium. Subepicardial transmembrane potentials were recorded with floating microelectrodes. Transmural tissue biopsies were obtained with a drill from the sites of extracellular potential measurements at various times after coronary occlusion. Tissue levels of adenosine triphosphate (ATP), creatine phosphate (CP), and lactate were determined in this tissue. Glycogen distribution was assessed histochemically. Early ischemic changes are T-Q depression (1.5 minutes), S-T elevation (4 minutes), unresponsivene88 (8 minutes), fall of CP (low and stable after 4 minutes), and rise in lactate (doubled within 10 minutes). Electrical activity temporarily returns between 30 and 50 minutes, while CP further decreases and lactate increases. After 2 hours, T-Q and S-T potentials have decreased, and cells have become unresponsive in the central ischemic zone; levels (in /unoles per gram dry weight) for CP and ATP are < 1, for lactate circa 240. In the electrical border zone, intermediate metabolic values are found. No transmural electrical or metabolic gradients are present. In the border, zones with normal glycogen content interdigitate with zones depleted of glycogen. If occlusion is released after 2 hours, ATP, CP, and lactate levels do not change in central and border sites. In the border during reperfuaion, cells with nearly normal transmembrane action potentials are in close proximity to unresponsive cells with low resting membrane potentials. These findings suggest that the ischemic border is composed of interdigitating normal and ischemic zones sharply demarcated from each other. Ore Res 44: 576-588, 1979

Effects of ischemia on rat myocardial function and metabolism in diabetes.

Abstract: The function and metabolism of hearts removed from diabetic rats and subsequently. perfused in vitro were investigated. Diabetic hearts perfused under aerobic conditions had higher tissue levels of total CoA and long-chain acyl-CoA, lower levels of total camitine, but higher levels of long-chain acyl camitine esters, and used glucose at slower rates than did normal hearts. At low levels of cardiac work, mechanical function of the diabetic hearts was not significantly different than normal hearts for perfusion periods of up to 65 minutes. A mild form of whole heart ischemia (i.e., a 50% reduction in coronary flow) was tolerated just as well by hearts from diabetic rats as by those from normal rats. This degree of ischemia accelerated glucose use in normal but not in diabetic hearts. Mild ischemia resulted in increased tissue levels of acyl esters of CoA and camitine in both normal and diabetic hearts, but the rise was greater in the diabetic tissue. A more severe form of ischemia resulted in a faster rate of ventricular failure in hearts from both normal and diabetic rats, but the rate of failure was fastest in the diabetic hearts. This earlier mechanical failure in diabetic tissue was associated with a more rapid rise in tissue long-chain acyl-CoA and acyl camitine esters. Tissue K+was lost during ischemic perfusion to about the same extent in both normal and diabetic hearts. Thus, early pump failure of diabetic hearts in response to ischemia was not associated with a greater loss of cellular K+ cire Res 44: 322-329, 1979

The role of autoregulation and tissue diastolic pressures in the transmural distribution of left ventricular blood flow in anesthetized dogs.

Abstract: distribution of left ventricular blood flow in anesthetized dogs The role of autoregulation and tissue diastolic pressures in the transmural 1524-4571 Copyright © 1979 American Heart Association. All rights reserved. Print ISSN: 0009-7330. Online ISSN: TX 72514 Circulation Research is published by the American Heart Association. 7272 Greenville Avenue, Dallas, 1979, 45:804-815 Circulation Research http://circres.ahajournals.org/content/45/6/804.citation located on the World Wide Web at: The online version of this article, along with updated information and services, is

Relationship between adenine nucleotide metabolism and irreversible ischemic tissue damage in isolated perfused rat heart.

Abstract: The relationship between energy metabolism and the extent of irreversible ischemic damage was examined in an isolated perfused working rat heart. The amount of cardiac work recovered after reperfusion of hearts exposed to severe global ischemia was dependent upon both the duration of ischemia and the type of substrate provided (either 5 mM glucose or 5 mM glucose + acetate). There appear to be two distinct phases in the ability to recover mechanical function in the reperfused ischemic heart. The second phase corresponds to the onset of severe irreversible tissue damage. Irreversible mitochondrial damage was not found to correspond with the onset of heart failure since the ATP/ADP ratio remained constant in the reperfused myocardium. Furthermore, there does not appear to be a direct correlation between the total ATP content and the extent of irreversible damage, either during ischemia or following reperfusion. However, the total adenine nucleotide content during ischemia showed dramatic changes which correspond temporally with the initiation of the second phase of damage. The observation that the adenine nucleotide pool becomes further depleted during reperfusion suggests that alterations in the salvage pathway for adenine nucleotide synthesis have occurred. Loss of adenine nucleotides appears to be an excellent marker for irreversible heart failure. Acetate provides some protection the the ischemic myocardium. The mechanism by which acetate mediates this protective effect is discussed.

Contractures and increase in internal longitudianl resistance of cow ventricular muscle induced by hypoxia.

Abstract: This study was performed to determine whether hypoxia in glucose-free solutions can increase the electrical resistance of intercellular junctions in ventricular muscle. Internal longitudinal resistance (Ri), mechanical tension, and transmembrane action potentials were measured simultaneously in cow ventricular trabeculae. The mean control value of Ri was 265 +/- 38 omegacm (mean +/- SE) at 34 degrees C. After 1 hour of hypoxia in glucose-free Tyrode's solution, it had increased by 300 +/- 41% (n = 11, P less than 0.001). The rise in Ri was closely related to the increase in resting tension (contracture). These effects were more pronounced during a second exposure to hypoxia and were potentiated by application of epinephrine, by increasing extracellular calcium concentration, and by increasing frequency of stimulation. Addition of glucose (50 mM) provided some protection against hypoxia. It is inferred that the increase in Ri is entirely due to the increase in the resistance of intercellular junctions (electrical uncoupling). Intracellular calcium may be responsible for both the contracture and the uncoupling.

Cyclic nucleotides and cardiac function.

Abstract: SEVENTEEN years ago Murad et al. (1962) provided the first suggestion that cyclic adenosine 3',5'monophosphate (cAMP) might be involved in cardiac function. Specifically, they found that the potency of several catecholamines (CA) to stimulate adenylate cyclase in membrane preparations of dog heart was similar to their in vivo potency as inotropic agents. Interest in this possibility heightened in 1965 when Robison et al. (1965) reported that epinephrine (EPI) injected into perfused rat hearts caused a rapid rise in cAMP, which was followed by enhanced contractile force and conversion of glycogen phosphorylase to the activated a form. Since that time much effort has been expended to define the role of cAMP and also of cyclic guanosine 3':5'-monophosphate (cGMP) in the actions of CA and other hormonal and neurohormonal agents on the heart; the subject has been reviewed periodically (Mayer, 1970 and 1974; Sobel and Mayer, 1973; Wollenberger, 1975). CA have multiple actions on the heart. They produce an increase in developed tension (positive inotropism), an increased rate of tension development, a reduction in time to peak tension, and a decrease in relaxation time so that the total time of systole is shortened. They alter ion movements, particularly of Ca and K. Increased inward current of Ca results in elevation of the plateau phase of the action potential; the repolarization phase of the action potential is accelerated. CA also stimulate metabolic events, particularly glycogenolysis and lipolysis. Except for increase in tension, these effects are produced exclusively by activation of ^-receptors. cAMP has been implicated with varying degrees of certainty in all of these actions.

Protracted ventricular tachcardia induced by premature stimulation of the canine heart after coronary artery occlusion and reperfusion.

Abstract: The effects of premature ventricular stimuli were studied in two groups of dogs with infarcts, one group subjected to permanent occlusion of the left anterior descending coronary artery and the other to temporary occlusion for 2 hours. In dogs with permanent occlusion, spontaneous ventricular arrhythmias occurred after 3-6 hours. In 13 dogs with temporary occlusion, ventricular arrhythmias occurred immediately after reperfusion and then persisted. In five dogs with temporary occlusion, ventricular arrhythmias did not occur spontaneously until 13-15 hours after occlusion. On days 2-9 after surgery, after sinus rhythm had returned, the ventricles of each awake dog were stimulated. After permanent occlusion, premature stimuli occurring on the T wave usually induced from one to 10 repetitive responses on days 2-4. Protracted ventricular tachycardia (lasting greater than 10 seconds) was induced in only two of 10 dogs. The response to premature stimuli was similar after temporary occlusion when ventricular arrhythmias did not occur spontaneously until 13-15 hours after occlusion. Protracted tachycardia was not induced. In the dogs with temporary occlusion, which initially had continuous arrhythmias, premature stimuli occurring on the T wave on days 3-5 after surgery induced both repetitive responses and protracted ventricular tachycardia. Stimuli applied to the ventricles during tachycardia terminated it. Histological studies on all infarcts showed that, after permanent occlusion, necrosis was uniform; after temporary occlusion, viable myocardium survived in the necrotic region. These salvaged myocardial fibers may provide reentrant pathways, causing long-lasting tachycardia.

Cardiac contractile proteins. Adenosine triphosphatase activity and physiological function.

Abstract: This review has pointed out the good correlation frequently observed between ATPase activity of various contractile protein preparations and contractile function of various muscles including the myocardium. Some of the variables in the measurement of the various ATPases and the relationship of these measurements to physiological ATPase in the intact myofibril have been mentioned. The possible roles of changes in the light chains of sulfhydryl groups in the control of ATPase activity have been outlined. The possibility that phosphorylating reactions might exert control over physiological activity remains to be clarified. It is evident that, despite the large amount of research that has been done, our understanding of how the biochemistry of contractile proteins relates to physiological function is in its infancy, and only with a more complete elucidation of the underlying biochemistry of the components of contractile proteins of physiological and pathophysiological adaptations become evident.

End-systolic pressure determines stroke volume from fixed end-diastolic volume in the isolated canine left ventricle under a constant contractile state.

Abstract: We studied the effect of systolic pressure and volume changes on the end-systolic pressure at a fixed end-systolic volume in the left ventricle of excised, cross-circulated canine hearts. Instantaneous ventricular volume was controlled and both end-diastolic and end-systolic volumes were clamped, as preprogrammed by a volume servo pump system. Ventricular ejection was completed at the end of natural systole. When the onset and velocity of ejection were widely varied during contractions with a given set of end-diastolic and end-systolic volumes, the end-systolic pressure was little affected by the changes in the systolic pressure and volume under a stable contractile state. When the end-diastolic volume was increased from the isovolumic condition, the end-systolic pressure at the same end-systolic volume decreased (P < 0.05) from the peak isovolumic pressure by 5-14%, for an ejection fraction of 40-70%. When the end-systolic volume was decreased while the end-diastolic volume was fixed, the end-systolic pressure decreased in proportion to end-systolic volume. These results were interpreted to indicate that, when ejection ends at the end of systole, stroke volume of the ventricle with a given end-diastolic volume is determined predominantly by the end-systolic pressure rather than by the entire systolic courses of the pressure and volume, drc Res 44; 238-249, 1979

The cardiac and vascular factors that determine systemic blood flow.

Abstract: THE CARDIOVASCULAR system is a closed circuit. At any given moment, the rate at which blood returns to the heart from the venous system (venous return) may differ considerably from the rate at which the heart pumps it out into the arterial system (cardiac output). Under steady state conditions, however, cardiac output (CO) and venous return (VR) are virtually equal. Therefore, it probably is better not to distinguish between CO and VR under such conditions, but simply to consider the total blood flow (OJ around the circuit. There has been a tendency on the part of some investigators to explain steady state changes in CO in response to certain conditions (e.g., blood loss, exercise, vasoactdve drugs) by invoking changes in VR. Such an explanation is meaningless, however. These conditions affect Q. for reasons that merit analysis, and such changes in Q are, of course, attended by equal changes in CO and VR at equilibrium. However, to explain the steady state change in CO on the basis of a change in VR is a patent example of circular reasoning; it is tantamount to explaining a change in Q on the basis of a change in Q.

Potential arrhythmogenic electrophysiological derangements in canine Purkinje fibers induced by lysophosphoglycerides.

Abstract: We have recently detected accumulation of lysophosphoglycerides, catabolites of phospholipids, in ischemic myocardium early after coronary occlusion. In the present study we delineated effects of selected concentrations of albumin-bound lysophosphatidyl choline (LPC) comparable to those accompanying ischemia in vivo on action potentials of isolated canine Purkinje fibers. Lysophosphoglycerides induced concentration-dependent (0.75-3.0 mM) decreases in resting membrane potential, overshoot of phase 0, maximal velocity of upstroke (Vmax) of phase 0, and action potential duration. The highest concentrations (2.0-3.0 mM) induced fractionation of the action potential into several components, unresponsiveness to external stimulation, and enhanced automaticity at normal and reduced membrane potentials. LPC induced a rightward shift in the membrane response curve, a 40-fold prolongation of conduction time, and an increase in the ratio of effective refractory period to action potential duration such that the effective refractory period persisted beyond action potential duration, resulting in postrepolarization refractoriness. These electrophysiological alterations were entirely reversible after 70 minutes of perfusion without LPC, with the exception of a persistent depression in the Vmax of phase 0. Lysophosphatidyl ethanolamine (LPE) elicited alterations in action potentials indentical to those elicited by LPC. Furthermore, LPC (3.0 mM) induced comparable alterations in action potentials recorded from isolated rabbit papillary muscles. Since lysophospholipids accumulate early after myocardial ischemia, and since concentrations equivalent to those occurring in vivo induce electrophysiological alterations resembling those seen in ischemic myocardium in vivo, lysophosphoglycerides may be of major importance as biochemical mediators of malignant dysrhythmia induced by ischemia.

The effects of variations in conductivity and geometrical parameters on the electrocardiogram, using an eccentric spheres model.

Abstract: The effects of variations in the volume conductor properties of the torso on the electrocardiogram were studied by means of a theoretical eccentric spheres model. The model includes a blood cavity, cardiac muscle layer, pericardium, lung region, skeletal muscle layer, and subcutaneous fat. The source of the field is a double-layer spherical cap located within the myocardium. The following effects regarding the electrocardiogram (ECG) potentials were determined: (1) blood augments the potential, but less than predicted by simpler published models; (2) in anemia, high potentials are expected, whereas in polycythemia, voltages are reduced; (3) abnormally low lung conductivity (emphysema) causes low surface potentials whose magnitude is controlled by the low conductivity skeletal muscle layer; (4) low voltages result both from low and high pericardial conductivities; (5) the surface potential increases with increasing myocardial conductivity; (6) low skeletal muscle conductivity (Pompe's disease) causes high surface potentials; (7) obesity lowers the potential only slightly; (8) a thick myocardium, protruding into the lung region, slightly augments the potential; (9) an increase in the thickness of the myocardium at the expense of the blood cavity causes a decrease in potential; (10) the potential increases with increasing heart size; and (11) the location of the heart within the torso has a very significant effect on the surface potential distribution.

Differential effects of adenosine and nitroglycerin on the action potentials of large and small coronary arteries.

Abstract: We used intracellular microelectrodes to study some membrane electrical properties of isolated large (>1.0 nun) and small (<500 /un) coronary arteries of the dog. The resting membrane potential (Em) was not significantly different in large arteries and small arteries (average of -56 mV and -53 mV, respectively) nor was the input resistance (9 MΩ and 10 MΩ, respectively). Spontaneous action potentials were not present in vessels of either size, and action potentials could not be induced by electrical stimulation. Addition of tetraethylammonium ion (TEA, 10 mM) rapidly induced overshooting action potentials on electrical stimulation in both large and small arteries. The amplitude of the action potential increased as a function of log [Ca1+]o, the slope of the curve being 30 mV/decade in the large and small arteries, thus demonstrating that CaI+ carries most of the inward current during the action potential. Verapamil (10−6 M) blocked these Ca1+-dependent action potentials in both the large and small coronaries. Adenosine (1CT6 M) blocked the action potential in the small coronary arteries but had no effect on the action potential in the large coronary arteries. In contrast, nitroglycerin (10−6M) blocked the action potential in the large coronary arteries but not in the small arteries. The results of this study demonstrate that adenosine blocks Ca1+ inward current preferentially in small coronary arteries, and nitroglycerin blocks the Ca1+ current preferentially in large coronary arteries. These observations are consonant with a role for adenosine in the metabolic regulation of coronary blood flow in the small coronary vessels. cire Res 44:176-182, 1979

The effects of geometry, elasticity, and external pressures on the diastolic pressure-volume and stiffness-stress relations. How important is the pericardium?

Abstract: The concept of an incremental elastic modulus is applied in the quantification of passive elastic stiffness-stress relations of intact heart muscle, and a transmural pressure-volume relation for the left ventricle is subsequently derived in terms of geometry, muscle elasticity, and external pressures to assess their importance. Physiological and clinical applications of this method indicate that: (1) stiffness-stress relations obtained on the basis of pressure-volume data from dog hearts are not significantly different from those obtained from muscle strips excised from these same hearts; (2) shape and the presence of right ventricular, pericardial, or pleural pressures are of secondary importance in an assessment of passive elastic stiffness; and (3) dramatic shifts in the left ventricular intracavity pressure-volume relations following drug interventions are primarily due to the presence of substantial pericardial pressures; however, the transmural pressure-volume relations are not markedly altered, implying no alteration in the intrinsic ventricular compliance.

Effects of unilateral stellectomy upon cardiac performance during exercise in dogs.

Abstract: The role of the right and left stellate ganglion (RSG, LSG) in the cardiac response to exercise was determined in 34 chronically instrumented dogs. The dogs were divided into three groups: control, left stellectomized (LSGx), and right stellectomized (RSGx). Heart rate (HR), left circumflex coronary flow velocity (CF), and left ventricular pressure were measured during a graded submaximal exercise program on a motor-driven treadmill. At the greatest work load, 6.4 kph and 16% grade, HR in the control group was 235 ± 6 beats/min, after LSGx was 258 ± 6 beats/min (P < 0.05), and after RSGx was 157 ± 7 beats/min (P < 0.01). The maximal derivative of left ventricular pressure increased to 7373 ± 501 mm Hg/sec in the control group; after LSGx it reached 8233 ± 759 mm Hg/sec [not significant (NS)], and after RSGx, 5524 ± 305 mm Hg/sec (NS). Control CF increased to 48 ± 3 cm/sec, after LSGx it increased to 57 ± 3 cm/sec (P < 0.05), and after RSGx to 42 ± 5 cm/sec (NS). After RSGx most dogs did not reach the greatest work load, and the comparison was made at the level attained. Arrhythmias during exercise appeared in 8% of control dogs, in 11% after LSGx, and in 86% after RSGx. It is concluded that: (1) sympathetic control of HR is mediated primarily by the RSG; (2) LSGx does not impair myocardial contractility because of compensatory mechanisms exerted by the RSG, and (3) RSGx increases the likelihood of arrhythmias during exercise. Ore Res 44: 637-645, 1979

Hemodynamic responses of the sheep fetus to vasopressin infusion.

Abstract: The effects of intravenous infusion vasopressin on the circulation the fetus were studied in lambs utero with chronically maintained intravascular catheters. Vasopressin infused doses of 0.91-2.26 mU/min per kg fetal weight resulted in plasma levels arginine vasopressin of 6.8-36.4 /μU/ml; these levels are similar to those achieved during fetal hypoxia. Petal mean arterial blood pressure increased from control levels of 47 ± 1.7 to 56 1.9 nun Hg, and heart rate fell from 174 4.1to 144 ± 4.4 beats/min. Fetal cardiac output and its distribution actual organ blood flows were measured before and during vasopressin infusion by the radionuclide-labeled microsphere technique. Combined ventricular output did not change significantly, but there was a redistribution of flow, with a marked reduction of the proportion cardiac output to gastrointestinal and peripheral circulations and an increase in the percent of cardiac output to umbilical-placental, myocardial, and cerebral circulations. This redistribution was associated with a significant increase in fetal arterial Po» from 22 to 24 torr. Changes in heart rate, cardiac output, and distribution of cardiac output to various fetal organs are similar to those seen during fetal hypoxia and suggest that vasopressin release may play an important role in the fetal cardiovascular response to stress. cire Res 44: 430-436, 1979

Mechanism by which cyclic adenosine 3':5'-monophosphate-dependent protein kinase stimulates calcium transport in cardiac sarcoplasmic reticulum.

Abstract: We examined the mechanism by which cyclic AMP-dependent protein kinase (PK) stimulates the calcium pump of cardiac sarcoplasmic reticulum vesicles. The Ca1+ dependence of calcium uptake rates by 30 /μg/ml canine cardiac sarcoplasmic reticulum was measured at 25 °C in 120 mM KCl, 40 mM histidine buffer (pH 6.8), 5 mM MgATP, and an ATP-regenerating system (75 μg/ml pyruvate kinase + 5 mM phosphoenolpyruvate) with 50 mM phosphate as calcium-precipitating anion. Preincubation with PK, 100 /μg/ml, plus 1 fiM cyclic AMP for 10 minutes increased calcium uptake rates from 2- to 3-fold at Ca1+ concentrations between 0.25 and 2.0 fiM. This stimulation was associated with a decrease in the Ca1+ concentration needed to produce 50% maximal calcium uptake velocity from 2.38 ± 0.21 to 1.07 ± 0.10 /IM (n - 7, P< 0.001). The Ca1+ dependence of calcium uptake in nonphosphorylated cardiac sarcoplasmic reticulum vesicles exhibited positive cooperativity, whereas cooperativity was not evident in the corresponding preparations from ‘fast’ rabbit skeletal muscle. The estimated Hill coefficient for control vesicles was 1.77 ± 0.15; this value decreased significantly to 1.24 ± 0.08 (P < 0.01) after preincubation with PK. After exposure to PK, therefore, cardiac sarcoplasmic reticulum exhibited the low Ca1+ cooperativity seen with fast skeletal sarcoplasmic reticulum. Phosphorylation of cardiac sarcoplasmic reticulum by PK thus appears to increase the apparent Ca1+-sensitivity of the calcium pump while decreasing positive cooperativity between the two Ca1+-binding sites of the calcium pump. cire Res 44: 384-391,1979

alpha-Adrenoceptor attenuation of the coronary vascular response to severe exercise in the conscious dog.

Abstract: SUMMARY The hypothesis that a-adrenergic vasoconstriction could limit the extent of coronary vasodilation during spontaneous strenuous exercise was tested in normal mongrel dogs instrumented for the measurement of left circumflex coronary blood flow, aortic pressure, and left ventricular pressure. These signals were radiotelemetered at rest and during free-ranging exercise with dogs either in the unblocked condition, or after ^-receptor blockade (propranolol, 1 mg/kg), a-receptor blockade (phentolamine, 1-2 mg/kg), or combined ft- and a-receptor blockades. Heart rate was held constant by electrical stimulation throughout the exercise period. After a-receptor blockade alone, late diastolic coronary resistance decreased during exercise to a significantly lower (P < 0.01) level (0.36 ± 0.06 mm Hg/ml per min) than in the unblocked condition (0.52 ± 0.04 mm Hg/ml per min). In the presence of /9-adrenergic blockade, exercise induced insignificant increases in mean left circumflex coronary blood flow and decreases in late diastolic coronary resistance. In contrast, after pretreatment causing combined a and p blockade, both the increase (P < 0.05) in mean left circumflex coronary blood flow (22 ± 4 ml/min) and the decrease (P < 0.01) in late diastolic coronary resistance (0.35 ± 0.07 mm Hg/ml per min) during exercise were significantly greater. This enhanced coronary vascular dilation during exercise following a-receptor blockade could not be attributed to increased metabolically induced vasodilation secondary to changes in aortic pressure, heart rate, left ventricular systolic pressure, or left ventricular dP/dt. These observations strongly support the hypothesis that a receptors in the coronary circulation can act to attenuate alterations in coronary vascular resistance, even during periods of high sympathetic discharge, as occurs during severe exercise. Ore Res 45: 884-660, 1979 BECAUSE of the striking ability of the heart to match an increase in metabolic demand with an increase in nutrient supply, it has been presumed that control of the coronary circulation is primarily an intrinsic phenomenon involving the release of vasoactive metabolites from myocardial cells (Berne, 1964). In recent years, however, work by a number of investigators supports the concept that the coronary circulation is also under direct neural control. For instance, it has become increasingly apparent that sympathetic activation can result in a-adrenergic-mediated coronary vasoconstriction, which in turn can compete with metabolic vasodilator influences, and thus modulate alterations in coronary vascular resistance (Mohrman and Feigl, 1978). Although the existence of sympathetic coronary vasoconstrictor activity appears to be well documented, the physiological importance of such a mechanism remains unresolved. Previous work in

Mechanical and morphological properties of arterial resistance vessels in young and old spontaneously hypertensive rats.

Abstract: We studied alterations in structural and mechanical properties of mesenteric arterial resistance vessels from young (6-week) and old (50-week) spontaneously hypertensive (SHR)and matched normotensive Wistar-Kyoto (WKY) rats. Emphasis was placed upon relating the active tension capabilities of these vessels to their smooth muscle cell content. Cylindrical segments, 0.7 mm long with internal diameters of 150 micrometer, were mounted in a myograph capable of recording circumferential vessel wall tension and dimensions. Comparisons of vessel morphology and mechanics were performed at a normalized internal circumference, L1,where active tension (delta T1) is near maximum. Arterial wall and medial hypertrophy were observed in young and old SHR. Since the percent smooth muscle cells within the media for SHR was similar to that of WKY, both increased smooth muscle cell and connective tissue content account for the medial hypertrophy. These differences in SHR vessels were reflected directly in their passive and active mechanical properties. Fully relaxed vessels from SHR were less compliant, and upon activation at L1 (high potassium depolarization), delta T1 was not different for young SHR and WKY, but values for old SHR were 35% greater (P less than 0.05) than for WKY. When relating the active force generation of the vessel to the actual smooth muscle cell area, values for smooth muscle cell stress (force/area) were similar for SHR and WKY at both ages. In addition, similarities were observed for active dynamic mechanical measurements of Young's modulus and half response time. Genetic hypertension in rats therefore appears to be associated with the development of increased vessel contractility determined by a greater number of smooth muscle cells which possess contractile properties similar to those of normotensive vessels.