bluuebunny/crossref_metadata_2025 huggingface dataset:
A computer study of the left ventricular performance based on fiber structure, sarcomere dynamics, and transmural electrical propagation velocity.
Authors: Beyar R , Sideman S
Published: June 2012

A model of the left ventricle which combines a spheroidal geometry with a spatial fiber angle distribution is presented. The mechanics of each muscle fiber is described by its passive stress-strain relationship, active stress-strain relationship, and an activation function (half a sinusoid) which represents the time-dependent degree of activation of the fiber. A stress-strain rate relationship which characterizes the muscle fibers is used to calculate the mechanics of left ventricular contraction during ejection. Furthermore, a radial electrical signal propagation from the endocardium to the epicardium is used here as a first approximation to the actual depolarization sequence. The model is used to describe the process of contraction throughout the systole. The different calculated parameters and indices of left ventricular function are presented and discussed for different preloading, afterloading and contractility conditions. The maximum elastance is found to be an optimal macroscale parameter of contractility, as it is completely preload and afterload independent, and is a good reflection of the active microscale sarcomere stress-strain relationship.
Quinidine is a competitive antagonist at alpha 1- and alpha 2-adrenergic receptors.
Authors: Motulsky H J , Maisel A S , Snavely M D , Insel P A
Published: June 2012

Although quinidine is known to have antiadrenergic effects in the cardiovascular system, the precise mechanism by which it exerts these effects is not well defined. We asked whether quinidine binds directly to adrenergic receptors. Radioligand-binding assays were used to identify alpha 1-adrenergic receptors [( 3H]prazosin-binding sites) on membranes prepared from rat heart and kidney, alpha 2-adrenergic receptor [( 3H]yohimbine-binding sites) on human platelets and rat kidney membranes, and beta-adrenergic receptors [( 125I]iodocyanopindolol-binding sites) on rat heart and kidney membranes. Although it did not effectively compete for binding to beta-adrenergic receptors, quinidine competed for binding to alpha 1- and alpha 2-adrenergic receptors and yielded equilibrium dissociation constants of 0.3-3 microM. Two other antiarrhythmic agents, lidocaine and procainamide, did not compete for binding to alpha-adrenergic receptors. Further experiments demonstrated that the interactions of quinidine with the cardiac alpha 1- and platelet alpha 2-adrenergic receptors were competitive and reversible. We conclude that that antiadrenergic actions of quinidine can be explained by occupancy and competitive blockade of alpha 1- and alpha 2-adrenergic receptors.
Histamine-induced rhythmic contraction of hog carotid artery smooth muscle.
Authors: Stein P G , Driska S P
Published: June 2012

Smooth muscle strips isolated from the hog common carotid artery can contract rhythmically, exhibiting low frequency, large amplitude oscillations in tension when stimulated with 10 microM histamine. Strips required at least 1.45 mM calcium and 2.5 mM potassium to exhibit this rhythmic activity. Rhythmic contractions could be converted to tonic contractions by removal of potassium or ouabain treatment. Relaxation by 2 mM lanthanum, 1 mM manganese, or 1 microM verapamil implies that the external medium is the source of calcium mediating the contractions. The involvement of adrenergic nerve terminals in this response was ruled out, since propranolol, phentolamine, tetrodotoxin, bretylium, or 6-hydroxydopamine treatment did not alter the oscillations. Blockade of H1 receptors with 0.1 microM diphenhydramine relaxed the muscle strips. The H2 receptor antagonist cimetidine (5 microM) had no effects. Attempts to obtain rhythmic contractions by stimulating with other vasoactive agents (norepinephrine, acetylcholine, 5-hydroxytryptamine, angiotensin II, and elevated potassium concentrations) were unsuccessful, suggesting that this is a specific histamine response mediated solely by H1 receptors. These results show that this large artery, commonly considered a multi-unit smooth muscle, can sometimes exhibit single-unit behavior.
Sarcolemmal phosphatidylethanolamine N-methylation in diabetic cardiomyopathy.
Authors: Ganguly P K , Rice K M , Panagia V , Dhalla N S
Published: June 2012

Phosphatidylethanolamine N-methylation was studied in cardiac sarcolemma 8 weeks after the induction of chronic experimental diabetes in rats by a streptozotocin injection (65 mg/kg, iv). Incorporation of radiolabeled methyl groups from S-adenosyl-L-methionine into intramembranal phosphatidylethanolamine, assayed under optimal conditions, confirmed the existence of three catalytic sites involved in the sequential methyl transfer reactions. Total methyl group incorporation at all three sites was significantly depressed in diabetic myocardium, but this change was reversible by a 14-day insulin therapy to the diabetic animals. Measurements of phospholipid N-methylation activity at different times indicated that the depression was evident at 6 weeks after the induction of diabetes. This defect was also seen for the individual methylated lipid products (monomethyl-, dimethylphosphatidylethanolamine, and phosphatidylcholine) specifically formed at each catalytic site. Experiments with different concentrations of S-adenosyl-L-methionine revealed that, for all three sites, the apparent affinity for the methyl donor did not change, whereas the apparent Vmax values were significantly lowered in diabetes. The results of this study identify a defect in the sarcolemmal phosphatidylethanolamine N-methylation in diabetic cardiomyopathy.
The effects of alpha 2-adrenergic and serotonergic receptor antagonists on cyclic blood flow alterations in stenosed canine coronary arteries.
Authors: Bush L R , Campbell W B , Kern K , Tilton G D , Apprill P , Ashton J , Schmitz J , Buja L M , Willerson J T
Published: June 2012

Platelets possess alpha 2-adrenergic and serotonergic (5-hydroxytryptamine) receptors which are thought to mediate the in vitro proaggregatory effects of epinephrine and serotonin, respectively. However, their importance in platelet aggregation in vivo is uncertain. In the present study, we evaluate the ability of yohimbine and ketanserin, relatively selective alpha 2-adrenergic and serotonin antagonists, respectively, to alter cyclic flow reductions in stenosed coronary arteries in open-chest, anesthetized dogs. These cyclic flow reductions, characterized by progressive declines in coronary blood flow interrupted by abrupt and, often spontaneous, restorations of flow, were produced by cylindrical constrictors placed on the left anterior descending coronary artery. A pulsed Doppler flow probe, placed proximal to the constrictor, was used to measure coronary blood flow. Regional myocardial blood flow was measured with 15-micron radiolabeled microspheres before coronary constriction and when coronary blood flow appeared to be at its nadir and zenith during cyclic flow reductions. After the cyclic flow reductions had been observed for 1 hour, yohimbine (1-2 mg/kg), ketanserin (0.25 or 0.5 mg/kg), or saline was given, and coronary blood flow and hemodynamics were monitored for another hour. The frequency of cyclic flow reductions and the mean of the three lowest nadirs of coronary blood flow (mean +/- SE) were compared between the first and second hours. Ketanserin, at doses of 0.25 and 0.50 mg/kg, virtually abolished cyclic flow reductions in all dogs tested. Yohimbine [1 mg/kg ( n = 14)] was partially effective in reducing the frequency (9.6 vs. 5.5 cyclic flow reductions/hr) and severity of cyclic flow reductions (nadirs of coronary blood flow = 6.2 +/- 2.4 vs. 20.9 +/- 6.1% of control). A higher dose of yohimbine [2 mg/kg (n = 7)] was no more effective. The frequency (9.3 +/- 0.9 vs. 9.3 +/- 1.0 CFR/hr) and severity (17.4 +/- 5.4 vs. 12.4 +/- 3.9% of control coronary blood flow) of cyclic flow reductions were not changed by saline. The relatively selective alpha 1-adrenergic antagonist, prazosin (0.01 mg/kg, iv), and the beta-adrenergic antagonist, propranolol (1-2 mg/kg, iv), did not affect the frequency or severity of cyclic flow reductions. Thus, the abilities of yohimbine to inhibit and ketanserin to abolish cyclic flow reductions in stenosed canine coronary arteries suggest that serotonin and, possibly, alpha 2-adrenergic agonists may influence cyclic flow alterations importantly in this model.
Role of angiotensin II in the altered renal function of congestive heart failure.
Authors: Ichikawa I , Pfeffer J M , Pfeffer M A , Hostetter T H , Brenner B M
Published: June 2012

Glomerular and tubule functions were assessed by micropuncture in rats with extensive myocardial infarction produced by ligation of the left coronary artery 4 weeks prior to study. When compared to sham-operated control rats, rats with myocardial infarction involving 40 +/- 4% of the left ventricular circumference had lower mean arterial pressure (96 +/- 5 vs. 122 +/- 4 mm Hg, P less than 0.005), and higher left ventricular end-diastolic pressure (24 +/- 3 vs. 5 +/- 0 mm Hg, P less than 0.001). Renal cortical microcirculatory dynamics of rats with myocardial infarction were characterized by reduced glomerular plasma flow rate (75 +/- 8 vs. 165 +/- 17 nl/min, P less than 0.005), but a proportionately lesser decline in single nephron glomerular filtration rate (28.0 +/- 2.8 vs. 41.7 +/- 3.1 nl/min, P less than 0.025), accounting for the observed rise in single nephron filtration fraction (0.38 +/- 0.02 vs. 0.25 +/- 0.02, P less than 0.005). These renal hemodynamic alterations in myocardial-infarcted rats were accompanied by a striking elevation in efferent arteriolar resistance (3.03 +/- 0.31 vs. 0.95 +/- 0.16 X 10(10) dyn X sec X cm-5, P less than 0.001). In addition, fractional proximal fluid reabsorption, assessed by end-proximal tubule fluid-to-plasma inulin concentration ratio, was elevated (2.21 +/- 0.12 vs. 1.64 +/- 0.09, P less than 0.025). The intravenous infusion of teprotide, an angiotensin I-converting enzyme inhibitor, led to the return of glomerular plasma flow rate, single nephron filtration fraction, single nephron glomerular filtration rate, efferent arteriolar resistance, and fractional proximal fluid reabsorption in myocardial-infarcted rats to, or toward, the levels found in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Release of endogenous catecholamines in the ischemic myocardium of the rat. Part A: Locally mediated release.
Authors: Schömig A , Dart A M , Dietz R , Mayer E , Kübler W
Published: June 2012

The accumulation of endogenous catecholamines within the extracellular space of the ischemic myocardium has been studied in the isolated perfused (Langendorff) heart of the rat subjected to various periods of complete ischemia, with subsequent collection of the reperfusate. Catecholamines and deaminated metabolites were measured by radioenzymatic methods, or high pressure liquid chromatography. Ischemic periods of less than 10 minutes are not associated with an increased overflow of catecholamines or metabolites. Longer periods of ischemia are accompanied by the overflow of noradrenaline and its deaminated metabolite 3,4-dihydroxyphenylglycol. This overflow increases with lengthening of the preceding ischemic period (10 minutes: 2.5 +/- 0.6, 20 minutes: 209.8 +/- 17.2, 60 minutes: 1270.5 +/- 148.1 pmol noradrenaline/g heart). Noradrenaline concentration is highest during the first minute of reperfusion, suggesting that the noradrenaline detected during reperfusion is released into the extracellular space of the myocardium during ischemia and is subsequently eluted. Experiments with variation of extracellular calcium concentration and with neuronal uptake (uptake1) blocking agents suggest that different mechanisms of catecholamine release are acting during the course of ischemia. A calcium-independent carrier-mediated efflux of noradrenaline from the nerve terminals is of major importance, using the same carrier as is normally responsible for transporting noradrenaline from the synaptic clefts into the neuronal varicosities. Thus, various uptake1-blocking agents diminish the noradrenaline overflow following ischemic periods of between 10 and 40 minutes. The noradrenaline overflow following longer periods of ischemia is unaffected by uptake1-blocking agents, and additional noradrenaline release at this time is probably consequent upon dissolution of cell membranes. Overflow of adrenaline and dopamine occurs to a minor degree (less than 5% of the corresponding noradrenaline overflow), and only after ischemic periods of more than 15 minutes.
Role of glycolytic products in damage to ischemic myocardium. Dissociation of adenosine triphosphate levels and recovery of function of reperfused ischemic hearts.
Authors: Neely J R , Grotyohann L W
Published: June 2012

The mechanism of irreversible damage to ischemic myocardium was investigated in the perfused rat heart. The time of transition from reversible to irreversible damage to contractile function was accelerated by accumulation of glycolytic products and increases in extracellular calcium. Both of these effects were largely independent of adenine nucleotide levels in the tissue. With zero coronary flow and 1.25 mM calcium the decrease in ability of the heart to recover ventricular function with reperfusion after 30 minutes of ischemia was directly correlated with accumulation of glycolytic products (as estimated by tissue lactate) during ischemia. The extent of lactate accumulation during ischemia was varied by preperfusing the hearts for 0, 10, or 15 minutes under anoxic, high coronary flow conditions to deplete tissue glycogen prior to ischemia, and by adding lactate back to the perfusate of these hearts during the ischemic period. Recovery of ventricular function was inversely related to tissue lactate during ischemia and varied from 28 to 92%, even though there was little or no change in tissue levels of residual adenosine triphosphate. Increasing extracellular calcium accelerated the time of onset of irreversible damage with little or no change in residual adenosine triphosphate levels. At any given calcium concentration, the time-dependent declines in the ability of the heart to recover ventricular function was also largely independent of adenosine triphosphate levels. These studies suggest a major role of anaerobic glycolytic products (lactate, hydrogen ion, or NADH) in ischemic damage to the heart that is unrelated to loss of tissue adenine nucleotides. With zero or low flow ischemia, this effect may result in irreversible damage to the myocardium before adenine nucleotides are reduced to critically low levels.
Ryanodine as a tool to determine the contributions of calcium entry and calcium release to the calcium transient and contraction of cardiac Purkinje fibers.
Authors: Marban E , Wier W G
Published: June 2012

Our object was to assess the relative roles of transsarcolemmal calcium entry and intracellular calcium release in the contraction of cardiac Purkinje fibers. We observed intracellular calcium transients, membrane potential, and contraction in aequorin-injected canine cardiac Purkinje fibers exposed to highly selective pharmacological modifiers of excitation-contraction coupling. To influence selectively the release of calcium from the sarcoplasmic reticulum, we used the plant alkaloid, ryanodine. To influence calcium entry, selectively, we used either the calcium channel antagonist, nitrendipine, or the calcium channel agonist, Bay k 8644. Ryanodine alone (1 microM) reduced both components of the intracellular aequorin luminescence signal (L1 and L2). In three muscles, the luminescence signals were 3% of control in amplitude (standard error of the mean, 2%) without two distinct components and the twitch tension was 2% of control (standard error of the mean, 3%), whereas the action potential was prolonged. The aequorin signal and twitch remaining in ryanodine were abolished by the calcium antagonist nitrendipine (10 microM), which also lowered the action potential plateau, consistent with the block of functional calcium channels. In two experiments, the calcium-channel agonist, Bay k 8644, in the presence of ryanodine, increased the aequorin luminescence and the contraction, but only to a very small fraction of their control values. Sodium withdrawal in potassium-free, ryanodine-containing solution produced large slow increases in calcium and tension, showing that tension could still be produced, that aequorin remained functional, and that sodium/calcium exchange was not inhibited by ryanodine. Caffeine increased intracellular calcium, showing that calcium stores were not depleted.(ABSTRACT TRUNCATED AT 250 WORDS)
Transmission of intrathoracic pressure to the intracranial space during cardiopulmonary resuscitation in dogs.
Authors: Guerci A D , Shi A Y , Levin H , Tsitlik J , Weisfeldt M L , Chandra N
Published: June 2012

Elevation of intrathoracic pressure during cardiopulmonary resuscitation generates carotid pressure and flow, but also increases intracranial pressure. This increase in intracranial pressure may limit cerebral blood flow. Therefore, we performed studies designed to quantify the extent of this transmission and to identify the mechanism of transmission of intrathoracic pressure to the intracranial space during cardiopulmonary resuscitation in dogs. Intracranial pressure increased during the chest compression phase of all modes of cardiopulmonary resuscitation tested. During simultaneous compression-ventilation cardiopulmonary resuscitation, change in intracranial pressure (mm Hg) = 0.33 change in intrathoracic pressure (mm Hg) + 2.02 (r = 0.86) and was not significantly different from the relationship observed during conventional cardiopulmonary resuscitation. The magnitude of transmission of intrathoracic pressure to the intracranial space was increased by binding the abdomen and by raising the baseline intracranial pressure. No single route accounted for transmission of intrathoracic pressure to the intracranial space during cardiopulmonary resuscitation. Intracranial pressure fluctuations were unrelated to either carotid arterial or jugular venous pressure, and were found instead to be the result of pressure transmission by blood in non-valved veins and by cerebrospinal fluid. This was determined by three maneuvers. First, obstruction of cerebrospinal fluid flow by ligation of the cervical spinal cord reduced intracranial pressure (P less than 0.001) and made the change in intracranial pressure equivalent to pressure changes at the confluence of the intracranial venous sinuses, without affecting pressure changes at the confluence of the intracranial venous sinuses. Second, ligation of the cervical spinal cord and one of the two longitudinal vertebral veins adjacent to the cervical cord reduced the pressure changes in the intracranial space and at the confluence of the intracranial venous sinuses to about 60% of the levels observed when the cervical cord alone was ligated. Thus, the non-valved longitudinal vertebral veins appear to be the vascular channels of critical importance to pressure transmission. Finally, pressure changes in the thoracic cerebrospinal fluid were increased (P less than 0.05) by cord ligation, even after exsanguination minimized pressure transmission via blood-filled channels, indicating direct transmission of intrathoracic pressure through intervertebral foramina to the cerebrospinal fluid.(ABSTRACT TRUNCATED AT 400 WORDS)
Sodium pump inhibition, enhanced calcium influx via sodium-calcium exchange, and positive inotropic response in cultured heart cells.
Authors: Barry W H , Hasin Y , Smith T W
Published: June 2012

The effects of sodium pump inhibition produced by exposure to the cardiac glycosides, ouabain or dihydroouabain, or by reduction in extracellular potassium to 1.0 mM, on contractile state and sodium-calcium exchange were studied in primary monolayer cultures of chick embryo ventricular cells. Ouabain, 10(-6)M, dihydroouabain, 5 X 10(-5)M, and extracellular potassium of 1.0 mM all induced similar and prominent positive inotropic effects. These effects were accompanied, in each case, by 40-50% inhibition of the rate of active uptake of 42K and by similar increases in steady state sodium content. Stimulation of the rate of 45Ca uptake on exposure to zero extracellular sodium occurred in response to extracellular potassium (1.0 mM) or to glycoside concentrations that induced a positive inotropic effect and sodium-potassium pump inhibition. Reactivation of the sodium pump after return from 1.0 to 4.0 mM extracellular potassium was rapid and was associated with membrane hyperpolarization and slowing of spontaneous beating rate. With pump reactivation under these circumstances, the time course of disappearance of stimulation of sodium-calcium exchange on exposure to zero extracellular sodium was similar to the time course of loss of the positive inotropic effect. Under physiological conditions (4.0 mM extracellular potassium), exposure to positively inotropic but nontoxic concentrations of ouabain or dihydroouabain caused a small but consistent increase in unidirectional calcium influx, but had no discernible effect on calcium efflux. Since similar inotropic effects were produced for comparable degrees of glycoside or low extracellular potassium-induced sodium pump inhibition and increases in cellular sodium content, sodium pump inhibition rather than a glycoside-specific change in calcium binding appears to underlie the inotropic response. These findings are further consistent with the view that the primary mechanism of the positive inotropic effects of digitalis and low extracellular potassium in this experimental preparation is sodium pump inhibition resulting in increased intracellular sodium. We suggest that increased calcium influx via sodium-calcium exchange is the principal mechanism whereby increased intracellular sodium results in enhanced calcium availability to the myofibrils, but an additional effect on calcium efflux is not excluded.
Optimal power generation by the left ventricle. A study in the anesthetized open thorax cat.
Authors: van den Horn G J , Westerhof N , Elzinga G
Published: June 2012

We studied the interaction of the left ventricle and the systemic arterial bed in the open thorax cat. In the steady state, the ventricle can be characterized by the pump function graph (i.e., the relationship between mean left ventricular pressure and mean outflow). From this pump function graph, the apparent source resistance of the heart is found. Apparent source resistance is defined as the ratio of the difference between maximal and actual mean left ventricular pressure, and mean outflow. The arterial system can be characterized by the ratio of mean aortic pressure and mean flow (peripheral resistance). The pressure and flow at which the heart operates is defined as the working point. We have investigated whether the ventricle in the intact cat is working optimally, i.e., that it cannot increase work output further at the end-diastolic volume, contractile state, and prevailing heart rate. This condition is considered as "matching" of ventricle and load. It could be shown that optimal power is transferred when the ratio of peripheral and apparent source resistance equals twice the ratio of mean aortic and mean left ventricular pressure (the matching principle). In four cats, we observed that mean aortic and mean left ventricular pressures are proportionally related. Mean external power (the time integral of the product of pressure and flow divided by cycle length) and steady power (the product of mean pressure and mean flow) were found to be proportional as well. These proportionalities allow for the calculation of peripheral resistance and mean external power from the pump function graph. Pump function graphs were determined in three groups: control (n = 9), atrial pacing (n = 8), and halothane (n = 5). We compared the ratio of peripheral and source resistance at the working point and at the point of optimal work output (expressed in steady ventricular power). It could be shown that, in all investigated groups, the power optimum and the working point coincide. It was concluded that circulatory control in the intact anesthetized cat keeps the ventricle at optimal work output under the conditions studied.
Ultrastructural morphometric analysis of myocardium from dogs, rats, hamsters, mice, and from human hearts.
Authors: Schaper J , Meiser E , Stämmler G
Published: June 2012

Volume densities of mitochondria, myofibrils, and unspecified cytoplasm were measured by ultrastructural morphometry in myocardium from dogs, rats, hamsters, mice, and in biopsied tissue from human hearts. Human myocardium was composed of 23% mitochondria, 59% myofibrils, and 18% cytoplasm. Volume densities for mitochondria were 22% for dogs, 28% for rats and hamsters, and 32% for mice. Myofibrillar volume densities were highest in dogs with 63%, 57% for rats and hamsters, and 49% for mice. Differences were significant between all except man and dog, and rat and hamster. In an extensive analysis of canine myocardium, it could be shown that the quantitative composition of tissue from the left ventricular free wall (anterior, lateral, posterior) and the papillary muscles was identical. There were also no differences between subepi- and subendocardium as well as the midmyocardium. Volume densities from longitudinal sections were identical to those from transversal sections. Fixation with glutaraldehyde by perfusion or immersion provided identical results. There were no differences between volume densities in samples from the left ventricular free wall (anterior, lateral, and posterior) in rats, hamsters, and mice. It is concluded that each mammalian species is characterized by a very typical quantitative composition of the myocardium. The increase in mitochondrial volume correlated well with the increase in heart rate and oxygen consumption in smaller animals. These quantitative data are regarded as the morphological correlate of the differing functional capacity of hearts from different species.
New studies of the excitatory sodium currents in heart muscle.
Authors: Fozzard H A , January C T , Makielski J C
Published: June 2012

After decades of frustration with inadequate methods, cardiac electrophysiologists have developed new techniques for superior control of membrane potential by use of single cells, and they have begun careful study of cardiac Na+ currents. Direct recordings of the behavior of single Na+ channels have been made by the newly developed patch clamp technique. Biochemists have made excellent progress purifying and characterizing the Na+ channel proteins, and there has been some initial success in reconstituting these partially purified channels into lipid bilayers, where their function can be studied. Even at this early stage of development of these new techniques, several conclusions are warranted: The cardiac Na+ currents are not accurately described by the original Hodgkin-Huxley mathematical formulation, making undesirable the further use of this model for study of cardiac excitation and conduction. We need to keep an open mind as to the kinetic behavior of Na+ channels, until the newer experimental techniques provide a more complete picture. Although the cardiac Na+ channel strongly resembles Na+ channels in other excitable tissues, important differences remain, reinforcing the idea that the detailed molecular structure of the cardiac Na+ channel will be different from its close relatives in other excitable cells. The density of Na+ channels in heart cell membranes is much less than in nerve and fast twitch skeletal muscle. The Na+ channels are the focus of action of many drugs and pathological processes. The tools are at hand for a complete description of the Na+ channel, including its gating and its molecular structure. We can expect considerable progress in this decade.
Evidence for a specific receptor site for lidocaine, quinidine, and bupivacaine associated with cardiac sodium channels in guinea pig ventricular myocardium.
Authors: Clarkson C W , Hondeghem L M
Published: June 2012

According to the modulated receptor hypothesis, sodium channels have a specific receptor site for local anesthetic and antiarrhythmic drugs. Thus, in the presence of a high concentration of two drugs, competitive displacement of one drug by another may occur. Furthermore, if a drug that has relatively rapid post-stimulation recovery kinetics (e.g., lidocaine) displaces another drug with relatively slow recovery kinetics (i.e., quinidine or bupivacaine), then a net reduction in sodium channel blockade is expected at certain stimulation rates. We tested this prediction, using the maximum upstroke velocity of the ventricular action potential as an indicator of drug-free sodium channels. A single sucrose gap technique was used to stimulate guinea pig papillary muscles, and to control membrane voltage at all times except during the action potential upstroke. Drug-induced inhibition of maximum upstroke velocity increased as the stimulation rate was increased, and was significant (P less than 0.05) at stimulation rates between 2.5 and 4 Hz in the presence of 43 microM lidocaine (n = 5), and between 0.15 and 4 Hz in the presence of 3.5 microM bupivacaine (n = 4). The addition of 43 microM lidocaine to a perfusate containing 3.5 microM bupivacaine resulted in a net increase in maximum upstroke velocity that was significant at rates between 1 and 3.3 Hz, with a maximum increase of 25 +/- 6% at 1.6 Hz. In contrast, addition of 43 microM lidocaine to a perfusate containing 15 microM quinidine did not result in a significant change in maximum upstroke velocity at driving rates between 0.05 and 3.3 Hz (P greater than 0.2; n = 4). However, evidence for displacement of quinidine by lidocaine could be demonstrated by measuring post-stimulation recovery after a conditioning train of 19 10-msec pulses applied at 28 Hz. With this stimulation protocol, 41 +/- 4% of maximum upstroke velocity recovered slowly from block with a time constant of 3.7 +/- 1.2 seconds at - 100 mV in the presence of 15 microM quinidine (n = 5). In the presence of a mixture of 43 microM lidocaine and 15 microM quinidine, this slow component was significantly reduced to 16 +/- 7% (n = 5; P less than 0.01), while 71 +/- 13% of maximum upstroke velocity recovered with a time constant of 115 +/- 21 msec, typical of lidocaine-blocked channels. A two-drug version of the modulated receptor theory was formulated. The effects of drug mixtures could be accounted for by this model.(ABSTRACT TRUNCATED AT 400 WORDS)
The significance of the late fall in myocardial PCO2 and its relationship to myocardial pH after regional coronary occlusion in the dog.
Authors: Khuri S F , Kloner R A , Karaffa S A , Marston W , Taylor A D , Lai N C , Tow D E , Barsamian E M
Published: June 2012

After acute regional coronary occlusion, myocardial tissue PCO2, as measured by mass spectrometry, rises, reaches a peak, and then gradually falls. This late fall in myocardial tissue PCO2 could be due to (1) a gradual increase in tissue blood flow (and hence improved carbon dioxide washout), (2) a gradual consumption of tissue bicarbonate, (3) a gradual reduction in the production of carbon dioxide due to progressive cellular damage, or (4) an artifact caused by the continued presence of the mass spectrometer probe in the ischemic tissue. To determine which of these four mechanisms is responsible for the late fall in myocardial tissue PCO2, we subjected 27 anesthetized open-chest dogs to 3-hour occlusion of the left anterior descending coronary artery. Both myocardial tissue PCO2 and intramyocardial hydrogen ion concentration were measured in the myocardial segment supplied by the left anterior descending coronary artery. Ten dogs (group 1) were killed after the occlusion (occlusion I), and 11 dogs (group 2) underwent reocclusion (occlusion II) at the same site after a 45-minute period of reflow. Regional myocardial blood flow was measured periodically by the intramural injection of 127Xe. Changes in myocardial tissue PCO2 and hydrogen ion concentration were related to ultrastructural changes in the tissues adjacent to the myocardial tissue PCO2 probe. Regional myocardial blood flow remained unchanged throughout the 3-hour occlusion, ruling out increased carbon dioxide washout as a cause for its late fall. Tissue hydrogen ion concentration, as measured by a new lead glass electrode, correlated well with myocardial tissue PCO2, with the reduction in regional myocardial blood flow, and with ischemic damage assessed histologically. Myocardial hydrogen ion concentration also exhibited a late fall after the occlusion, from a peak of 199.8 +/- 27.8 nmol/liter to 91.9 +/- 12.1 nmol/liter (mean +/- SEM). This ruled out consumption of tissue bicarbonate as the cause for the late fall in myocardial tissue PCO2. Peak rise in myocardial tissue PCO2 after occlusion II (71.2 +/- 7.9 mm Hg) was significantly lower than peak myocardial tissue PCO2 after occlusion I (116.7 +/- 13.9 mm Hg, P less than 0.001). The difference between these latter two values, as well as the magnitude of fall in myocardial tissue PCO2 during occlusion I, related directly to the degree of histological damage observed.(ABSTRACT TRUNCATED AT 400 WORDS)
Differential effects of central angiotensin II and substance P on sympathetic nerve activity in conscious rats. Implications for cardiovascular adaptation to behavioral responses.
Authors: Unger T , Becker H , Petty M , Demmert G , Schneider B , Ganten D , Lang R E
Published: June 2012

The centrally induced effects of angiotensin II and substance P on the cardiovascular system and on neuronal efferent activity of the splanchnic, renal, and adrenal nerves were investigated in chronically instrumented conscious rats. The pressor responses to substance P injected into the lateral brain ventricle were accompanied by marked and short latency increases in heart rate, cardiac output, splanchnic, renal, and adrenal nerve activity, and a rise in plasma noradrenaline and adrenaline. Behaviorally, an arousal-type reaction was observed. In contrast, the pressor responses to intracerebroventricular angiotensin II were associated with initial decreases in heart rate, cardiac output, splanchnic, renal, and adrenal nerve activity, and a fall in plasma noradrenaline at the time of the maximal blood pressure increase. In some but not all animals, a second blood pressure peak associated with increases in heart rate and splanchnic nerve activity was observed after several minutes. Incomplete chronic sinoaortic baroreceptor deafferentiation prevented the angiotensin II-induced fall in heart rate but not the initial fall in splanchnic nerve activity. The decreases in splanchnic nerve activity also occurred in diabetes insipidus rats and persisted in Long Evans rats after vascular vasopressin receptor blockade with d(CH2)5AVP, despite marked reductions of the pressor responses in both groups. Peripheral alpha-adrenoceptor blockade with prazosin or ganglion blockade with hexamethonium inhibited the central angiotensin II pressor responses only in combination with vasopressin receptor blockade. On the other hand, either sympatholytic drug, alone, abolished the pressor responses in the diabetes insipidus rats. This indicates that in intact conscious rats the central pressor effects of angiotensin II are initiated by vasopressin release but become dependent on the sympathetic nervous system when vasopressin is absent or not effective. When rats were allowed to drink in response to angiotensin II, a further sharp rise in blood pressure occurred, together with increases in heart rate and splanchnic nerve activity. The results demonstrate fundamental differences in the mechanisms by which central pressor peptides can influence cardiovascular and autonomic function. It is conceivable that the distinct sympathetic response patterns to central angiotensin II and substance P receptor stimulation form part of a specific cardiovascular adjustment to the individual behavioral reactions, such as drinking, as in the case of angiotensin II, or arousal within the central processing of pain, as in the case of substance P.
Failure of atriopeptin II to cause arterial vasodilation in the conscious rat.
Authors: Lappe R W , Smits J F , Todt J A , Debets J J , Wendt R L
Published: June 2012

The cardiovascular actions of the synthetic natriuretic peptide, atriopeptin II, were examined in conscious unrestrained spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. The animals were chronically instrumented with miniaturized pulsed Doppler flow probes to allow measurement of regional blood flow, or with an electromagnetic flow probe on the ascending aorta to facilitate the measurement of cardiac output in the conscious rat. Intravenous infusion of increasing doses of atriopeptin II (0.25-4 micrograms/kg per min) caused a dose-dependent fall in mean arterial pressure in the hypertensive and normotensive rats. Blood flow in the renal, mesenteric, and hindquarters vascular beds was markedly decreased during the infusion of atriopeptin II, and regional vascular resistance was significantly increased in both groups of rats. Heart rate was significantly elevated (47 +/- 14 beats/min) in the spontaneously hypertensive rats during atriopeptin II infusion, but no change in heart rate was observed in the Wistar rats. In the hypertensive rats, atriopeptin II caused a marked dose-dependent decrease in cardiac output (maximal decrease = -39 +/- 4%) and stroke volume (maximal decrease = -48 +/- 4%). Central venous pressure and left atrial pressure were also significantly reduced during atriopeptin II infusion. Total peripheral resistance was increased over the infusion protocol by 26 +/- 3%. These data suggest that atriopeptin II infusion markedly attenuated cardiac output in the conscious spontaneously hypertensive rats. Total and regional vascular resistances were increased, possibly through reflex compensatory mechanisms, to maintain arterial pressure in the face of decreased cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of acetylcholine on action potential characteristics of atrial and ventricular myocardium after bilateral cervical vagotomy in the cat.
Authors: Kovacs R J , Bailey J C
Published: June 2012

Acetylcholine, the parasympathetic neurotransmitter, shortens the action potential duration of cat atrial muscle cells, but not ventricular muscle cells. In mammalian species, atrial tissue receives a richer cholinergic nerve supply than ventricular tissue. To determine whether chronic withdrawal of cholinergic tone might influence the subsequent response of these tissues to cholinergic stimulation, we examined the effect of acetylcholine on the action potentials of atrial and ventricular myocytes from cats with intact vagi and cats after chronic bilateral cervical vagotomy. Following bilateral cervical vagotomy, physostigmine (10(-6) M) failed to alter atrial tension development or action potential duration. Acetylcholine produced shortening of the action potential duration in atrial muscle from cats with intact vagi and in cats following bilateral cervical vagotomy. However, the degree of shortening produced by acetylcholine after bilateral cervical vagotomy was significantly greater (P less than 0.001). In ventricular muscle from cats with intact vagi, acetylcholine did not alter action potential duration. In ventricular muscle from cats after bilateral cervical vagotomy, acetylcholine shortened the action potential duration. Maximal effect was seen at a concentration of 10(-5) M where acetylcholine shortened action potential duration at 90% repolarization from a control value of 179 +/- 4 to 150 +/- 7 msec. Atropine (10(-6) M) reversed the effects of acetylcholine. Addition of propranolol (10(-6) M) to the superfusate or pretreatment of the animals with reserpine (2 mg/kg, ip) 24 hours before sacrifice failed to alter the response of ventricular muscle cells to acetylcholine.(ABSTRACT TRUNCATED AT 250 WORDS)
Surface densities of diaphragmed fenestrae and transendothelial channels in different murine capillary beds.
Authors: Milici A J , L'Hernault N , Palade G E
Published: June 2012

Fenestrated capillaries are provided with two types of regular discontinuities: fenestrae with negatively charged diaphragms, and transendothelial channels fitted with two diaphragms, of which the luminal one is uncharged. These structures are expected to affect macromolecular exchanges on the basis of size and charge. We have detected variations in the surface density of fenestrations and transendothelial channels (normalized to 1 micron of capillary endothelial profiles in sections) in selected areas of different murine organs, i.e., kidney cortex, duodenal mucosa, and exocrine pancreas. The survey was limited to endothelial segments less than or equal to 400 nm thick, and covered a total length of endothelial profiles of 1180 microns, 730 microns, and 1189 microns in the exocrine pancreas, intestinal mucosa, and kidney cortex, respectively. At least 1000 transendothelial openings were recorded by scoring for easily recognizable fenestrations, transendothelial channels, and unknowns, the latter representing either of the above in grazing sections. The linear density of all transendothelial openings taken together was found to vary among the different capillary beds (kidney cortex greater than intestinal mucosa greater than exocrine pancreas). This same sequence was observed for the linear densities of fenestrations, transendothelial channels, and unknowns considered individually. The values obtained were as follows: kidney cortex, 1.35 fenestrations per micron, 0.25 transendothelial channels per micron, 0.52 unknowns per micron; intestinal mucosa, 0.92 fenestrations per micron, 0.10 transendothelial channels per micron, 0.38 unknowns per micron; exocrine pancreas, 0.58 fenestrations per micron, 0.04 transendothelial channels per micron, 0.27 unknowns per micron. The differences in distribution of transendothelial openings among fenestrated capillary beds probably reflect capillary permeability modulations connected with the functions of these various organs.
The left ventricular dP/dtmax-end-diastolic volume relation in closed-chest dogs.
Authors: Little W C
Published: June 2012

I investigated the relation of the maximum rate of left ventricular pressure rise to the end-diastolic volume and the comparison of the maximum rate of left ventricular pressure rise-end-diastolic volume relation to the end-systolic pressure-volume relation, using the time-varying elastance model. These studies were performed in 11 dogs chronically instrumented to measure left ventricular pressure and determine left ventricular volume from three orthogonal dimensions. During vena caval occlusions, the relations between the maximum rate of left ventricular pressure rise and end-diastolic volume were described by straight lines (r = 0.97 +/- 0.01, mean +/- SD). Dobutamine increased the slope of the maximum rate of left ventricular pressure rise-end-diastolic volume relation to 358 +/- 94% of control. This increase was greater than the 244 +/- 61% increase in the slope of the end-systolic pressure-volume relation (P less than 0.005). The volume intercepts of the maximum rate of left ventricular pressure rise-end-diastolic volume relation and end-systolic pressure-volume relation were similar and were not significantly altered by dobutamine. The ratio of the slope of the maximum rate of left ventricular pressure rise-end-diastolic volume relation to the slope of the end-systolic pressure-volume relation divided by the time from end-diastole to end-systole was similar before (2.2 +/- 0.7) and after dobutamine (2.3 +/- 0.7, P = NS). Angiotensin II did not significantly alter the maximum rate of left ventricular pressure rise-end-diastolic volume relation generated by caval occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Direct observation of the "oxygen paradox" in single rat ventricular myocytes.
Authors: Stern M D , Chien A M , Capogrossi M C , Pelto D J , Lakatta E G
Published: June 2012

By phase contrast microscopy with video length tracking, we followed the sequence of morphological changes in individual isolated rat ventricular myocytes during anoxia followed by reoxygenation. Cells appeared normal during early anoxia. After a duration of anoxia T1, which varied from 17-47 minutes in different cells, each cell abruptly contracted an average of 33% in length to an inert rectangular form presumed to be a rigor state. Cells which were reoxygenated before the onset of rigor showed normal morphology and an unchanged extent of shortening on field stimulation, compared to control. Cells that were reoxygenated after a time in the rigor state, T2, either partially recovered to a shortened rectangular form capable of stimulated twitches or rounded up rapidly to a disordered hypercontracture form. The distribution of T1 was the same for cells which recovered and which hypercontracted. In contrast, the outcome of reoxygenation depended markedly on T2: all cells that were reoxygenated after less than 10 minutes of rigor recovered function, whereas all cells that spent more than 20 minutes in rigor hypercontracted when reoxygenated. The hypercontracture appears to be the cellular analog of the "oxygen paradox" in whole hearts. Its occurrence is reliably related to duration of rigor state but not to duration of hypoxia, because of marked cellular variability in the time of onset of rigor.
Transmural myocardial deformation in the canine left ventricle. Normal in vivo three-dimensional finite strains.
Authors: Waldman L K , Fung Y C , Covell J W
Published: June 2012

To examine transmural finite deformation in the wall of the canine left ventricle, closely spaced columns of lead beads were implanted at a single site on the left ventricular free wall. The three-dimensional coordinates of these myocardial markers were obtained with high-speed biplane cineradiography. Any four noncoplanar markers forming small tetrahedral volumes (less than or equal to 0.1 cc) were used to calculate finite normal and shear strains with respect to a cardiac coordinate system at end diastole. Due to the symmetry of the finite strain tensor, the algebraic eigenvalue problem could be solved to compute principal strains and the directions of the principal axes of deformation with respect to the reference coordinates. An examination of the principal strains in a number of tetrahedra in five animals indicates that deformation increases with depth beneath the epicardium. For example, the transmural variation of principal shortening strain averages -0.014 +/- 0.009 per 10% increment in thickness from epicardium to endocardium. Furthermore, shortening and thickening strains at midwall and deeper are too large (0.10 to 0.40) to be described accurately by infinitesimal theory. These strains are often accompanied by substantial in-plane and transverse shears which are not predicted by typical membrane or shell theories, indicating that these theories must be applied with caution when computing indices of regional ventricular performance. The directions of the principal axes of shortening vary substantially less than the fiber direction varies across the wall (20 degrees - 40 degrees compared with 100 degrees - 140 degrees for fiber direction), supporting the concept that there are substantial interactions between neighboring fibers in the left ventricular wall.