bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipoxygenase products induce neutrophil activation and increase endothelial permeability after thrombin-induced pulmonary microembolism.
Authors: Perlman M B , Johnson A , Jubiz W , Malik A B
Published: June 2012

We examined the mechanism of the neutrophil (PMN)-dependent increase in pulmonary vascular permeability to protein after thrombin-induced pulmonary microembolism. Humoral factors that activate PMNs after thrombin-induced pulmonary microembolism were characterized in pulmonary lymph obtained from unanesthetized sheep challenged with intravenous infusion of alpha-thrombin. Time-dependent increases in PMN migration, aggregation, and superoxide anion (O2-) generation were induced by the pulmonary lymph obtained within 20 minutes after thrombin infusion. The pulmonary lymph neutrophil activating factors present in ether extracts of lymph had retention times of leukotriene B4 (LTB4) and monohydroxyeicosatetraenoic acids (HETEs) by high-performance liquid chromatography. The postthrombin lymph samples containing the LTB4 and HETEs increased PMN O2- generation and endothelial monolayer permeability to 125I-albumin in the presence of PMNs layered on the endothelial monolayers. Control lymph samples replete with LTB4, 5-HETE, and 15-HETE induced increases in PMN O2- generation and endothelial monolayer permeability to 125I-albumin in the presence of PMNs layered on the endothelial monolayers. Maximal increases in PMN O2- production and endothelial permeability occurred when LTB4, 5-HETE, and 15-HETE were coincubated with PMNs, indicating a synergistic action of these mediators in inducing PMN activation. Endothelial monolayer permeability to 125I-albumin did not increase with postthrombin lymph samples obtained after pretreatment with the 5-lipoxygenase inhibitor, L-651,392. The results indicate that lipoxygenase products generated in the lungs after thrombin-induced microembolism contribute to increased endothelial permeability secondary to PMN activation.
Load responsiveness of protein synthesis in adult mammalian myocardium: role of cardiac deformation linked to sodium influx.
Authors: Kent R L , Hoober J K , Cooper G
Published: June 2012

Exposure of adult mammalian myocardium to increased hemodynamic loads augments cardiac protein synthesis, ultimately leading to hypertrophy of the affected chamber. This established relationship between loading conditions and protein synthesis was examined in terms of two questions. First, is there a basic difference between the anabolic effect of a passive load imposed on diastolic myocardium and that of an active load generated by systolic myocardium? This issue was addressed by measuring [3H]phenylalanine incorporation into muscle protein in either quiescent or contracting ferret papillary muscles, set at known isometric lengths. Myocardial protein synthesis increased in proportion to total muscle tension in each case, with an equivalent relation describing both quiescent and contracting muscles. Synthesis of two contractile proteins, actin and myosin heavy chain, were enhanced by muscle loading. Thus, a quantitative rather than qualitative difference between the anabolic effects of diastolic and systolic loading was demonstrated. Second, since increased sodium influx is an initial cellular response requisite to the growth-inducing activity of many substances, and since sodium entry through stretch-activated ion channels is stimulated by deformation of the sarcolemma, does cardiac deformation during increased loading promote sodium influx as a signal to increase anabolic activity? In either quiescent or contracting papillary muscles, the rate of 24Na+ uptake was found to increase with load. Streptomycin, a cationic blocker of the mechanotransducer ion channels, was without effect on protein synthesis in stimulated but slack muscles; however, it inhibited, in a dose-related manner, the augmented protein synthesis otherwise observed in contracting muscles developing tension. At 500 microM, streptomycin did not reduce active tension, but it did reduce the synthesis of both actin and myosin heavy chain. In a second pharmacologic approach, inotropic agents were chosen which uniformly increased muscle tension development but which had contrasting effects on sodium influx. Protein synthesis increased in the presence of Na+ influx enhancers, monensin or veratridine; however, protein synthesis decreased in the presence of amiloride, a sodium influx inhibitor. Thus, myocardial protein synthesis varied directly with sodium influx despite the positive inotropic effect observed with each of these agents. In addition, inhibition of protein synthesis by ouabain demonstrated that activation of the Na+ pump is required for the anabolic effect of load.(ABSTRACT TRUNCATED AT 400 WORDS)
"Reperfusion injury" by oxygen-derived free radicals? Effect of superoxide dismutase plus catalase, given at the time of reperfusion, on myocardial infarct size, contractile function, coronary microvasculature, and regional myocardial blood flow.
Authors: Przyklenk K , Kloner R A
Published: June 2012

Do oxygen-derived free radicals, generated at the time of reperfusion, lethally injure viable, previously ischemic myocardium, damage vascular endothelium, and impair recovery of postischemic contractile function? To address these issues, 23 anesthetized open-chest dogs underwent 2 hours of left anterior descending coronary artery occlusion followed by 4 hours of reperfusion. Immediately prior to reflow, each dog was randomized to receive either the free radical scavenging agents superoxide dismutase (SOD) + catalase, or saline alone. SOD + catalase had no significant beneficial effect on infarct size measured by triphenyltetrazolium staining: area of necrosis averaged 38.5 +/- 6.1% vs. 46.3 +/- 6.2% of the area at risk in treated compared with control animals respectively (p = NS). Furthermore, infusion of SOD + catalase did not alter contractile function of the viable subepicardium: mean segment shortening (measured using sonomicrometry) at 4 hours postreperfusion was -23 +/- 5% of baseline, preocclusion values in controls dogs and -24 +/- 9% of preocclusion values in animals that received the scavenging agents. However, SOD + catalase treatment preserved the endocardial microvasculature (assessed by semiquantitative electron microscopic analysis) and enhanced regional myocardial blood flow after reperfusion. Specifically, mean score for microvascular injury was 0.41 +/- 0.14 vs. 0.10 +/- 0.08 (p less than 0.05) in control compared with SOD + catalase treated groups, and blood flow averaged 0.56 +/- 0.11 vs. 1.27 +/- 0.33 ml/min/g tissue (p less than 0.05), respectively, in the previously ischemic endocardium at 2 hours postreflow. Thus, SOD + catalase given at the time of reperfusion had no acute beneficial effect on either the extent of myocyte necrosis or postischemic contractile function in this canine model. SOD + catalase did, however, attenuate both endocardial vascular injury and the "low reflow" phenomenon. These data suggest that microvascular injury and low reflow following prolonged (2 hour) but transient coronary occlusion may be mediated by oxygen-derived free radicals generated at the time of reperfusion.
Effect of reduced energy metabolism and reperfusion on the permeability and morphology of the capillaries of an isolated rete mirabile.
Authors: Rasio E A , Bendayan M , Goresky C A
Published: June 2012

The effects of reduction in energy metabolism were explored in the eel rete mirabile, an organ composed predominantly of capillaries. In vitro experiments showed that glycolysis is the major pathway of energy production in this capillary tissue, and that iodoacetate, KCN, and low PO2 in combination markedly reduce its ATP generation. When in situ energy generation was inhibited by this combination during countercurrent perfusion of the arterial and venous capillaries of the rete, an approximate doubling of the intercapillary barrier permeability for human [125I]albumin, [14C]sucrose, and 22Na was found. Structural damage was evident, but the intercellular junctions remained intact. The effect of cessation of flow for 30 minutes, followed by reperfusion, was then explored. Stasis alone altered the structure, chiefly of the venous capillary endothelium, but not the permeability of the intercapillary barrier. Stasis with a hypoxic medium containing the inhibitors of energy generation, followed by reperfusion with oxygenated control medium, resulted in a progressive breakdown of the intercapillary barrier, with a threefold to fourfold increase in solute (labeled albumin, sucrose, and sodium) permeability, evolving during early reperfusion, but no change for labeled water permeability. Morphologically, the endothelial cells, especially those in venous capillaries, showed substantial damage; they appeared vacuolated, their cytoplasm was extracted, and cytoplasmic and membrane debris were found in the lumen; intercellular junctions remained intact. Local pericyte detachment with interstitial edema also appeared. Thus, stasis and reperfusion amplified the effects of reduction in energy generation and hypoxia on both permeability and morphological change.
Distribution and three-dimensional structure of intercellular junctions in canine myocardium.
Authors: Hoyt R H , Cohen M L , Saffitz J E
Published: June 2012

Electrotonic coupling of cardiac myocytes at gap junctions may influence patterns of conduction in myocardium. To delineate the three-dimensional structure and distribution of intercellular junctions, we analyzed serial ultrathin sections of canine myocardium with transmission electron microscopy and disaggregated myocytes with scanning electron microscopy. Morphometric analysis of left ventricular myocardium sectioned in three orthogonal planes revealed that 80% of total gap junctional membrane occurred in large, ribbon-like gap junctions oriented transversely at cell end processes. The remaining 20% of gap junctional membrane was contained in small gap junctions located within plicate segments (interdigitating regions of cell-to-cell adhesion) of intercalated disks. In serial ultrathin sections, all gap junctions were contiguous with plicate segments. Thus, true "lateral" gap junctions do not exist in working ventricular myocytes and would not likely be able to withstand shear forces created by laterally sliding cells. Examination of serial plastic sections with light microscopy revealed complex overlapping of myocytes such that individual myocytes were connected at intercalated disks to an average of 9.1 +/- 2.2 other myocytes. These observations provide an improved understanding of the extent and distribution of cell junctions and should facilitate experimental and model studies of conduction in myocardium.
Stimulation of renal sympathetic activity by static contraction: evidence for mechanoreceptor-induced reflexes from skeletal muscle.
Authors: Victor R G , Rotto D M , Pryor S L , Kaufman M P
Published: June 2012

Static muscular contraction in anesthetized animals has been firmly established to reflexly increase arterial pressure. Although group III and IV muscle afferents are known to be responsible for this reflex pressor response, there is no evidence that the stimulation of muscle mechanoreceptors, many of which are supplied by group III fibers, plays a role in causing this contraction-induced reflex effect. To provide this evidence, we recorded renal sympathetic nerve activity in chloralose-anesthetized cats while contracting the triceps surae muscles. We found that static contraction tripled renal nerve activity within three seconds of its onset, an increase that was abolished by cutting the L6 and S2 dorsal roots. On average, the contraction-induced increase in renal nerve activity was observed 0.8 +/- 0.1 seconds after the onset of this maneuver. In addition, intermittent tetanic contractions synchronized renal nerve discharge so that a burst of activity was evoked by each contraction. A similarly synchronized renal nerve discharge was evoked in paralyzed cats by electrical stimulation of the tibial nerve at five times motor threshold, a current intensity that activates group III afferents. We conclude that, in anesthetized animal preparations, mechanoreceptors with group III afferents contribute to the reflex stimulation of renal sympathetic outflow evoked by muscular contraction.
Effects of atrial natriuretic peptide on transmural blood flow and reactive hyperemia in the presence of flow-limiting coronary stenosis in the awake dog: evidence for dilation of the intramural vasculature.
Authors: Chu A , Stakely A , Lin C C , Cobb F R
Published: June 2012

The effects of atrial natriuretic peptide (ANP) on transmural myocardial blood flow distribution and the reactive hyperemic response in the presence and absence of flow-limiting coronary stenosis were examined in chronically instrumented conscious dogs. Ten-second coronary occlusion without subsequent flow restriction resulted in marked reactive hyperemic responses (Doppler flow probes), mean flow debt repayment was 481 +/- 55%. When the 10-second coronary occlusions were followed by a 20-second partial restriction that allowed normal preocclusion coronary inflow, the subsequent reactive hyperemia was significantly augmented, mean flow debt repayment was 938 +/- 91% (p less than 0.05). Pretreatment with ANP (3 micrograms/kg) did not alter the flow debt repayment after a 10-second occlusion without restriction (474 +/- 30%, NS) but attenuated the augmentation of reactive hyperemia resulting from the 20-second inflow restriction, flow debt repayment (613 +/- 66%, NS). Regional myocardial blood flow to the ischemic region was measured during restricted inflow after a 10-second coronary occlusion before and after ANP pretreatment. Before ANP, subendocardial flow decreased (0.54 +/- 0.04 ml/min/g) and subepicardial flow significantly increased (1.03 +/- 0.12 ml/min/g) when compared with the nonischemic zone (subendocardial, 1.03 +/- 0.09 ml/min/g; subepicardial, 0.87 +/- 0.09 ml/min/g, p less than 0.05), indicating maldistribution of the restricted inflow. The resultant subendocardial-to-subepicardial ratio in the ischemic region was significantly decreased when compared with the nonischemic region (0.56 +/- 0.03 vs. 1.18 +/- 0.04, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Molecular basis of complement activation in ischemic myocardium: identification of specific molecules of mitochondrial origin that bind human C1q and fix complement.
Authors: Kagiyama A , Savage H E , Michael L H , Hanson G , Entman M L , Rossen R D
Published: June 2012

Mitochondria may be a source of molecules that activate complement during ischemic injury to myocardium, providing therewith a stimulus for infiltration of polymorphonuclear leukocytes. To identify specific molecules that activate the classical complement pathway, detergent lysates of canine cardiac mitochondria were fractionated by polyacrylamide gel electrophoresis and transferred electrophoretically to nitrocellulose paper (NCP). The NCP replicas of the gels were incubated with isolated C1q and fresh sera as a source of complement, washed briefly, and overlaid with sensitized sheep erythrocytes (RBC) in agarose. A cluster of four to six molecules between 45 and 53 kDa as well as four others, 34, 30, 26, and 23 kDa, consumed complement thereby preventing complement-mediated lysis of sensitized sheep RBC in the agarose overlay. Additional molecules reactive with C1 were identified by their ability to bind isolated human C1q and to serve as assembly sites for later acting complement components. Sites of localization of complement were demonstrated by incubating NCP replicas of fractionated mitochondria with antisera specific for C1q, C3, C5, and C9, followed by peroxidase-conjugated anti-immunoglobulin and substrate. A total of 12 C1q binding molecules ranging in size from 67 kDa to 23 kDa, which can fix later acting complement components, were identified. At least two of these reacted with antisera prepared against canine cardiac lymph collected in the first 3-4 hours after a 45-minute coronary artery occlusion. These studies present direct evidence that specific molecules, released from subcellular fractions of myocardial cells rich in mitochondria, can activate the complement cascade.
Differential control of adrenal and renal sympathetic nerve activity during hemorrhagic hypotension in rats.
Authors: Victor R G , Thorén P , Morgan D A , Mark A L
Published: June 2012

The reflex mechanisms that produce the neurocirculatory adjustments to hemorrhagic hypotension are incompletely understood. The goal of this study was to determine if hemorrhagic hypotension in rats produces differential effects on sympathetic outflow to the adrenal gland and kidney and if the two sympathetic nerve responses are governed by different reflex mechanisms. We performed simultaneous multifiber recordings of adrenal and renal sympathetic nerve activity (SNA) during 8 minutes of sustained hemorrhagic hypotension to a mean arterial pressure of 50 mm Hg in chloralose-anesthetized Sprague-Dawley rats with a) baroreceptors intact, b) cervical vagotomy, c) sinoaortic baroreceptor denervation, and d) combined vagotomy plus sinoaortic denervation. During hemorrhagic hypotension in rats with intact baroreceptors, renal SNA decreased by 31 +/- 10% (mean +/- SEM, p less than 0.05 vs. control) and heart rate decreased from 384 +/- 13 to 365 +/- 16 beats per minute (p less than 0.05), but adrenal SNA increased by 69 +/- 10% over control (p less than 0.05). The decreases in renal SNA and heart rate were reversed by cervical vagotomy but not by atropine, which indicates vagal afferent mediation. In contrast, the increases in adrenal SNA during hemorrhage were not affected by vagotomy alone or by sinoaortic denervation alone but were markedly attenuated by combined sinoaortic denervation and vagotomy, which indicates redundancy in the baroreflex control of adrenal SNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Response of myocardial metabolites to graded regional ischemia: 31P NMR spectroscopy of porcine myocardium in vivo.
Authors: Schaefer S , Camacho S A , Gober J , Obregon R G , DeGroot M A , Botvinick E H , Massie B , Weiner M W
Published: June 2012

The changes in myocardial high energy phosphates and pH during regional ischemia, and their potential role in mediating functional abnormalities, is unclear. To determine the degree of regional blood flow reduction required to induce changes in high energy phosphates and pH, and to correlate these metabolic changes with alterations in blood flow, 31P nuclear magnetic resonance spectroscopy was employed in an in vivo porcine model of graded coronary stenosis. Simultaneous measurements of regional blood flow and phosphate compounds were made during various steady-state degrees of regional ischemia in which subendocardial blood flow was reduced by as much as 80%. ATP did not fall over the total range of graded ischemia, while phosphocreatine (PCr), inorganic phosphate (Pi), and pH all changed progressively after blood flow was reduced below 50% of normal. The ratio of PCr/Pi (a measure of the energy reserve of the myocardium) was strongly correlated to subendocardial blood flow (r = 0.94) and declined by 25% when blood flow was reduced by only 21% below normal. These findings indicate that PCr/Pi is a sensitive marker of ischemia and support the hypothesis that the in vivo energy status of the myocardium is closely coupled to myocardial blood flow.
Right ventricular concentric hypertrophy and left ventricular dilatation by ductal constriction in fetal rats.
Authors: Momma K , Takao A
Published: June 2012

Fetal cardiac changes due to ductal constriction by maternal ingestion of nonsteroidal anti-inflammatory drugs were studied morphologically in near-term rats as an animal model, and results were compared with values of control 1 (C1, twenty-first day) and control 2 (C2, twenty-second day). The fetal ductus was constricted (-70%) (p less than 0.05) by maternal administration of 10 mg/kg indomethacin. Dilatation of the right ventricle and evidence of congestive heart failure including increased pericardial effusion (+200%) (p less than 0.05) and an increase in water content in the abdominal wall were present at 1, 4, and 8 hours after drug administration. At 24 hours after drug administration, concentric right ventricular hypertrophy was shown by a diminished right ventricular cavity (-36% vs. C2) (p less than 0.05), increased right ventricular wall thickness (+70% vs. C2) (p less than 0.05), and increased right ventricular mass (+31% vs. C1) (p less than 0.05). Left ventricular dilatation was indicated by an increased cavity volume (+87% vs. C2) (p less than 0.05) and increased muscle mass (+29% vs. C1 [p less than 0.05] or +9% vs. C2 [p greater than 0.05]). Both the wet and dry weights of the ventricles were increased. In conclusion, fetal ductal constriction caused right ventricular hypertrophy, diminished right ventricular cavity, and left ventricular dilatation and hypertrophy at 24 hours after drug administration in rats after initial congestive failure.
Low Ca2+ reperfusion and enhanced susceptibility of the postischemic heart to the calcium paradox.
Authors: Kirkels J H , Ruigrok T J , Van Echteld C J , Meijler F L
Published: June 2012

This study was designed to define the effect of postischemic low Ca2+ perfusion on recovery of high-energy phosphates, intracellular pH, and contractile function in isolated rat hearts. Phosphorus-31 nuclear magnetic resonance spectroscopy was used to follow creatine phosphate, adenosine triphosphate, intracellular inorganic phosphate, and intracellular pH during control perfusion (15 minutes), total ischemia (30 minutes), and reperfusion (30 minutes). In Group I the perfusate [Ca2+] was 1.3 mmol/l throughout the experiment, whereas in Group II the perfusate [Ca2+] was reduced to 0.05 mmol/l during the first 10 minutes of reperfusion. Hearts from Group III were not made ischemic but were subjected to 10 minutes of low Ca2+ perfusion followed by 20 minutes of normal Ca2+ perfusion. During low Ca2+ reperfusion (Group II) recovery of high-energy phosphates and pH was significantly better than in controls (Group I). However, after reexposure to normal Ca2+, metabolic recovery was largely abolished, coronary flow was suddenly impaired, and contracture developed without any rhythmic contractions. These observations indicated the occurrence of a calcium paradox rather than postponed ischemia-reperfusion damage. On the other hand, normoxic hearts (Group III) tolerated temporary perfusion with 0.05 mmol/l Ca2+ very well with respect to left ventricular developed pressure, coronary flow, and metabolic parameters. In conclusion, postischemic low Ca2+ (0.05 mmol/l) perfusion may reduce reperfusion damage, but at the same time ischemia appears to enhance the susceptibility of the heart to the calcium paradox.
Improved safety factor for triphasic defibrillator waveforms.
Authors: Jones J L , Jones R E
Published: June 2012

Newly developed biphasic waveforms improve defibrillation efficacy both by reduction of defibrillation threshold and by amelioration of shock-induced dysfunction depending on the relative shape of the first and second pulses. Each of these independent effects improves the waveform's safety factor, the ratio between the shock intensity that produces a specific degree of postshock dysfunction and the shock intensity that produces defibrillation (or cellular excitation). Symmetrical waveforms reduce defibrillation threshold to about 60% that of the corresponding monophasic waveform, probably by reduction of excitation threshold for ischemic cells, but increase postshock arrhythmias. Biphasic waveforms with 10% "tails" reduce postshock arrhythmias. This study tests the hypothesis that these independent mechanisms for improvement of defibrillation efficacy can be combined into a single triphasic waveform that will have a higher safety factor than either of the two biphasic waveforms of which it is composed. Cultured myocardial cells were subjected to high-intensity electric-field stimulation with a control monophasic rectangular waveform, a symmetrical biphasic waveform, and a triphasic waveform consisting of the biphasic waveform with an added 10% "tail." Each waveform portion was 5 msec in duration. Photocell mechanograms monitored contractile activity. We found that the duration of postshock arrest of spontaneous contractile activity increased with stimulus intensity for all waveforms. The voltage gradient producing a 4-second arrest after the biphasic waveform shock was 80.6 +/- 1.3% that of the control waveform (100%), while the voltage gradient for the triphasic waveforms was 87.1 +/- 0.73% of control. The difference between biphasic and triphasic waveforms was significant (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of acutely increased right ventricular afterload on work output from the left ventricle in conscious dogs. Systolic ventricular interaction.
Authors: Feneley M P , Olsen C O , Glower D D , Rankin J S
Published: June 2012

In seven conscious, chronically instrumented dogs, left ventricular volume was calculated with an ellipsoidal model from the anteroposterior, septal-free wall, and base-to-apex left ventricular dimensions, measured by implanted ultrasonic transducers. Matched micromanometers measured left and right ventricular transmural and transseptal pressures. Ventricular pressures and volumes were varied by inflation of implanted vena caval and pulmonary arterial occluders. When compared with vena caval occlusion at matched left ventricular end-diastolic volumes, graded pulmonary arterial occlusions were associated with higher right ventricular systolic pressures, reduced left-to-right transseptal systolic pressure gradients, and leftward systolic septal displacement, with increased septal-free wall segment shortening (all p less than 0.05). Graded pulmonary arterial occlusions, like vena caval occlusions, reduced left ventricular end-diastolic volume, but left ventricular stroke work at a given end-diastolic volume was greater during pulmonary arterial occlusions (2,674 +/- 380 10(-3) erg) than during vena caval occlusion (1,886 +/- 450 10(-3) erg, p less than 0.05). These data indicate that, while transient pulmonary arterial occlusion reduces left ventricular preload, the concomitant increase in right ventricular systolic pressure, which is the pressure external to the interventricular septal segment of the left ventricle, augments septal shortening and assists left ventricular pump function at a given preload through direct systolic ventricular interaction.
Rapid electrophysiological changes leading to arrhythmias in the aerobic rat heart. Photosensitization studies with rose bengal-derived reactive oxygen intermediates.
Authors: Hearse D J , Kusama Y , Bernier M
Published: June 2012

The objective of this study was to determine whether reactive oxygen intermediates (e.g., singlet oxygen and the superoxide radical) can rapidly induce electrophysiological disturbances leading to the genesis of arrhythmias, even in the absence of ischemia and reperfusion. Rat hearts (n = 6 per group) were perfused aerobically at 37 degrees C for 10 minutes without rose bengal and for 5 minutes with rose bengal (250 nmol/l), during which time no changes in coronary flow or heart rate were observed. Hearts were then uniformly illuminated for 20 minutes with green light (530-590 nm) from 200 fiber optic cables. With light and without rose bengal, or vice versa, all hearts remained stable. However, in the illuminated rose bengal group, electrophysiological changes (inversion of the terminal portion of the T wave and an increase in Q-T interval) were observed within 11.8 +/- 2.1 seconds (i.e., less than 60 beats). All hearts exhibited ventricular premature beats (within 2.2 +/- 0.7 minutes) and ventricular tachycardia (within 2.8 +/- 0.7 minutes) before the occurrence of complete atrioventricular block (within 5.5 +/- 0.9 minutes). During the illumination period, coronary flow progressively fell in the rose bengal-perfused hearts from 11.6 +/- 0.5 ml/min to 2.0 +/- 0.4 ml/min (p less than 0.05 when compared with any control group). When a similar progressive reduction in coronary flow was mimicked (with or without rose bengal), no arrhythmias occurred.(ABSTRACT TRUNCATED AT 250 WORDS)
Alterations in calcium antagonist receptors and sodium-calcium exchange in cardiomyopathic hamster tissues.
Authors: Wagner J A , Weisman H F , Snowman A M , Reynolds I J , Weisfeldt M L , Snyder S H
Published: June 2012

The Syrian cardiomyopathic (CM) hamster (BIO 14.6) develops a progressive cardiomyopathy characterized by cellular necrosis, hypertrophy, and, eventually, cardiac dilatation and congestive heart failure. Several lines of evidence implicate cellular calcium overload as an important etiologic factor. We previously reported an increased number of receptors for calcium antagonist drugs, which block voltage-dependent calcium channels, in heart, skeletal muscle, and brain tissue of these hamsters in the early necrotic stage of the disease. To better characterize the pathophysiological significance of this abnormality we evaluated calcium antagonist receptor binding and Na+-Ca2+ exchange in CM and control hamsters at different stages of disease as documented by quantitative histopathologic assessment. In CM hamsters as young as 10 days, an age previously thought to be before the onset of disease, we identified cardiac myocyte hypertrophy, a twofold increase in calcium antagonist receptor binding in heart and brain, and a 50% increase in skeletal muscle. Overt histological lesions were present in skeletal muscle at 25 days and in heart between 28-30 days. The size of cardiac lesions increased over time and changed from necrotic foci with cellular infiltration to fibrotic or calcified lesions by 360 days. Myocardial cellular hypertrophy persisted through the late stages of the disease (360 days), but increased calcium antagonist binding was present in heart only to 6 months of age, in skeletal muscle to 90 days, and in brain to 30 days. Na+-Ca2+ exchange in heart was normal until 15 days and then increased by 400% at 30 days suggesting that this augmentation might be a secondary response to the earlier increase in calcium antagonist receptors. At 360 days cardiac Na+-Ca2+ exchange was decreased by 50%, likely reflecting progressive cardiac damage. The increase in calcium antagonist receptors in CM animals as young as 10 days supports the hypothesis that abnormalities in voltage-dependent calcium channels play a role in the pathophysiology of CM hamsters.
Electrophysiological determinants of antidromic reentry induced during atrial extrastimulation. Insights from a pacing model of Wolff-Parkinson-White syndrome.
Authors: Lehmann M H , Tchou P , Mahmud R , Denker S T , Akhtar M
Published: June 2012

The electrophysiology of antidromic reentry, a less common phenomenon than orthodromic reentry, remains a poorly understood aspect of the Wolff-Parkinson-White (WPW) syndrome. We used a pacing model of ventricular preexcitation in patients without WPW, so that electrophysiological events in the normal pathway during atrial extrastimulation (A1-A2 technique) could be precisely delineated without the obscuring effect of an actual accessory pathway. Ventricular preexcitation was simulated by an A1-V1 sequential basic drive with A2-V2 extrastimulation at progressively shorter A1-A2 (equal to V1-V2) coupling intervals. At each coupling interval tested within the zone of atrioventricular (A-V) nodal effective refractory period (since anterograde block of A2 was considered mandatory for manifestation of antidromic reentry), responses were assessed after A2 alone (method I), V2 alone (method II), and A2 plus V2 (method III, the complete preexcitation model). The entire pacing protocol was performed at two A-V intervals, short (50 msec) and long (150-180 msec), thereby simulating different proximities between the A pacing site and "accessory pathway" location. Of 47 consecutive unmedicated patients screened for the study protocol, 38 failed to meet minimal prerequisites for possible initiation of antidromic reentry because of failure in 18 (38% of total) to achieve anterograde A-V nodal block of A2, even though 1:1 ventriculoatrial conduction to cycle lengths less than or equal to 500 msec (less than or equal to 400 msec in 12) was present; and poor or absent ventriculoatrial conduction in the others. The nine remaining candidates underwent the full pacing protocol. Antidromic reentry (retrograde atrial response following V2 in method III) was observed in only two cases (4% of total), and both were associated with retrograde His-Purkinje system delays (documented by method II) occurring in tandem with a long A-V interval, thereby allowing for completion of retrograde A-V nodal recovery after penetration by A2. Indeed, such a prolonged recovery time prevented initiation of antidromic reentry in six of the nine patients (proven by intact ventriculoatrial conduction in method II). Retrograde A-V nodal block of V2, independent of A2, prevented an antidromic echo in one case. Findings in our model help to clarify the various factors, including specific anterograde and retrograde A-V nodal properties; anatomic relation between the accessory and normal pathways; and the retrograde His-Purkinje system delays, that must prevail in a concerted fashion to permit the initiation of antidromic reentry during the A1-A2 technique in patients with the WPW syndrome.
Shortening velocity and myosin and myofibrillar ATPase activity related to myosin isoenzyme composition during postnatal development in rat myocardium.
Authors: Cappelli V , Bottinelli R , Poggesi C , Moggio R , Reggiani C
Published: June 2012

The relation between functional properties of the contractile apparatus, such as shortening velocity and ATPase activity, and myosin isoenzyme composition was studied in ventricular myocardium of adult (60-90-day-old) rats and of newborn (3-day-old) and young (10- and 20-day-old) rats. In adult animals, variations of isomyosin pattern were produced by reducing food intake and by changing the thyroid state. Hyperthyroidism was induced with triiodothyronine daily injection for 15 days; hypothyroidism was induced with iodine-free diet and KClO4 in drinking water for 50-60 days. The following parameters were studied: 1) calcium-magnesium-activated and magnesium-activated ATPase activity of washed and purified myofibrils, 2) calcium-activated ATPase activity of purified myosin, 3) isomyosin composition and relative content of alpha-myosin heavy chains (alpha-MHCs), and 4) force-velocity curve of left and right ventricle papillary muscles. To take into account the difference in excitation-contraction coupling between newborn and adult myocardium, the determination of the force-velocity curve was repeated in Krebs' solution with normal [CaCl2] (2.5 mM) and in Krebs' solution with high [CaCl2] (10 mM). During postnatal growth, the relative content of alpha-MHC increased and reached a maximum at about 20 days. Pronounced increases of myofibrillar and myosin ATPase activity and in shortening velocity occurred during the same period. In adult hyperthyroid rats, alpha-MHC content as well as enzymatic activity and shortening velocity were higher than in control adult animals. Hypothyroidism and food deprivation caused a decrease of alpha-MHC content and a reduction of both enzymatic activities and shortening velocity. The study of the relations between alpha-MHC relative content and functional parameters showed that 1) in ventricular myocardium of adult rats a linear relation existed between alpha-MHC content and myosin and myofibrillar ATPase activity and shortening velocity, and 2) in newborn and young rat ventricular myocardium, both enzymatic activities and shortening velocity were lower than would have been expected on the basis of the linear relation described above. This latter observation could be accounted for by a variation in specific activity of myosin during postnatal development or by the presence of peculiar isomyosins that cannot be detected with usual electrophoretic techniques.
Effects of recombinant human tumor necrosis factor alpha, lymphotoxin, and Escherichia coli lipopolysaccharide on hemodynamics, lung microvascular permeability, and eicosanoid synthesis in anesthetized sheep.
Authors: Kreil E A , Greene E , Fitzgibbon C , Robinson D R , Zapol W M
Published: June 2012

We infused recombinant human tumor necrosis factor alpha (rhTNF alpha), lymphotoxin (rhLT), and Escherichia coli 0111:B4 lipopolysaccharide (LPS) into anesthetized sheep with a lung lymph fistula to compare their effects on systemic and pulmonary hemodynamics, lung lymph dynamics, and eicosanoid release. rhTNF alpha (25-150 micrograms/kg, n = 6 sheep), but not rhLT (25 micrograms/kg, n = 3), rapidly increased lung lymph and plasma levels of 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha) and caused profound systemic vasodilation and hypotension. Meclofenamate pretreatment (10 mg/kg) of three other sheep given 25 micrograms/kg rhTNF alpha prevented the increase of lymph and plasma 6-k-PGF1 alpha levels, systemic vasodilation, and the early (less than 2 hrs) but not the late (4-6 hours) hypotension caused by rhTNF alpha. LPS (1 micrograms/kg, n = 11) induced a briefer increase of lymph 6-k-PGF1 alpha levels than did rhTNF alpha while plasma 6-k-PGF1 alpha levels did not increase. LPS induced more gradual hypotension than did rhTNF alpha but did not cause systemic vasodilation. LPS and rhTNF alpha, but not rhLT, increased lymph thromboxane B2 (TXB2) levels during the first hour of study, whereas only LPS acutely increased plasma TXB2 levels. LPS caused acute pulmonary vasoconstriction and greater acute pulmonary artery hypertension than did either rhTNF alpha or rhLT. Whereas LPS-treated sheep required less fluid transfusion than rhTNF alpha-treated sheep to maintain mean systemic arterial pressure greater than 50 mm Hg, LPS infusion caused a greater increase of lung lymph protein clearance. rhTNF alpha caused minimal alterations of lung microvascular permeability. We conclude that eicosanoid mediators contribute importantly to differences of systemic and pulmonary hemodynamics caused by these agents in sheep. rhTNF alpha cannot account for all of the LPS-induced hemodynamic, lung lymph, and eicosanoid responses in sheep.
Effect of left ventricular volume on right ventricular end-systolic pressure-volume relation. Resetting of regional preload in right ventricular free wall.
Authors: Yamaguchi S , Tsuiki K , Miyawaki H , Tamada Y , Ohta I , Sukekawa H , Watanabe M , Kobayashi T , Yasui S
Published: June 2012

Effect of left ventricular (LV) volume on right ventricular (RV) end-systolic pressure-volume relation (ESPVR) was investigated, and the mechanism was examined from a standpoint of the alteration of RV free wall mean fiber length. Twelve cross-circulated isovolumically contracting canine hearts in which both ventricular volumes were controlled independently were used, and RV-ESPVR was determined at three different LV volume levels. At small (10.2 +/- 0.6 ml), middle (15.3 +/- 1.0 ml), and large (20.5 +/- 1.4 ml) LV volume, the slope of the RV-ESPVR was 2.63 +/- 0.13, 2.74 +/- 0.13, and 2.89 +/- 0.12 mm Hg/ml, respectively, and each value was significantly different from the others (p less than 0.01). The volume intercept (V0) of the relation (RV-V0) was significantly decreased with the increment of LV volume (RV-V0 in small, middle, and large LV volume; 3.92 +/- 0.68, 3.39 +/- 0.67, and 2.87 +/- 0.71 ml, respectively; p less than 0.01). In nine hearts, RV free wall lengths in latitudinal and meridional direction were measured at three LV volume levels when RV volume was held constant (16.1 +/- 1.1 ml). RV latitudinal end-diastolic length was significantly augmented with increasing LV volume (latitudinal length in small, middle, and large LV volume; 9.68 +/- 0.55, 9.81 +/- 0.56, and 9.92 +/- 0.55 mm, respectively). RV meridional end-diastolic length also increased significantly with increasing LV volume.(ABSTRACT TRUNCATED AT 250 WORDS)
Constitutive relations and finite deformations of passive cardiac tissue II: stress analysis in the left ventricle.
Authors: Humphrey J D , Yin F C
Published: June 2012

We present a new approach for estimation of transmural distributions of stress and strain in the equatorial region of a passive left ventricle. We employ a thick-walled cylindrical geometry, assume that myocardium is incompressible, and use a three-dimensional constitutive relation that yields a material symmetry consistent with observed transmural variations in muscle fiber orientations. Moreover, we consider finite deformations including inflation, extension, twist, and transmural shearing and suggest a new method for determination of the requisite deformation parameters directly from experimental strain data. We show representative transmural distributions of stress and strain, and perform a parametric study to illustrate differing predictions of stress induced by varying boundary conditions, muscle fiber orientations, or modes of deformation. Our analysis can be used to guide and check future predictions of cardiac stresses, and to guide experimentalists by suggesting the accuracy of measurements essential for stress analysis in the heart.
Enhanced sensitivity of heart cells to adenosine and up-regulation of receptor number after treatment of guinea pigs with theophylline.
Authors: Wu S N , Linden J , Visentin S , Boykin M , Belardinelli L
Published: June 2012

Experiments were carried out in hearts from guinea pigs that were fed either the adenosine receptor antagonist theophylline (0.6 mg/ml) or no drug. The A1 adenosine receptor radioligand [125I]aminobenzyladenosine bound to a single affinity class of receptors in heart cell membranes from control animals with Bmax and KD of 18.3 +/- 1.0 fmol/mg protein and 3.7 +/- 0.6 nM, respectively (n = 8). Heart cell membranes from animals fed theophylline for 2, 7, and 14 days bound the radioligand with about the same affinity, but the number of binding sites was significantly increased (p less than 0.01) to 30.6 +/- 1.7 (n = 3), 30.0 +/- 0.8 (n = 3), and 27.3 +/- 2.9 (n = 4), respectively. Nearly identical results were obtained with membranes prepared from enzymatically dispersed ventricular myocytes. Fourteen days of theophylline treatment also produced a small increase (12%, p less than 0.01) in the number of binding sites in membranes derived from cerebral cortexes. Isolated ventricular myocytes prepared from animals fed no drug or theophylline for 7 days were used to determine the effect of adenosine on 20 nM isoproterenol-stimulated calcium current (ICa) measured by the whole-cell patch-clamp technique. Adenosine reduced isoproterenol-stimulated ICa without affecting the activation or inactivation kinetics of the current; ICa density was reduced less by 5 microM adenosine in cells from control (25 +/- 3 to 21 +/- 3 microA/microF) than in cells from theophylline-fed animals (26 +/- 5 to 17 +/- 2 microA/microF). Although a high concentration (0.5 mM) of adenosine abolished isoproterenol-stimulated ICa in cells from control or theophylline-fed animals, the IC50 for adenosine was sixfold less in cells derived from theophylline-fed animals than in cells from control animals (4.6 +/- 0.6 microM and 28.3 +/- 1.4 microM, respectively, p less than 0.01). In contrast, the increase in ICa in response to isoproterenol alone and the potency of acetylcholine to antagonize this effect of isoproterenol were the same in both groups of cells. A maximally effective concentration of R-phenylisopropyladenosine (0.1 mM) inhibited isoproterenol-stimulated cyclic AMP accumulation less in cardiomyocytes from control than from theophylline-fed animals (28.7 +/- 1.8% vs. 42.0 +/- 4.2%, p less than 0.05). In summary, exposure of the myocardium to theophylline increases the number of adenosine receptors and the effects of receptor occupancy by agonists. These findings imply that the endogenous concentration of adenosine is high enough in the normoxic guinea pig heart to chronically maintain adenosine receptors in a partially down-regulated state.
Effects of chronic hypertension and its reversal on arteries and arterioles.
Authors: Stacy D L , Prewitt R L
Published: June 2012

The reversibility of functional and structural microvascular alterations in chronic renal hypertension has not been established. Twelve weeks after surgery to induce hypertension, in vivo arteriolar and venular dimensions were measured in the cremaster muscle of rats with one-kidney, one-clip hypertension (1K1C), rats in which the clip was removed after 8 weeks (1KNT), and controls. Systolic blood pressure was significantly elevated after 3 days in 1K1C rats and reached a plateau by 6 weeks. In 1KNT rats, systolic blood pressures were similar to 1K1C rats but were normalized 1 day after unclipping. A marked medial-intimal hypertrophy was found by histological techniques in the thoracic and abdominal aortae (45% and 69%, respectively) but not in cremaster feeding arteries of 1K1C rats. These arterial changes were reversed after unclipping. In 1K1C rats, medial-intimal area decreased in first- through fourth-order (1A, 2A, 3A, and 4A) arterioles along with a decline in relaxed diameter (41%, 30%, 20%, and 21%, respectively), which was only partially restored after unclipping. Heart weight was increased by 67% in 1K1C rats, but it did not differ between 1KNT and controls. Therefore, the reversal of chronic renal hypertension can normalize gross structural alterations in the heart and large vessels, but more time may be required to normalize completely the arteriolar changes. These data indicate that long-term structural adaptations in renal hypertension are different in arterioles and arteries, and they may be related to chronic changes in blood flow and/or pressure.
Absence of effects of cyclosporine on myocardial lymphocyte subsets in Coxsackievirus B3 myocarditis in the aviremic stage.
Authors: Kishimoto C , Abelmann W H
Published: June 2012

To test the therapeutic efficacy of immunosuppression with cyclosporine upon the aviremic stage of coxsackievirus B3 (CB3) myocarditis, 2-week-old BALB/c mice were inoculated with 3 x 10(2) plaque-forming units of CB3, and the effects of cyclosporine on peripheral, splenic, and myocardial lymphocyte subsets were investigated. Cyclosporine, 25 mg/kg/day, was administered subcutaneously daily on days 10-31 (experiment 1) and days 30-51 (experiment 2). Treated groups were compared with infected controls for each experiment. In experiment 1, the survival rate of the cyclosporine-treated group was low (17/25 vs. 24/25, p less than 0.05). The severity of myocardial lesions and the distribution of lymphocyte subsets in myocardium and spleen on days 15-18 did not differ between treated and control groups; on the other hand, the percentages of peripheral Thy 1.2+ (pan T) and L3T4+ (activated helper T) cells on days 15-18 were decreased in the treated group, and those of B, Lyt 1+ (helper/inducer T), and Lyt 2+ (suppressor/cytotoxic T) subsets did not differ significantly. Notably, myocardial interleukin-2 receptor (IL-2R) positive cells, through which cyclosporine is considered to act, were scarce in both groups. In experiment 2, survival rates of two groups did not differ (treated, 32/34; untreated, 34/34; p = NS). The severity of myocardial lesions and the distribution of splenic lymphocyte subsets on days 35-38 also were not different between two groups. The percentages of peripheral lymphocyte subsets (Thy 1.2+ and L3T4+) were decreased in the treated group; those of B, Lyt 1+, and Lyt 2+ subsets did not differ significantly. In experiments 1 and 2, the thymus/body weight ratio in the treated groups was smaller than in the untreated group, but the spleen/body weight ratio in the treated group did not differ from the untreated group; histologically, medullary cellular depletion was evident in the thymus, not in the spleen, of the treated groups. We conclude that cyclosporine failed to change the distribution of lymphocyte subsets in the spleen as well as in the myocardium in CB3 myocarditis although it had effects on the peripheral blood and thymus, which may account for the higher mortality in the treated groups. The absence of beneficial effects of cyclosporine upon the CB3-infected myocardium may be related to the paucity of cyclosporine-sensitive cells (IL-2R, L3T4, and Lyt 2 positive cells) in the myocardium.