bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatty acid analogue accumulation: a marker of myocyte viability in ischemic-reperfused myocardium.
Authors: Miller D D , Gill J B , Livni E , Elmaleh D R , Aretz T , Boucher C A , Strauss H W
Published: June 2012

A 3-methyl substituted radioiodinated long chain fatty acid analogue was evaluated as an agent for the noninvasive detection of altered fatty acid uptake in reperfused, postischemic myocardium. This iodinated fatty acid analogue, 15-(para-iodophenyl)-3-methyl pentadecanoic acid, was given intravenously at 3 hours of reperfusion following 15 minutes (Group 1, n = 5 dogs) or 60 minutes (Group 2, n = 5 dogs) of left anterior descending coronary artery occlusion. Myocardial blood flow (MBF) was measured during occlusion and reperfusion with radiolabeled microspheres administered via the left atrium. Paired ultrasonic subendocardial crystals were placed in the ischemic perfusion bed to assess regional left ventricular systolic function at baseline, during ischemia and reperfusion. Electron microscopic analysis and staining with triphenyltetrazolium chloride (TTC) was performed. Groups 1 and 2 dogs had similar (p = NS) myocardial blood flows during occlusion. TTC positive 1 g endocardial segments from Group 1 (n = 98) and Group 2 (n = 71) had 37% greater fatty acid analogue activity (0.26 +/- 0.04 vs. 0.19 +/- 0.09 percent injected dose per gram; p less than 0.05) compared with TTC negative segments from Group 2 dogs (n = 37). When fatty acid analogue activity was related to near simultaneous reperfusion blood flow, this ratio was 27% greater (p less than 0.05) in TTC positive segments (0.38 +/- 0.1) compared with TTC negative (0.30 +/- 0.16) segments, and 9% greater than normal (0.35 +/- 0.09; p less than 0.05). While ischemic regions from both Groups 1 and 2 dogs became similarly dyskinetic during occlusion (systolic shortening, -11 +/- 6 vs. -11 +/- 2%; p = NS), TTC negative segments remained akinetic (= 1 +/- 7%) at 3 hours of reperfusion while TTC positive zones had recovered partial systolic function (8 +/- 22%). Electron microscopy confirmed the presence of reversible ultrastructural changes in TTC positive regions. A 60-minute occlusion, 3-hour reperfusion model adapted for in vivo single photon emission computed tomography showed a similar excess of 123I fatty acid activity over flow when compared to perfusion (as measured with 201Tl) in the ischemic border zone of 4/4 canine myocardial infarcts. We conclude that the accumulation of this non-beta-oxidized fatty acid analogue noninvasively identifies zones of discordance between fatty acid and flow distribution that are characteristic of ischemically "stunned" but viable myocardium.
Angiotensin II amplification of alpha-adrenergic vasoconstriction: role of receptor reserve.
Authors: Purdy R E , Weber M A
Published: June 2012

Angiotensin II (Ang II) is known to enhance the vasoconstrictor response to norepinephrine (NE). In the present study, this interaction was investigated using isolated rabbit femoral artery rings mounted in tissue baths for the measurement of isometric contraction. Exposure to 3 x 10(-10) M Ang II caused a contraction that was less than 5% of the maximal response to NE. In the presence of Ang II, the NE dose-response curve shifted to the left twofold and the maximal response was not changed. The calcium channel antagonist nifedipine, 1 x 10(-7) M, caused a modest inhibition of the response to NE in either the presence or absence of Ang II. In contrast, nifedipine abolished the leftward shift of the NE dose-response curve caused by Ang II. Femoral arteries were pretreated with benextramine to cause partial alpha-adrenoceptor inactivation. The maximal contractile response to NE in these tissues was between 20% and 40% of that in control vessels, indicating that alpha-adrenoceptor reserve had been eliminated. In benextramine-pretreated vessels, the presence of 3 x 10(-10) M Ang II caused a modest leftward shift of the NE dose-response curve but increased the maximal responses to all NE concentrations by 200% to 800%. Nifedipine caused a modest inhibition of the response to NE in the absence of Ang II. In contrast, the enhanced response to NE in the presence of Ang II was nearly abolished. These results support our conclusions that 1) Ang II enhances the vasoconstrictor response to alpha-adrenergic stimulation, 2) the magnitude of enhancement is greater under conditions of reduced alpha-receptor reserve, and 3) calcium channel activation plays a major role in the amplified response.
Evidence for two components of sodium channel block by lidocaine in isolated cardiac myocytes.
Authors: Clarkson C W , Follmer C H , Ten Eick R E , Hondeghem L M , Yeh J Z
Published: June 2012

The effects of lidocaine on sodium current in cardiac myocytes isolated from cat and guinea pig were investigated using the whole-cell variation of the patch-clamp technique. Lidocaine (43-200 microM) reduced sodium current during repetitive depolarizing pulses in a use-dependent manner. To clarify the nature of the use-dependent block, we characterized the time course of block development using a two-pulse protocol. Two distinct phases of block development were found: a rapid phase (tau = 1-6 msec) having a time course concurrent with the time course of channel activation, and a slower phase (tau = 100-900 msec), which developed after channels inactivated. The amplitude of the block during the rapid phase of development was a steep function of transmembrane voltage over the range of -70 to +20 mV. The voltage-dependence was similar to that for sodium channel activation (sodium conductance) but was too steep to be attributed solely to the passive movement of a singly charged molecule under the influence of the transmembrane voltage gradient. These results suggest that use-dependent block of sodium channels in cardiac tissue may result from an interaction of lidocaine with sodium channels in the activated as well as the inactivated channel states. Possible mechanisms underlying the fast component of block are discussed.
Modulation by the thyroid state of intracellular calcium and contractility in ferret ventricular muscle.
Authors: MacKinnon R , Gwathmey J K , Allen P D , Briggs G M , Morgan J P
Published: June 2012

The purpose of this study was to determine whether the cardiac contractile abnormalities induced by hyperthyroidism or hypothyroidism are caused by changes in intracellular Ca2+ handling or by alterations in the distribution of isoenzymes of ventricular myosin. Right ventricular papillary muscles obtained from euthyroid ferrets and ferrets treated with L-thyroxine (hyperthyroid) or methimazole (hypothyroid) were loaded with the calcium indicator aequorin for recording intracellular Ca2+ levels during isometric contraction. In muscles from the hypothyroid ferrets, peak tension was reduced and the duration of contraction prolonged compared to the controls; these changes were associated with a Ca2+ transient of decreased amplitude and prolonged duration. Hyperthyroidism produced opposite changes in the time course of the Ca2+ transient and the associated isometric contraction. Native polyacrylamide gel electrophoresis was performed on myosin extracted from the right ventricular free wall of control and treated ferrets. The hyperthyroid state was associated with new myosin formation as indicated by the appearance of three myosin bands on the pyrophosphate gel. Gels of myosin from hypothyroid and euthyroid ferrets showed a single band that migrated with the slowest of the three bands from the hyperthyroid ferrets. These results suggest that changes in both Ca2+ handling and myosin isoenzymes may contribute to the contractile abnormalities observed in hyperthyroidism. Alterations in intracellular Ca2+ handling alone may account for the contractile changes induced by hypothyroidism.
Arteriolar control of capillary cell flow in striated muscle.
Authors: Sweeney T E , Sarelius I H
Published: June 2012

This study tests the hypothesis that capillary perfusion is controlled in groups rather than at the level of the individual capillary. We measured cell flux (using cells labeled with substituted tetramethyl rhodamine isothiocyanate, XRITC) and vessel diameter in adjoining arterioles of the terminal vasculature of hamster cremaster muscle (Nembutal, 70 mg/kg i.p.) during rest and hyperemia (10(-4) M adenosine). In terminal arterioles (TAs), 32 of 68 vessels showed cell flux increases from rest to hyperemia exceeding 25 times (i.e., 47% of TAs were relatively unperfused at rest). In vessels feeding TAs (TAFs), 33 of 95 (34%) were relatively unperfused at rest. Cell flux heterogeneity in TAFs decreased significantly by 27% from rest to hyperemia; the corresponding decrease (16%) in TAs was not significant. Thus, unperfused TAFs are present in a proportion which reflects capillary recruitment in hamster cremaster (Sarelius et al, Am J Physiol 1981;241:H317) while TAs are not, and TAFs independently modulate flow distribution distally while TAs do not. The data therefore support the conclusion that TAFs control cell flow in the distal microvasculature. Analysis of normalized ranked maximal diameters showed that TAFs unperfused at rest tend to be the smaller vessels at any tissue site.
Characteristics of flow-mediated brachial artery vasodilation in human subjects.
Authors: Sinoway L I , Hendrickson C , Davidson W R , Prophet S , Zelis R
Published: June 2012

In an effort to determine whether arterial conductance vessels dilate in response to increased blood flow stimuli, brachial artery area (cm2) and diameter (cm) were derived by simultaneous measurement of forearm blood flow (ml/min.100 ml) and brachial artery blood flow velocity (cm/sec) following the release of arterial occlusion. Measurements were made at rest and at the time of maximal flow after the release of graded periods of forearm arterial occlusion (20 seconds to 10 minutes). These studies showed a graded large vessel dilation following occlusions of up to 1 minute (baseline diameter, 0.33 +/- 0.01; after 1 minute occlusion, 0.45 +/- 0.02 cm; p less than 0.05) after which time diameter plateaued (after 10 minutes of occlusion, 0.48 +/- 0.02 cm). In addition, the time course of diameter and flow changes after 3 minutes of arterial occlusion were examined. Flow was maximal at 5 seconds but diameter was maximal at 15-30 seconds after release. Furthermore, the half time for the return of diameter to baseline was longer than that for blood flow. We also measured the diameter after forearm heating (42 degrees C) and noted a substantial increase in diameter (before heating, 0.32 +/- 0.01; after heating, 0.39 +/- 0.02 cm; p less than 0.05). Finally, we applied pressure to the venous side of arteriovenous fistulae in five hemodialysis patients. This maneuver was associated with large reductions in forearm blood flow (baseline flow, 63.3 +/- 10.6; venous compression flow, 36.0 +/- 4.4 ml/min.100 ml; p less than 0.05) and a decrease in brachial artery size (baseline diameter, 0.63 +/- 0.07; venous compression diameter, 0.58 +/- 0.06 cm; p less than 0.05). We conclude that 1) the human brachial artery size changes in response to changes in blood flow, and 2) the maximal dilation occurs after maximal flow is noted. Although alternate explanations are possible for each of our observations, our results are most consistent with a flow-mediated, localized vasodilating process.
Cardiovascular effects of neuropeptide Y in rat brainstem nuclei.
Authors: Tseng C J , Mosqueda-Garcia R , Appalsamy M , Robertson D
Published: June 2012

Central catecholaminergic neurons are involved in cardiovascular regulation. Neuropeptide Y (NPY) coexists with adrenaline and noradrenaline in the rat brain, and interactions among these substances have been studied. The purpose of this study was to investigate the possible role of NPY in central cardiovascular control. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Intramedullary microinjection (60 nl) of NPY (0, 46.5 fmol, 465 fmol, 1.5 pmol, and 4.65 pmol) was made into the nucleus tractus solitarii (NTS), into the area postrema, and into the C1 area in the rostroventrolateral medulla. Injection site was identified by L-glutamate administration and confirmed histologically. Unilateral injection of NPY into the NTS produced a prominent dose-related decrease in heart rate and systolic and diastolic blood pressure (-106 +/- 8 beats/min, -56 +/- 2 mm Hg, and -33 +/- 2 mm Hg, respectively after 4.65 pmol NPY, n = 7, p less than 0.001). Maximal changes occurred at 30 seconds and recovered in 10 minutes for blood pressure and 20 minutes for heart rate. Injection into the area postrema produced an initial increase in heart rate and mean blood pressure (+23 +/- 2 beats/min and +18 +/- 2 mm Hg) followed by a prolonged decrease in heart rate and mean blood pressure (-14 +/- 4 beats/min and -15 +/- 2 mm Hg, respectively, n = 7, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Vagally induced block and delayed conduction as a mechanism for circus movement tachycardia in frog atria.
Authors: Rosenshtraukh L V , Zaitsev A V , Fast V G , Pertsov A M , Krinsky V I
Published: June 2012

Episodes of tachycardia induced by strong vagal stimulation in spontaneously beating isolated atria of frog (Rana temporaria) were studied with multielectrode mapping technique. These episodes were inducible in 19 of 39 preparations. The arrhythmia started several seconds after cessation of vagal stimulation strong enough to cause sinus arrest, without electrical stimulation of the myocardium. The arrhythmia consisted of two to 20 beats (6 +/- 4, mean +/- SD, n = 42) with a cycle length of 100-500 msec. Recording from 32 sites with spatial resolution of 1-2 mm showed that the arrhythmia was due to intra-atrial circus movement. The estimated perimeter of the reentrant circuit ranged from 6 to 20 mm. In circuits of the minimal size, the average conduction velocity along the circuit was as low as 2-3 cm/sec. Paroxysms of the tachycardia were always preceded by vagally induced nonuniform depression of conduction, with some areas of atria being completely blocked. As the vagal influence decreased, the blocked areas recovered in an inhomogeneous manner, their unblocking being significantly (p less than 0.05) delayed after inhibition of tissue cholinesterase by proserine. The reentrant tachycardia was initiated when a sinus impulse arrived during certain phase of the unblocking. Unlike the well-known mechanism of reentrant excitation, which is based on inhomogeneous refractoriness and critically timed extrabeat(s), the circus movement in our model depended on vagally induced conduction block and could be launched by a single sinus impulse.
Anti-cholinergic effects of quinidine, disopyramide, and procainamide in isolated atrial myocytes: mediation by different molecular mechanisms.
Authors: Nakajima T , Kurachi Y , Ito H , Takikawa R , Sugimoto T
Published: June 2012

Effects of quinidine, disopyramide, and procainamide on the acetylcholine (ACh)-induced K+ channel current were examined in single atrial cells, using the tight-seal, whole-cell clamp technique. The pipette solution contained guanosine-5'-triphosphate (GTP) or guanosine-5'-O-(3-thiotriphosphate) (GTP-gamma S, a nonhydrolysable GTP analogue). In GTP-loaded cells, not only ACh but also adenosine induced a specific K+ channel current via GTP-binding proteins (G) by activating muscarinic ACh or adenosine receptors. Quinidine and disopyramide depressed the ACh-induced K+ current quite effectively. Procainamide had a weak inhibitory effect. Quinidine also depressed adenosine-induced K+ current, while the effect of disopyramide on adenosine-induced current was much smaller than that on ACh-induced current. In GTP-gamma S-loaded cells, the K+ channel was uncoupled from the receptors and was activated irreversibly, probably due to direct activation of G proteins by GTP-gamma S. Quinidine depressed the GTP-gamma S-induced K+ current just as in the cases of ACh- and adenosine-induced currents of GTP-loaded cells. Disopyramide had only a weak inhibitory effect and procainamide showed no effect. From these results, it is strongly suggested that the major mechanisms underlying the anti-cholinergic effects of quinidine, disopyramide, and procainamide are different; quinidine may inhibit the muscarinic K+ channel itself and/or G proteins, while disopyramide and high doses of procainamide may mainly block functions of muscarinic ACh receptors in atrial myocytes.
Calmodulin modulation of single sarcoplasmic reticulum Ca2+-release channels from cardiac and skeletal muscle.
Authors: Smith J S , Rousseau E , Meissner G
Published: June 2012

Sarcoplasmic reticulum (SR) contains a Ca2+-conducting channel that is believed to play a central role in excitation-contraction coupling by releasing the Ca2+ necessary for muscle contraction. The effects of calmodulin on single cardiac and skeletal muscle SR Ca2+-release channels were studied using the planar lipid bilayer-vesicle fusion technique. Calmodulin inhibited Ca2+-release channel opening by reducing the mean duration of single-channel open events without having an effect on single-channel conductance. Inhibition by calmodulin was dependent on Ca2+ concentration and occurred in the absence of ATP. The effects of calmodulin were reversed by mastoparan, a calmodulin-binding peptide. Two other calmodulin antagonists [calmidazolium and N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide] modified the gating behavior of the channel in the absence of exogenous calmodulin in a concentration- and Ca2+-dependent manner. Our results suggest that calmodulin can modulate excitation-contraction coupling by directly interacting with the SR Ca2+-release channel of cardiac and skeletal muscle.
Polyamines mediate androgenic stimulation of calcium fluxes and membrane transport in rat heart myocytes.
Authors: Koenig H , Fan C C , Goldstone A D , Lu C Y , Trout J J
Published: June 2012

The androgenic steroid hormone testosterone induced an early (less than 30-60 seconds) stimulation of endocytosis, hexose transport, and amino acid transport, monitored by the temperature-sensitive uptake of horseradish peroxidase, 2-deoxyglucose, and alpha-aminoisobutyrate, respectively, in rat ventricle cubes and acutely isolated ventricular myocytes. This stimulation was time- and concentration-dependent and was maximal at 10(-9) to 10(-8) M testosterone, consistent with androgen-receptor mediation. EGTA (2.5 mM), La3+ (1 mM), and verapamil (100 microM) ablated the hormonal response. The calcium ionophore A23187 (10 microM) induced an acute stimulation of endocytosis, amino acid transport, and hexose transport which was not further increased by testosterone (10(-8) M), suggesting a common effector pathway. Testosterone (10(-8) M) also evoked a rapid (less than 30 seconds) stimulation of 45Ca influx and efflux. Testosterone (10(-8) M) induced a rapid (less than 5 seconds) transient increase in ornithine decarboxylase (ODC) activity peaking (twofold to threefold) at 60 seconds, and an early (15 seconds) transient accumulation of polyamines peaking at 60 seconds in isolated myocytes. The specific, irreversible ODC inhibitor alpha-difluoromethylornithine (DFMO, 5-10 mM) blocked the testosterone-evoked increase in ODC activity and polyamine levels and the stimulation of Ca2+ fluxes, endocytosis, hexose transport, and amino acid transport. Putrescine (0.5-1 mM), the ODC product, reversed DFMO inhibition and restored the increase in polyamines, 45Ca fluxes, and Ca2+-dependent membrane transport processes. These results demonstrate that rapid, transient ODC-regulated polyamine synthesis is essential for androgenic stimulation of Ca2+ fluxes and membrane transport processes in ventricular myocytes. These findings support a model for signal transduction in which newly synthesized polyamines serve as intracellular messengers to regulate transmembrane Ca2+ movements, Ca2+-dependent membrane transport functions, and other Ca2+- and polyamine-sensitive processes in cardiac myocytes.
Role of vagosympathetic fibers in the control of adrenocorticotropic hormone, vasopressin, and renin responses to hemorrhage in fetal sheep.
Authors: Wood C E , Chen H G , Bell M E
Published: June 2012

Hemorrhage stimulates endocrine and cardiovascular reflex responses that are appropriate for returning blood volume and pressure to prehemorrhage levels. Fetal sheep respond to hemorrhage with increases in plasma adrenocorticotropic hormone (ACTH), cortisol, and vasopressin concentrations and plasma renin activity, but little is known about the afferent limb of the reflex(es) controlling these responses. Fetal sheep between 128 and 133 days' gestation were chronically prepared with vascular catheters. Five fetal sheep were subjected to bilateral section of the cervical vagosympathetic trunks; six fetal sheep were not vagotomized. Four to six days after surgery, the fetuses were subjected to withdrawal of 10 ml of blood every 10 minutes for 2 hours (130 ml total). Vagotomized fetal sheep responded to the hemorrhage with a greater decrease in central venous pressure than the intact fetuses and a slower restitution of fluid to the vascular space (estimated to be 17% of the hemorrhage volume in 2 hours) than the intact fetuses (estimated to be 28% of the hemorrhage volume in 2 hours). Both groups of fetuses, however, responded to the hemorrhage with increases in fetal plasma ACTH, cortisol, and vasopressin concentrations and plasma renin activity that were not significantly different. A posteriori analysis of the data by correlation analysis revealed that the fetal ACTH, vasopressin, and renin responses to the hemorrhage were more highly correlated to the changes in fetal arterial pH than to changes in fetal mean arterial pressure or central venous pressure. The results suggest that the ACTH, vasopressin, and renin responses to hemorrhage in the fetus be mediated by chemoreceptors, not by cardiovascular mechanoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Two components of transient outward current in canine ventricular myocytes.
Authors: Tseng G N , Hoffman B F
Published: June 2012

Repolarization during phase 1 of cardiac action potential is important in that it may influence both impulse conduction in partially depolarized tissue and action potential duration. Thus, it is important to know the properties and regulation of the underlying currents. In about 50% of canine ventricular myocytes, the actin potential displays a phase 1 of fast repolarization and a prominent notch between phase 1 and the plateau. A transient outward current is responsible for both. This current is composed of two components: one (Ito1) blocked by 4-aminopyridine and the other (Ito2) blocked by manganese. In the present study, we characterized each of the components in isolation from the other. Both had an activation threshold between -30 and -20 mV. At the same voltage, Ito1 was larger than Ito2 and had a shorter time to peak. The peak current-voltage relationship for Ito1 was almost linear, but that for Ito2 was bell-shaped. Ito1 decayed during sustained depolarization with a single exponential time course: tau less than 30 msec at all voltages. It recovered from inactivation with a voltage-dependent time course: tau = 70 msec at -90 mV and 720 msec at -40 mV. Ito2 was augmented by elevating [Ca2+]o or by isoproterenol. It was inhibited by caffeine, ryanodine, or a preceding transient inward current, suggesting that it was activated by intracellular calcium released from sarcoplasmic reticulum. We conclude that Ito1 and Ito2 in canine ventricle are similar to those described for many other cardiac tissues, but the kinetics of Ito1 are significantly faster than in other tissues.
Consequences of regional inotropic stimulation of ischemic myocardium on regional myocardial blood flow and function in anesthetized swine.
Authors: Schulz R , Miyazaki S , Miller M , Thaulow E , Heusch G , Ross J , Guth B D
Published: June 2012

Determination of the effect of inotropic stimulation on regionally ischemic and hypokinetic myocardium is complicated when intravenous administration of the inotropic agent also causes stimulation of nonischemic adjacent and distant regions, thereby altering global ventricular hemodynamics. To obviate such events, 16 anesthetized swine were studied during regional inotropic stimulation by infusion of dobutamine hydrochloride (2.5 +/- 1 microgram/min) into the cannulated left anterior descending coronary artery. Coronary inflow was controlled by a pump in an extracorporeal circuit. Two groups of swine with different degrees of ischemia were studied. In the first group of animals (n = 8), reduction in coronary inflow to produce a fall in coronary artery pressure (CAP) from 114 +/- 7 mm Hg to 62 +/- 2 mm Hg caused a decrease in percent systolic wall thickening (%WTh) from 34.6 +/- 8.1% to 25.4 +/- 5.8% (p less than 0.005). In the second group of animals (n = 8), CAP was decreased to 46 +/- 5 mm Hg (control: 115 +/- 8 mm Hg) and % WTh decreased from 34.1 +/- 16.4% to 10.4 +/- 6.9% (p less than 0.001). Subendocardial blood flow was reduced from 1.41 +/- 0.38 ml/min/g to 0.65 +/- 0.13 ml/min/g (group 1, p less than 0.001) and from 1.08 +/- 0.22 ml/min/g to 0.24 +/- 0.08 ml/min/g (group 2, p less than 0.001). Regional infusion of dobutamine caused asynchronous ventricular contraction with early systolic augmentation in wall thickening followed by late systolic thinning. Therefore, during hypoperfusion regional myocardial function assessed by %WTh remained unchanged (26.2 +/- 5.8%, p = NS) in group 1 and decreased significantly to 1.6 +/- 5.1% (p less than 0.041) in group 2. Subendocardial blood flow decreased to 0.44 +/- 0.15 ml/min/g in group 1 (p less than 0.005) and to 0.15 +/- 0.07 ml/min/g in group 2 (p less than 0.012). To account for the augmented early systolic thickening that occurred during asynchronous contraction, a myocardial work index was developed in which the sum of the instantaneous left ventricular pressure-wall thickness product was calculated for estimation of regional myocardial work. Increases in this work index were apparent with the addition of dobutamine at both levels of hypoperfusion. This significant enhancement in regional myocardial function in group 2 caused a significant increase of 16% (p less than 0.009) in overall left ventricular power during ejection. Thus, regional inotropic stimulation with dobutamine caused enhancement of maximum work of the ischemic myocardium in the steady state despite a further decrease in subendocardial blood flow.
A central mechanism of acute baroreflex resetting in the conscious dog.
Authors: Tan W , Panzenbeck M J , Hajdu M A , Zucker I H
Published: June 2012

The role of the central nervous system in the mechanism(s) involved in acute carotid baroreflex resetting was studied in six conscious, chronically instrumented, aortic-denervated dogs. Dogs were prepared for reversible vascular isolation of the carotid sinuses. Acute baroreflex resetting was induced by holding the left carotid sinus pressure (LCcsp) at a given value for 20 minutes using a pulsatile pressure control system while at the same time keeping the right carotid sinus pressure (RCSP) at a subthreshold level (approximately 40 mm Hg). At the end of the 20 minutes, the LCcsp) was reduced to approximately 20 mm Hg, and a baroreflex (RCSP-mean arterial pressure [MAP]) curve was generated on the right carotid sinus using static-step increases in carotid sinus pressure. At the control LCcsp of 100 mm Hg, the RCSP-MAP baroreflex had a threshold pressure (Pth) of 86.6 +/- 3.1 mm Hg and a set point pressure (Psp) of 104.7 +/- 2.5 mm Hg. Increasing LCcsp) to 140 mm Hg for 20 minutes caused these parameters for the right carotid baroreflex to increase. Pth and Psp increased by 18.4 +/- 4.0 and 14.2 +/- 3.0 mm Hg, respectively (p less than 0.05). The baroreflex curve, therefore, was shifted upward and to the right. Decreasing LCcsp to 60 mm Hg caused Pth and Psp to decrease by 24.7 +/- 5.0 and 18.1 +/- 2 mm Hg, respectively (p less than 0.05). The baroreflex curve was therefore shift downward and to the left. The percent of resetting of Pth and Psp was 46 +/- 9% and 36 +/- 8%, respectively, when LCcsp was 140 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)
Fibrosis-induced reduction of endomyocardium in the rat after isoproterenol treatment.
Authors: Jalil J E , Janicki J S , Pick R , Abrahams C , Weber K T
Published: June 2012

Isoproterenol treatment leads to endomyocardial fibrosis with muscle fibers encircled by fibrillar collagen. This study was undertaken in the rat to determine if muscle encased in collagen would subsequently become either necrotic or atrophic. For this purpose, we monitored the fibrillar nature of myocardial collagen, its alignment with muscle, and the morphology of the endomyocardium, together with the response in diastolic and systolic myocardial stiffness, immediately on completion (10 days) and 30 days after a course of subcutaneous isoproterenol (500 micrograms/kg/day). We found 1) left ventricular hypertrophy at 10 and 30 days with an increase in collagen volume fraction (p less than 0.01) that consisted of a meshwork of thick and thin collagen fibers that encircled endomyocardial muscle, 2) a variable reduction in endocardial muscle fiber diameter at 30 days with the greatest thinning seen in muscle encircled by fibrous tissue, and 3) an elevation (p less than 0.01) in the slope of the diastolic stress-strain relation at 10 and 30 days. The developed systolic stress-strain relation, which was elevated at 10 days (p less than 0.01), declined (p less than 0.05) with the reduction in endomyocardial muscle mass. Thus, endomyocardial muscle, encircled by fibrillar collagen, will atrophy over time, and this leads to a reduction in active stiffness. These findings may, in part, explain why progressive ventricular dysfunction accompanies chronic myocardial disease with endomyocardial fibrosis.
Nonuniform vasomotor responses of the coronary microcirculation to serotonin and vasopressin.
Authors: Lamping K G , Kanatsuka H , Eastham C L , Chilian W M , Marcus M L
Published: June 2012

Large-conduit coronary arteries respond to vasoactive stimuli differently than smaller coronary arterioles, but the quantitative effects of many vasoactive stimuli at various levels of the microvasculature remain unknown. To determine the site of constriction or dilation to serotonin and vasopressin in the coronary microcirculation, we studied microvascular responses in the left ventricle of anesthetized cats (n = 36). To compensate for motion due to contraction of the heart, the epicardium was visualized with stroboscopic epi-illumination controlled by a computer to flash once per cardiac cycle in mid-diastole, making the vessels appear stationary. Serotonin (16 micrograms/kg/min) or vasopressin (0.5 units/min) was infused into the left atrium while maintaining aortic pressure constant with a snare on the descending aorta or inferior vena cava. Myocardial blood flow was measured with radioactive microspheres. During infusion of serotonin, aortic pressure and heart rate did not change, but myocardial perfusion increased 90 +/- 38% (mean +/- SEM) from a control value of 159 +/- 27 ml/min.100 g. Arteries and arterioles larger than 90 microns constricted in response to serotonin (control 159 +/- 12 microns; percent change -18 +/- 3; range -41 to 10%) while arterioles less than 90 microns dilated to serotonin (control 54 +/- 7 microns; percent change 22 +/- 9; range -10 to 62%). During infusion of vasopressin, aortic pressure and heart rate did not change, and myocardial perfusion decreased 16 +/- 7% (control, 147 +/- 18 ml/min.100 g).(ABSTRACT TRUNCATED AT 250 WORDS)
Amiodarone: biochemical evidence for binding to a receptor for class I drugs associated with the rat cardiac sodium channel.
Authors: Sheldon R S , Hill R J , Cannon N J , Duff H J
Published: June 2012

Amiodarone has multiple pharmacological effects in heart. Electrophysiological data suggest that among its other effects, amiodarone is a sodium channel blocker. Using a radioligand assay, we determined whether amiodarone interacted with a previously described receptor for type I agents associated with the cardiac sodium channel. The radioligand was [3H]batrachotoxinin A 20 alpha-benzoate ([ 3H]BTXB), a toxin that binds to the activated state of the sodium channel. We have previously shown that class I antiarrhythmic drugs inhibit [3H]BTXB binding. The purpose of this study was to assess whether amiodarone and other class III agents interact with this receptor. Amiodarone inhibited [3H]BTXB binding in a dose-dependent fashion, with an estimated IC50 value of 3.6 microM. This IC50 value is similar to reported clinically effective serum concentrations of amiodarone. In contrast to amiodarone, the IC50 values for other class III drugs (bretylium, sotalol, bethanidine, N-acetylprocainamide) were much higher than their therapeutic concentrations and bore no relation to them. Scatchard analysis of [3H]BTXB binding showed that amiodarone reduced the maximal binding for [3H]BTXB; this finding indicates irreversible inhibition or (more likely) allosteric inhibition by amiodarone. The latter agrees with electrophysiological data suggesting that amiodarone binds to inactivated sodium channels. Sodium channel blockade by amiodarone may contribute to its overall electrophysiological effect.
Ventriculoarterial coupling in normal and failing heart in humans.
Authors: Asanoi H , Sasayama S , Kameyama T
Published: June 2012

To investigate coupling between the heart and arterial system in normal subjects and cardiac patients, we determined both the slope of the left ventricular end-systolic pressure-volume relation (ventricular elastance) and the slope of the arterial end-systolic pressure-stroke volume relation (effective arterial elastance) in three groups of subjects: group A, 12 subjects with ejection fraction of 60% or more; group B, seven patients with ejection fraction of 40-59%; and group C, nine patients with ejection fraction of less than 40%. We also determined the left ventricular stroke work, end-systolic potential energy, and the ventricular work efficiency defined as stroke work per pressure-volume area (stroke work + potential energy). In group A, ventricular elastance was nearly twice as large as arterial elastance. This is a condition for a maximal mechanical efficiency. In group B, ventricular elastance was almost equal to arterial elastance. This is a condition for maximal stroke work from a given end-diastolic volume. In group C, ventricular elastance was less than one half of arterial elastance, which resulted in increased potential energy and decreased work efficiency. Thus, the present study suggests that ventriculoarterial coupling is normally set toward higher left ventricular work efficiency, whereas in patients with moderate cardiac dysfunction, ventricular and arterial properties are so matched as to maximize stroke work at the expense of the work efficiency. Neither the stroke work nor the work efficiency is near maximum for patients with severe cardiac dysfunction.
Alterations in cardiac sarcoplasmic reticulum calcium transport in the postischemic "stunned" myocardium.
Authors: Krause S M , Jacobus W E , Becker L C
Published: June 2012

This study examined the possibility that the postischemic mechanical depression observed in the "stunned" myocardium is a result of an alteration in the control of intracellular calcium. Regional myocardial stunning was produced in five open-chest dogs by eight to twelve 5-minute occlusions of the left anterior descending coronary artery, alternated with 10-minute reflow periods and followed by a final 60-minute period of reperfusion. Systolic segment shortening in the postischemic zone, measured by sonomicrometry, fell from 14.9% at baseline to -1.1% at the end of reperfusion. Sarcoplasmic reticulum isolated from stunned myocardium demonstrated a 17% reduction in oxalate-supported 45Ca2+ transport compared with sarcoplasmic reticulum from normal myocardium (0.93 vs. 1.12 mumol Ca2+/mg protein/min, p less than 0.005). There was also a 20% decrease in the maximal activation by Ca2+ of the sarcoplasmic reticulum Ca2+, Mg2+-ATPase (2.46 vs. 1.96 mumol Pi/mg protein/min, p less than 0.005), and a downward shift in the Ca2+-activation curve of the Ca2+, Mg2+-ATPase. These results indicate that myocardial stunning is associated with damage to the calcium-transport system of the sarcoplasmic reticulum. Altered intracellular control may contribute to the inability of the stunned heart to maintain normal mechanical function.
Intermittent coronary sinus occlusion after coronary arterial ligation results in venous retroperfusion.
Authors: Beyar R , Guerci A D , Halperin H R , Tsitlik J E , Weisfeldt M L
Published: June 2012

Coronary sinus occlusion retards necrosis of ischemic myocardium. To test the hypothesis that coronary sinus occlusion induces retrograde venoarterial flow, the coronary arteriovenous pressure gradient and the coronary arterial oxygen saturation were measured distal to a left anterior descending coronary artery ligature in dogs. In parallel, we constructed a mathematical model of known coronary physiology to characterize pressure and flow patterns during coronary sinus occlusion. In dogs, coronary sinus occlusion produced a systolic pressure gradient between the coronary artery and the coronary sinus of -20 +/- 9 mm Hg (higher venous pressure, p less than 0.0001) and a positive diastolic gradient of 3 +/- 5 mm Hg (lower venous pressure p less than 0.01). An average reduction in the oxygen saturation in the ligated coronary artery of 20 +/- 13% was also observed (p less than 0.005) consequent to admixture of venous (desaturated) blood. By graded inflation of the coronary sinus balloon, it was demonstrated that desaturation of arterial blood typically occurs above a coronary sinus systolic pressure of 40-50 mm Hg. The mathematical model indicates the possibility of venoarterial pressure gradients and reversal of flow at the microcirculatory level during coronary sinus occlusion. These studies provide evidence that retrograde flow into the ischemic zone occurs in association with intermittent coronary sinus occlusion. Thus, alternating flow over the ischemic territory may be the mechanism of myocardial salvage during intermittent coronary sinus occlusion.
N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor.
Authors: Stamler J , Mendelsohn M E , Amarante P , Smick D , Andon N , Davies P F , Cooke J P , Loscalzo J
Published: June 2012

Recent evidence suggests that endothelium-derived relaxing factor exhibits properties of nitric oxide. Like nitric oxide, it inhibits platelet function and mediates its effects by elevating intracellular cyclic GMP. In this study we have investigated the role of reduced thiol in the mechanism of action of endothelium-derived relaxing factor on platelets. Bovine aortic endothelial cells were grown on microcarrier beads and pretreated with aspirin before use. Endothelial cells stimulated with bradykinin or exposed to stirred medium expressed a dose-dependent inhibition of platelet aggregation that was potentiated by the reduced thiol, N-acetylcysteine. Endothelial cell-mediated platelet inhibition was attenuated by methylene blue. Inhibition of platelet aggregation by endothelial cells was associated with a rise in platelet intracellular cyclic GMP, an effect that was enhanced by N-acetylcysteine. These data show that 1) the reduced thiol N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor and 2) this effect is associated with increasing intracellular platelet cyclic GMP levels.
Volatile anesthetics block intercellular communication between neonatal rat myocardial cells.
Authors: Burt J M , Spray D C
Published: June 2012

The effects of halothane and ethrane on gap junction-mediated intercellular communication and on membrane excitability were examined in cultured neonatal rat cardiac myocytes using whole-cell voltage-clamp and current-clamp techniques. Excitability was maintained at doses of both anesthetics that reversibly abolished current flow through junctional membranes. The degree of reduction of junctional conductance was a steep function of the dose of anesthetic; complete block occurred at lower aqueous concentrations of halothane than ethrane. The time course for loss of communication was rapid; 90% reduction of initial junctional conductance occurred in less than 15 seconds after exposure to 2 mM halothane or 4 mM ethrane. Recovery of junctional conductance and junctional permeability to intracellularly injected Lucifer yellow was rapid and complete on washout of the anesthetics. As junctional conductance was reduced by halothane or ethrane exposure, unitary conductance of the gap junctional channels remained constant at about 50 pS. Uncoupling by these anesthetics is thus attributable to a decrease in the number of conducting channels rather than to reduction of the channel's unitary conductance. The data are discussed with regard to the possible role of this intercellular communication pathway in the arrhythmias and alterations of conduction velocity and contractility produced by volatile anesthetics.
Direct measurement of changes in intracellular calcium transients during hypoxia, ischemia, and reperfusion of the intact mammalian heart.
Authors: Kihara Y , Grossman W , Morgan J P
Published: June 2012

In studies of ischemia and reperfusion, a major experimental problem has been the inability to measure intracellular ionized calcium ([Ca2+]i) in the intact heart. We have developed a new approach in which the bioluminescent calcium indicator aequorin is used to measure [Ca2+]i in the isolated, coronary-perfused ferret heart. Aequorin is loaded into subepicardial myocytes of the left ventricle, and the signals are recorded simultaneously along with isovolumic left ventricular (LV) pressure at a constant pacing rate. This system shows 1) no attenuation or change of time course of LV pressure development or coronary perfusion pressure after aequorin loading; 2) consistent responses to physiological interventions and drugs; 3) individual aequorin and pressure signals that do not require signal averaging for analysis; and 4) [Ca2+]i levels comparable with those reported in tissue or isolated myocyte cell preparations. During 5 minutes of hypoxia, diastolic [Ca2+]i and LV diastolic pressure increased while the systolic values of both [Ca2+]i and pressure decreased. The peak-to-peak systolic [Ca2+]i versus LV isovolumic pressure relation remained close to the control curve. In contrast, during 3 minutes of global ischemia, LV systolic and diastolic pressures fell rapidly, while [Ca2+]i increased substantially. The [Ca2+]i versus pressure relations for both systole and diastole shifted to the right, indicating desensitization of the contractile apparatus to [Ca2+]i. These results provide evidence that different primary mechanisms determine the systolic and diastolic responses to acute hypoxia versus ischemia. During hypoxia, changes in [Ca2+]i handling probably play a major role, while during ischemia, changes in the Ca2+ sensitivity of the myofilaments appear to be of primary importance in the modulation of contractile dysfunction.
Comparison of the effects of increased myocardial oxygen consumption and adenosine on the coronary microvascular resistance.
Authors: Kanatsuka H , Lamping K G , Eastham C L , Dellsperger K C , Marcus M L
Published: June 2012

The purposes of this study were to determine if coronary dilation secondary to an increase in myocardial oxygen consumption (MVO2) affects the microcirculation in a homogeneous or heterogeneous manner and to determine if comparable degrees of coronary dilation produced by increasing MVO2 or exogenous (intravenous adenosine) or endogenous (intravenous dipyridamole) adenosine have similar effects in the coronary microcirculation. The epimyocardial coronary microcirculation was observed through an intravital microscope by stroboscopic epi-illumination in anesthetized open-chest dogs. Aortic pressure and heart rate were controlled by an aortic snare and atrioventricular sequential pacing, respectively, during experimental procedures. In group 1 (n = 15), coronary arterial microvessel diameters were measured under control condition and during rapid pacing at 300 beats/min, which doubled MVO2. Increases in MVO2 caused heterogeneous vasodilation in coronary arterial microvessels (40-380 microns). There was an inverse relation between control diameter and percent increase in diameter. In group 2 (n = 15) or group 3 (n = 10), adenosine or dipyridamole was infused intravenously to increase myocardial perfusion to the same level as that obtained with rapid pacing. Adenosine and dipyridamole did not change MVO2. Adenosine and dipyridamole also caused heterogeneous vasodilation, but the effects of adenosine and dipyridamole were restricted to arterial microvessels smaller than 150 microns. From these results, we conclude that increases in MVO2 produce widespread but heterogeneous vasodilation, that is, greater dilation in smaller arterial microvessels. Comparable increases in coronary flow produced by increasing MVO2 or endogenous and exogenous adenosine do not produce identical changes in the distribution of coronary microvascular resistance.
Cellular uncoupling can unmask dispersion of action potential duration in ventricular myocardium. A computer modeling study.
Authors: Lesh M D , Pring M , Spear J F
Published: June 2012

Although slow conduction is a requirement for the preparation of sustained reentry, it alone is not sufficient for the initiation of reentry. Additionally, unidirectional block and recovery of excitability distal to the site of block must occur. Thus, a comprehensive description of the electrophysiological determinants of reentry must explain both slow conduction and unidirectional block. Although there is a growing body of research exploring the influence of axial resistivity and anisotropy on slow conduction, somewhat less is known about the relation of axial resistivity to spatial dispersion of action potential duration, a condition favorable to the development of unidirectional block. We hypothesized that when cells are well coupled, local differences in intrinsic action potential duration are not evident and that, as axial resistivity increases, local variation in action potential duration becomes manifest. We tested this hypothesis in a numerical model of electrical propagation in a grid of resistively coupled ionic current sources simulating a sheet of ventricular myocardium. Spatial dispersion of intrinsic action potential duration was simulated by varying the magnitude of the fully activated slow inward conductance in Beeler-Reuter membrane ionic kinetics. By then altering coupling resistance, we showed that dispersion of manifest action potential duration is masked in the setting of normal low-resistance cellular coupling and unmasked by increased axial resistance. When nonuniform anisotropy was simulated, dramatic pacing-site-dependent changes in both the pattern of activation and dispersion of action potential duration were noted. These findings may be important in understanding the mechanism of reentrant tachycardia initiation in the border zone of chronic, healed myocardial infarctions where evidence suggests that abnormal cellular coupling is the predominant electrophysiological derangement. In this study, we have shown, using a detailed ionic current-based model of cardiac electrical propagation, that changes in axial resistivity can modulate how spatial dispersion of intrinsic action potential duration is manifest.