bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in pulmonary blood flow affect vascular response to chronic hypoxia in rats.
Authors: Rabinovitch M , Konstam M A , Gamble W J , Papanicolaou N , Aronovitz M J , Treves S , Reid L
Published: June 2012

We banded the left pulmonary artery in rats to investigate, in the same animal, the effect of both increased and decreased flow on the lung vasculature and to determine how these hemodynamic states modify the structural changes produced by a 2-week exposure to hypobaric hypoxia. In unanesthetized rats, pressures were recorded from the main pulmonary artery and aorta via indwelling catheters, cardiac output was calculated by the Fick principle, and pulmonary and systemic vascular resistance estimated. Technetium-99m macroaggregated albumin was injected and radionuclide activity counted separately over the right and left lungs as a measure of flow. At postmortem, right and left ventricles of the heart were weighed and the lungs injected to permit analysis of arteriograms and morphometric assessment of structural changes in the pulmonary vascular bed. Flow in the left lung was reduced to one-fifth normal in rats with left pulmonary artery bands. In "room air" rats, pressure proximal to the left pulmonary artery band and in the right lung was slightly higher than in nonbanded controls, but not as high as in nonbanded or banded hypoxic rats. Changes in flow and pressure in both lungs of "room air" rats with left pulmonary artery bands were associated with a mild degree of extension of muscle into peripheral pulmonary arteries normally nonmuscular, medial hypertrophy of normally muscular arteries, and reduced arterial density. These three structural changes were present in both lungs of "hypoxic" rats but were much more severe. High flow in the right lungs of "hypoxic rats" with left pulmonary artery bands worsened only the degree of extension. Decreased flow and pressure in the left lungs of these animals prevented both the extension and the medial hypertrophy of hypoxia, but not the severe reduction in arterial density. It seems that the latter may occur as a direct response to low oxygen tension, whereas extension and medial hypertrophy are influenced by altered flow and pressure, respectively.
On the mechanism of lysophosphatidylcholine-induced depolarization of cat ventricular myocardium.
Authors: Clarkson C W , Ten Eick R E
Published: June 2012

Lysophosphatidylcholine, a putative biochemical mediator of ischemia-induced arrhythmias, reduces the resting potential of ventricular muscle. To elucidate possible mechanisms of lysophosphatidylcholine-induced depolarization, we investigated the effects of lysophosphatidylcholine on the electrophysiological properties of cat ventricular muscle, using potassium ion-selective electrodes and conventional microelectrode, current-, and voltage-clamp techniques. Lysophosphatidylcholine (50 microM) decreased the sensitivity of the resting potential to changes in extracellular potassium concentration. Hyperpolarization of lysophosphatidylcholine-depolarized fibers by current-clamp methods failed to reveal two stable levels of resting potential. Depolarizing concentrations of lysophosphatidylcholine did not reduce the potassium equilibrium potential, as determined from the reversal potential of the time-dependent potassium current and measurements of intracellular potassium activity using potassium ion-selective electrodes. Lysophosphatidylcholine induced a depolarizing shift of the reversal potential for steady state current, and did not induce the formation of a negative slope region in the steady state current-voltage or background current-voltage relationships. Lysophosphatidylcholine induced an inward shift and linearization of the background current-voltage relationship negative to -30 mV, and the lysophosphatidylcholine-sensitive component of the background current was an inward rectifier with a reversal potential approximately equal to the potassium equilibrium potential. Lysophosphatidylcholine also reduced the amplitudes of the time-dependent potassium current, slow inward current, and the potassium accumulation and depletion currents. These results indicate that lysophosphatidylcholine-induced depolarization is due, in part, to reduced potassium conductance at voltages near the normal resting potential, and that lysophosphatidylcholine may act as a nonspecific depressant of membrane channels.
Voltage- and use-dependent effects of lidocaine on sodium current in rat single ventricular cells.
Authors: Sanchez-Chapula J , Tsuda Y , Josephson I R
Published: June 2012

We compared the blocking effects of the local anesthetics, lidocaine and benzocaine, on the sodium current, using single rat ventricular cells to obtain further information about the voltage dependence and kinetics of local anesthetic interaction with cardiac sodium channels. We used a hybrid voltage clamp system which employed a suction pipette for passing current and internal perfusion, and a microelectrode for membrane potential measurement. Lidocaine (20 microM) and benzocaine (100 microM) produced qualitatively similar effects on sodium current when test pulses were applied infrequently. Both of these agents decreased the peak sodium current without producing a shift of the current-voltage curve. They did, however, shift the inactivation curves of sodium current to hyperpolarized potentials; the V0.5 was shifted by -9.5 mV for lidocaine and by -5 mV for benzocaine. Lidocaine produced a significant use-dependent effect that was proportional to the duration of the voltage step. Benzocaine produced only minimal use-dependent effects. The characteristics of the lidocaine block suggest that this agent binds preferentially to inactivated sodium channels and that dissociation from resting channels is voltage-dependent. The differences in lipid solubility and molecular weight between lidocaine and benzocaine may explain the differences in their use-dependent blocking effects on sodium current.
Triggered ventricular rhythms in 1-day-old myocardial infarction in the dog.
Authors: El-Sherif N , Gough W B , Zeiler R H , Mehra R
Published: June 2012

Triggered activity developed in depolarized Purkinje fibers (maximum diastolic potential -59.3 +/- 9.9 mV) during superfusion with normal Tyrode's solution in 84% of subendocardial preparations from 1-day-old canine infarct. Triggered activity occurred when a delayed afterdepolarization attained threshold potential and spontaneously terminated after a subthreshold delayed afterdepolarization. Triggered activity was initiated either by stimulated beats or by the background slow Purkinje automaticity. When multiple stimulated beats were required, the amplitude of the afterdepolarization increased and the coupling interval decreased when the stimulation frequency and/or the number of stimulated beats increased. Varying degrees of entrance and exit block around sites of triggered activity were common, and some triggered activity manifested as a parasystolic rhythm. In preparations showing subthreshold delayed afterdepolarizations, both epinephrine (2.5 x 10(-6) M) and increasing [Ca++]o, (from 2.7 to 8.1 mM) increased the amplitude of afterdepolarizations and resulted in triggered activity. On the other hand, verapamil (2.2 x 10(-6) M) resulted in exit block around sites of triggered activity and/or completely suppressed afterdepolarizations and triggered activity. Isochronal mapping of endocardial activation during the initiation and perpetuation of triggered activity elucidated a focal site of origin from Purkinje fibers overlying the infarct and showed no evidence of a circus movement of excitation. The in vitro triggered activity may explain the spontaneous multiform ventricular rhythms seen in the intact heart.
L-palmitylcarnitine and calcium ions act similarly on excitatory ionic currents in avian ventricular muscle.
Authors: Inoue D , Pappano A J
Published: June 2012

Palmitylcarnitine, an amphiphile that accumulates in and leaks from ischemic heart tissue, affected the fast sodium ion channel and the slow calcium channel in avian ventricular muscle. In the presence of 5.4 mM external potassium ion, palmitylcarnitine reduced the maximum rate of rise of the action potential and increased action potential duration at the plateau level without changing the resting potential. Steady state inactivation of the maximum rate of rise, an index of fast sodium ion current, was shifted by 3-6 mV to more positive potentials by palmitylcarnitine. Elevation of external calcium ion to 5.4 mM (normal = 1.8 mM), like palmitylcarnitine, reduced the maximum rate of rise and shifted the voltage at which the action potential was half maximum by 3 mV to more positive potentials without changing the resting potential. Elevated external calcium ion, unlike palmitylcarnitine, reduced the duration of action potentials initiated from a resting potential of -80 mV. Palmitylcarnitine and elevated external calcium ion increased the amplitude, the maximum rate of rise, and duration of calcium ion dependent action potentials recorded in the presence of 25 mM [K+]0 that completely inactivated the fast sodium ion channel. Steady state inactivation of the maximum rate of rise of calcium-dependent action potentials was consistently shifted to more positive potentials by palmitylcarnitine (3 mV) and by elevated external calcium ion (6 mV) when the initial external calcium ion was 0.9 mM. Palmitylcarnitine, like elevated calcium, evoked a positive inotropic effect in the presence of propranolol. The similarity of the effects of palmitylcarnitine (3 X 10(-5) to 3 X 10(-4)M) with those of elevated external calcium is consistent with the hypothesis that palmitylcarnitine, like elevated external calcium, influences sodium and calcium channel operation by an effect on membrane surface charge.
Role of the autonomic nervous system in the release of rat submandibular gland kallikrein into the circulation.
Authors: Rabito S F , Orstavik T B , Scicli A G , Schork A , Carretero O A
Published: June 2012

We have previously demonstrated that the rat submandibular gland releases immunoreactive kallikrein into the circulation. To study the role of the autonomic nervous system in this release, submandibular gland blood flow and kallikrein concentration in peripheral arterial and venous blood from the gland were measured and secretion rates calculated before and after parasympathetic and sympathetic nerve stimulation (8V, 2 msec, 10 Hz) for 1 minute. Immunoreactive kallikrein in plasma was measured by radioimmunoassay, and timed collections of venous outflow were used to measure blood flow. During basal conditions, the unstimulated submandibular gland of the rat released immunoreactive kallikrein into blood at the rate of 0.92 +/- 0.07 ng/min. Parasympathetic stimulation increased blood flow 4-fold (before, 68.5 +/- 8.3 microliters/min; after, 253.5 +/- 76.2; P less than 0.05) without significantly changing immunoreactive kallikrein secretion rate. Sympathetic stimulation produced an 11-fold increase in blood flow (before, 64.9 +/- 9.3 microliters/min; after, 709.6 +/- 97.5; P less than 0.05) and a 57-fold increase in immunoreactive kallikrein secretion rate from the gland (before, 1.05 +/- 0.25 ng/min; after, 59.8 +/- 18.6; P less than 0.05). Sympathetic stimulation also produced a 4-fold increase in the concentration of immunoreactive glandular kallikrein in arterial plasma (before, 15.2 +/- 1.1 ng/ml; after, 56.2 +/- 12.9; P less than 0.05). Pretreatment with phentolamine (1 mg/kg) or prazosin (0.2 mg/kg) blocked the increase in kallikrein secretion rate produced by sympathetic stimulation. These results indicate that the sympathetic nervous system, through activation of alpha 1-adrenoreceptors, controls kallikrein secretion from the submandibular gland into the circulation. Released kallikrein may be responsible for the reactive vasodilation observed in the rat submandibular gland after sympathetic stimulation.
Reduced space constant in slowly conducting regions of chronically infarcted canine myocardium.
Authors: Spear J F , Michelson E L , Moore E N
Published: June 2012

Experiments were performed to test the hypothesis that a reduction in the space constant contributes to slow conduction in the infarcted myocardium of dogs 5-8 days after coronary artery occlusion and reperfusion. Standard microelectrode techniques were used to measure action potential characteristics and conduction velocity parallel to fiber orientation in normal and infarcted ventricular epicardial strips superfused in a tissue bath. The space constants were determined by measuring the decay of the transmembrane steady state electrotonic potential with distance from a suction electrode current source. In eight normal epicardial preparations, conduction velocity ranged between 0.305 and 0.603 m/sec, and the space constant was between 0.712 and 1.202 mm. In 10 infarcted epicardial preparations, in regions of slow conduction (0.032-0.299 m/sec), the space constant was reduced to values between 0.281 and 0.917 mm. Action potential amplitude and maximum rate of depolarization were also reduced in infarcted myocardium. There was a direct relationship between conduction velocity and space constant and maximum rate of depolarization. In infarcted tissues, two types of slow conduction occurred. Slow conduction was uniform down to a velocity of approximately 0.181 m/sec, and a space constant of 0.523 mm. Below these values, conduction was discontinuous with prepotentials associated with the action potential upstroke. Indirect evidence from our studies suggests that a depression in action potential depolarization and an increase in effective axial resistance contribute approximately equally to uniform slow conduction in the infarcted myocardium.
Intracardiac flow patterns in early embryonic life. A reexamination.
Authors: Yoshida H , Manasek F , Arcilla R A
Published: June 2012

Microangiography, using methylene blue injected at eight vitelline vein sites, was performed on 156 developing chick embryos at Hamburger-Hamilton stages 14-22. Two stream patterns were observed. Type A coursed sequentially through the dorsal portion of the sinus venosus, the cranial segments of the primitive atrium and atrioventricular canal, the ventral parts of the primitive ventricle and conus cordis, and, finally, the left branchial arches. Type B coursed through the ventral portion of the sinus venosus, the caudal segments of the primitive atrium and atrioventricular canal, the dorsal parts of the primitive ventricle and conus cordis, and, finally, the right branchial arches. Both streams flowed in parallel fashion in the conus cordis. At Hamburger-Hamilton stages 17-18, the dye stream from the right lateral vitelline vein was chiefly type A, whereas that from the left lateral vitelline vein was type B. At Hamburger-Hamilton stages 19-22, those patterns reversed, i.e., the right lateral vitelline vein stream ran as type B, whereas the left lateral vitelline vein stream assumed type A pattern. The cranial-caudal relationship of the two streams at the primitive atrium and atrioventricular canal is not consistent with the hypothesis that these streams separately expand the future right atrium and left atrium. Their parallel direction at the conus cordis does not support the theory that spiral septation is initiated by two spiral streams. The longitudinal separation of the two streams at and beyond the branchial arches also argues against aortico-pulmonary septation as a consequence of flow streaming. Our observations do not support the traditional flow-molding theory.
Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress.
Authors: Zarins C K , Giddens D P , Bharadvaj B K , Sottiurai V S , Mabon R F , Glagov S
Published: June 2012

The distribution of nonstenosing, asymptomatic intimal plaques in 12 adult human carotid bifurcations obtained at autopsy was compared with the distribution of flow streamline patterns, flow velocity profiles, and shear stresses in corresponding scale models. The postmortem specimens were fixed while distended to restore normal in vivo length, diameter, and configuration. Angiograms were used to measure branch angles and diameters, and transverse histological sections were studied at five standard sampling levels. Intimal thickness was determined at 15 degrees intervals around the circumference of the vessel sections from contour tracings of images projected onto a digitizing plate. In the models, laser-Doppler anemometry was used to determine flow velocity profiles and shear stresses at levels corresponding to the standard specimen sampling sites under conditions of steady flow at Reynolds numbers of 400, 800, and 1200, and flow patterns were visualized by hydrogen bubble and dye-washout techniques. Intimal thickening was greatest and consistently eccentric in the carotid sinus. With the center of the flow divider as the 0 degree index point, mid-sinus sections showed minimum intimal thickness (0.05 +/- 0.02 mm) within 15 degrees of the index point, while maximum thickness (0.9 +/- 0.1 mm) occurred at 161 +/- 16 degrees, i.e., on the outer wall opposite the flow divider. Where the intima was thinnest, along the inner wall, flow streamlines in the model remain axially aligned and unidirectional, with velocity maxima shifted toward the flow divider apex. Wall shear stress along the inner wall ranged from 31 to 600 dynes/cm2 depending on the Reynolds number. Where the intima was thickest, along the outer wall opposite the flow divider apex, the pattern of flow was complex and included a region of separation and reversal of axial flow as well as the development of counter-rotating helical trajectories. Wall shear stress along the outer wall ranged from 0 to -6 dynes/cm2. Intimal thickening at the common carotid and distal internal carotid levels of section was minimal and was distributed uniformly about the circumference. We conclude that in the human carotid bifurcation, regions of moderate to high shear stress, where flow remains unidirectional and axially aligned, are relatively spared of intimal thickening. Intimal thickening and atherosclerosis develop largely in regions of relatively low wall shear stress, flow separation, and departure from axially aligned, unidirectional flow. Similar quantitative evaluations of other atherosclerosis-prone locations and corresponding flow profile studies in geometrically accurate models may reveal which of these hemodynamic conditions are most consistently associated with the development of intimal disease.
Effects of acetylcholine on electrophysiological properties of rabbit cardiac Purkinje fibers.
Authors: Mubagwa K , Carmeliet E
Published: June 2012

The action of acetylcholine (10(-9)-10(-4) M) was investigated in isolated rabbit cardiac Purkinje fibers, using standard microelectrode recording of transmembrane potentials and two-microelectrode voltage clamp technique. In nonstimulated fibers, acetylcholine hyperpolarized the diastolic membrane potential and slowed or suppressed spontaneous activity. The hyperpolarization was more pronounced in low potassium solutions and in depolarized fibers; it was less marked in the presence of cesium (2 X 10(-2) M), and was suppressed by barium (3-5 X 10(-3) M). In stimulated fibers, acetylcholine shortened the action potential duration and shifted the plateau level to more negative values; this effect was influenced little by the stimulation frequency and not by chloride removal from the perfusing solution. In voltage-clamped preparations, acetylcholine shifted the holding current in the outward direction at potentials less negative than EK, while it shifted the current in the inward direction at potentials more negative than EK. The changes induced by acetylcholine were concentration-dependent (apparent KM: 1.5 X 10(-7) M); they were mimicked by carbachol (10(-8)-10(-5) M) and blocked by atropine (10(-8)-10(-7) M). The time course of the effects was biphasic: a maximum was reached in the first minute after addition of acetylcholine; thereafter, the effect decayed to a steady value. On removal of acetylcholine, a transient inversion of the changes produced by acetylcholine was observed, the magnitude of which depended on the acetylcholine concentration used and on the duration of exposure to acetylcholine. This time course was not abolished by pretreatment with physostigmine (10(-6) M), manganese ions (2 X 10(-3) M), or with adrenoceptor blockers [propranolol (2 X 10(-7) M) and/or phentolamine (10(-7)-10(-6) M)]. The results show that rabbit Purkinje fibers are as sensitive to acetylcholine as atrial preparations. The changes produced by acetylcholine are suggestive of an increase in an inward rectifying potassium ion conductance and are mediated by muscarinic receptor stimulation. The secondary decay in the effects of acetylcholine and their inversion on washout can be explained by a desensitization mechanism if it is assumed that the acetylcholine-sensitive channel is already functional in the absence of acetylcholine and is modulated in its conductance and/or open state probability by acetylcholine.
Alpha-adrenergic-mediated reduction in coronary blood flow secondary to carotid chemoreceptor reflex activation in conscious dogs.
Authors: Murray P A , Lavallee M , Vatner S F
Published: June 2012

We examined the late coronary vascular response to carotid chemoreceptor reflex activation in normal, conscious dogs instrumented for the measurement of right main and left circumflex coronary artery blood flows, arterial and right ventricular pressures, and arterial and coronary sinus blood gases and O2 contents. With heart rate held constant by electrical stimulation, and with respiration controlled or allowed to vary spontaneously, carotid chemoreceptor reflex activation (induced by intracarotid nicotine) elicited a striking biphasic coronary vascular response characterized by an early dilation (previously described) and a late constriction. For example, with respiration controlled and with the autonomic nervous system intact, carotid chemoreceptor reflex activation resulted in a late increase in arterial pressure (19 +/- 4%; P less than 0.002), absolute reductions in right main (24 +/- 4%; P less than 0.002), and left circumflex (12 +/- 2%; P less than 0.004) coronary blood flows, and increases in right (62 +/- 13%; P less than 0.002) and left (26 +/- 3%; P less than 0.0001) coronary resistances. This carotid chemoreceptor reflex activation-induced late coronary constriction was also associated with a concomitant increase in myocardial oxygen extraction, i.e., arterial oxygen content remained constant, while coronary sinus oxygen content decreased (19 +/- 6%; P less than 0.04). Neither propranolol nor atropine had any significant effect on the magnitude of the right coronary constriction. However, both the absolute reduction in right coronary blood flow and increase in right coronary resistance were abolished by phentolamine. Furthermore, either total cardiac denervation or adrenalectomy significantly attenuated (P less than 0.01) carotid chemoreceptor reflex activation-induced reductions in right coronary blood flow and increase in right coronary resistance. We conclude that, with autonomic nervous system activity intact, carotid chemoreceptor reflex activation can elicit an absolute reflexly mediated reduction in coronary blood flow in the normal, conscious dog, despite an increase in arterial pressure. The mechanism of this vasoconstriction involves alpha-adrenergic receptor stimulation mediated by both cardiac sympathetic nerves and circulating catecholamines.
Acetyl glyceryl ether phosphorylcholine (AGEPC). A putative mediator of cardiac anaphylaxis in the guinea pig.
Authors: Levi R , Burke J A , Guo Z G , Hattori Y , Hoppens C M , McManus L M , Hanahan D J , Pinckard R N
Published: June 2012

Platelet-activating factor is a novel phospholipid that has been implicated as an important mediator of acute allergic reactions. The intravenous administration of acetyl glyceryl ether phosphorylcholine, a pure, synthetic platelet-activating factor, causes electrocardiographic changes in the rabbit similar to those which are characteristic manifestations of systemic anaphylaxis. To determine whether platelet-activating factor contributes to anaphylactic cardiac dysfunction, we measured platelet-activating factor release from the sensitized guinea pig heart challenged in vitro with specific antigen and compared the resulting cardiac dysfunction with that induced by the injection of acetyl glyceryl ether phosphorylcholine into nonsensitized hearts. The results of these studies document that, during anaphylaxis in the isolated guinea pig heart, a platelet-activating factor is released into the coronary effluent that has physicochemical and functional properties similar to those of acetyl glyceryl ether phosphorylcholine. The intracardiac administration of acetyl glyceryl ether phosphorylcholine (10(-14) to 3 X 10(-9) mol) induced dose-related decreases in left ventricular contractile force (-5 to -85%) and coronary flow (-5 to -85%), as well as impaired atrioventricular conduction. The negative inotropic effect of acetyl glyceryl ether phosphorylcholine also was present in hearts perfused at constant flow. Although, in these hearts, acetyl glyceryl ether phosphorylcholine increased coronary resistance, which may have caused regional shunting and ischemia, it is unlikely that the negative inotropic effect of acetyl glyceryl ether phosphorylcholine was secondary to changes in coronary flow, since acetyl glyceryl ether phosphorylcholine also caused a dose-dependent negative inotropic effect in the electrically paced, noncoronary-perfused left atrium and right ventricular papillary muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
Passive stiffness of isolated cardiac and skeletal myocytes in the hamster.
Authors: Fish D , Orenstein J , Bloom S
Published: June 2012

Single cardiac myocytes and skeletal myocyte fragments, devoid of interstitial collagen but with intact glycocalyx, were prepared by mechanical disaggregation of hamster ventricular myocardium and caudal gracilis muscle, respectively. Passive stiffness was studied by examining the sarcomere length-tension relationship over the approximate Eulerian stress range of 0-20 mN/mm2 for cardiac myocytes and 0-120 mN/mm2 for skeletal myocytes. Creep and stress-relaxation became apparent only when cells were stretched to sarcomere lengths close to, or exceeding, 2.2 micron for the cardiac myocytes, and 2.7 micron for the skeletal myocytes. Stress-relaxation and creep occurred simultaneously, suggesting that the sarcomere is at least one of the structural components responsible for viscoelasticity. The differential strain stiffness constant was calculated from the regression of natural stress [Ln(mN/mm2)] against differential strain [(L-Lo)/Lo] and found to be 7.48 +/- 1.73 for the ventricular myocytes and 5.77 +/- 0.87 for the skeletal myocyte fragments. The natural strain stiffness constant was obtained from the regression of natural stress against natural strain [Ln(L/Lo)]. The natural strain stiffness constant was 30-50% higher than the differential strain constant. The high correlation coefficients obtained for both regressions indicate that the length-tension relationships for these isolated cardiac and skeletal myocytes can be very closely fitted to the single exponential function, sigma = C X exp[K(epsilon)]. The length-tension curves obtained for the skeletal myocyte fragments are qualitatively and quantitatively similar to those obtained by others with intact skeletal muscle. The cardiac myocyte length-tension curves are qualitatively, but not quantitatively, similar to those obtained with cardiac muscle. Isolated ventricular myocytes are stiffer than similarly isolated skeletal myocytes. These findings suggest that cellular structures contribute to myocardial stiffness in the hamster.
Atrophy reversal and cardiocyte redifferentiation in reloaded cat myocardium.
Authors: Thompson E W , Marino T A , Uboh C E , Kent R L , Cooper G
Published: June 2012

We have recently described rapid cardiac atrophy in response to decreased load. The present study was designed to determine whether this atrophy is solely a degenerative response of damaged myocardium or is, instead, an adaptive response of viable myocardium. A discrete portion of cat myocardium was unloaded by severing the chordae tendinae of a single right ventricular papillary muscle. One week later, the muscle was reloaded by attachment of its apex to the ventricular free wall. This allowed the load to be removed and restored without altering the blood supply, innervation, or frequency of contraction of the tissue. In myocardium unloaded for 1 week, the cardiocyte cross-sectional area and the volume densities of mitochondria and myofibrils decreased significantly. Large areas of cytoplasm were devoid of organelles, and the few remaining myofilaments were oriented in a variety of directions rather than longitudinally within the cell. Upon reloading for 1 week, the cardiocyte cross-sectional area, volume density of mitochondria, and ultrastructural organization all returned to normal. The volume density of the myofibrils increased toward control, and they reoriented with respect to the long axis of the cardiocyte. The contractile function of the papillary muscles, which was depressed as early as 1 day after unloading and almost absent at times later than 3 days after unloading, returned to normal after 2 weeks of reloading. This study demonstrates that adult mammalian myocardium responds to unloading with a marked loss of cellular differentiation, organization, and function which is fully reversible with reloading. This plasticity in response to load may well be the basic mechanism responsible for the development and maintenance of normal cardiac structure and function.
Calcium-dependent mechanical oscillations occur spontaneously in unstimulated mammalian cardiac tissues.
Authors: Kort A A , Lakatta E G
Published: June 2012

In quiescent rat ventricular myocardium, bathed in solution of 2 mM Ca++ or less, it has been previously demonstrated that spontaneous microscopic oscillatory cell motion is present and interacts with an incident laser beam to produce scattered light intensity fluctuations which can be monitored to quantify the underlying motion. The present study shows that scattered light intensity fluctuations are not present under any conditions in frog atrial or ventricular preparations, but do occur in each type of mammalian cardiac tissue studied in the unstimulated state. The magnitude of scattered light intensity fluctuations in mammalian tissues varies with species and cellular Ca++ loading. In some tissues, e.g., rabbit or ferret ventricle, either an increase in the Ca++ concentration in the perfusate [( Ca++]e), reduction of perfusate Na+ concentration [( Na+]e), or addition of cardiac glycosides was required to elicit scattered light intensity fluctuations; in other tissues, however, e.g., the canine Purkinje fiber, atria, and ventricle, and guinea pig atria, scattered light intensity fluctuations were present at 2 mM [Ca++]e in the absence of experimental Ca++ loading. Scattered light intensity fluctuations were not affected by LaCl3, or verapamil, and were reversibly abolished by caffeine. When the pCa in the myofilament space is kept constant in detergent "skinned" fibers, scattered light intensity fluctuations are not present during contractile activation. We conclude: that scattered light intensity fluctuations are due to spontaneous intracellular Ca++ oscillations that require a functional sarcoplasmic reticulum; that the potential to exhibit these oscillations is a fundamental property of mammalian excitable cardiac cells; and that, in many mammalian tissues, these oscillations are present in the unstimulated state, even in the absence of experimental perturbations to enhance cell Ca++ loading.
Maximal upstroke velocity as an index of available sodium conductance. Comparison of maximal upstroke velocity and voltage clamp measurements of sodium current in rabbit Purkinje fibers.
Authors: Cohen C J , Bean B P , Tsien R W
Published: June 2012

We compared the maximal upstroke velocity of action potentials in short rabbit Purkinje fibers with sodium currents measured with a two-microelectrode voltage clamp. The number of sodium channels available to open during a sudden depolarization was varied either by blockade with tetrodotoxin or by inactivation with steady depolarizations. In both cases, the maximal upstroke velocity was found to be a very nonlinear measure of the number of available sodium channels. For example, 3 microM tetrodotoxin blocks 85% of the sodium channels, but reduces the maximal upstroke velocity by only 33%. Voltage clamp and upstroke velocity experiments were reconstructed with a computer model of the rabbit Purkinje fiber preparation that was closely based on experimental measurements of passive cable properties and sodium channel characteristics. The simulations indicate that our voltage clamp measurements of sodium current accurately report changes in channel availability, but they also show that the maximal upstroke velocity is a strongly nonlinear index of available sodium conductance. Most of the nonlinearity arises from the activation kinetics of the sodium channels: as the pool of available channels decreases, a greater percentage of those channels activate and contribute inward current at the time of the maximal upstroke velocity. Simulations predict that the maximal upstroke velocity-available sodium conductance relationship would still remain nonlinear at 37 degrees C or under different stimulus conditions that give uniform or continuously propagated action potentials. The nonlinearity may invalidate inferences based on earlier maximal upstroke velocity experiments: the existence of two types of sodium channels with different tetrodotoxin sensitivity, steady state voltage dependence of tetrodotoxin block, voltage range over which sodium channels inactivate, and rapid, then slow recovery of sodium channel availability following a sudden repolarization. All of these conclusions need to be reevaluated.
Input impedance of the pulmonary arterial system in normal man. Effects of respiration and comparison to systemic impedance.
Authors: Murgo J P , Westerhof N
Published: June 2012

Input impedance of the pulmonary arterial system was determined in 10 subjects undergoing elective cardiac catheterization. No cardiovascular or pulmonary disease was found in these patients. In five of the subjects, systemic arterial impedance was also obtained, so that both systems could be compared. Pulmonary and systemic peripheral resistances were 79 +/- 9 dynes sec/cm5 (mean +/- SEM) and 1016 +/- 50 dynes sec/cm5, respectively. Characteristic impedance of the pulmonary circulation was lower than the characteristic impedance of the systemic circulation: 20 +/- 1 dynes sec/cm5 vs. 47 +/- 9 dynes sec/cm5, respectively. Pulmonary pressure and flow spectra for both systems are also presented. The amplitudes of the harmonics of pressure and flow are smaller for the pulmonary circulation, which is consistent with the lower pressures and more rounded waveforms of the normal pulmonary circulation. In all 10 subjects, input impedance of the pulmonary system was examined during both the inspiratory and expiratory phases of respiration. There was no difference between inspiration and expiration in either pulmonary vascular resistance (77 +/- 10 dynes sec/cm5 vs. 80 +/- 9 dynes sec/cm5, respectively), characteristic impedance (20 +/- 1 dynes sec/cm5 vs. 20 +/- 1 dynes sec/cm5) or in the overall impedance spectrum. Quiet respiration, thus, has no effect on the pulmonary arterial load, and changes in pressure and flow must result from alterations in right ventricular performance.
Augmented responses to vasoconstrictor stimuli in hypercholesterolemic and atherosclerotic monkeys.
Authors: Heistad D D , Armstrong M L , Marcus M L , Piegors D J , Mark A L
Published: June 2012

We examined effects of hypercholesterolemia and atherosclerosis on vasoconstrictor responses to norepinephrine and serotonin. Responses were compared in normal, atherosclerotic, and hypercholesterolemic but non-atherosclerotic cynomolgus monkeys. The hindlimb was perfused at constant flow so that changes in perfusion pressure indicated changes in vascular resistance. We measured the pressure gradient from the iliac to the dorsal pedal artery so that responses of the large artery segment could be determined. Serotonin decreased total hindlimb resistance in normal and hypercholesterolemic monkeys, but increased total resistance in atherosclerotic monkeys. There was a greater than 10-fold increase in constrictor responses of large arteries to serotonin in atherosclerotic monkeys, compared with normal and hypercholesterolemic monkeys. In contrast, we found that vasoconstrictor responses to norepinephrine are normal in atherosclerotic monkeys and increased in hypercholesterolemic monkeys prior to development of atherosclerosis. Hypercholesterolemia augmented responses of small vessels to norepinephrine. We conclude that, during early stages of hypercholesterolemia in cynomolgus monkeys, vasoconstrictor responses to norepinephrine are increased in small vessels. At a later stage, as atherosclerosis develops, responses to norepinephrine return to normal, but vasoconstrictor effects of large arteries to serotonin are greatly potentiated.
Evaluation of left ventricular contractile performance utilizing end-systolic pressure-volume relationships in conscious dogs.
Authors: Sodums M T , Badke F R , Starling M R , Little W C , O'Rourke R A
Published: June 2012

The relationship between left ventricular end-systolic pressure and volume has been proposed as a model of left ventricular contraction which may be useful for quantifying inotropic state independent of preload and afterload. Although the model has been well-validated in isolated hearts, systematic evaluation in conscious animals with an intact peripheral circulation has been limited. Accordingly, we derived end-systolic pressure-volume relationships in twelve conscious dogs, chronically instrumented to measure left ventricular pressure and dimensions from endocardial ultrasonic crystals in three orthogonal axes. We examined the linearity of the end-systolic pressure-volume relationship, its response to alterations of inotropic state and the peripheral circulation, and the influence of beta-adrenergic reflexes. End-systolic pressure-volume relationships were constructed by linear regression of end-systolic pressure-volume coordinates produced by transient inferior vena caval occlusions during atrial pacing. The relations were highly linear; of 127 inferior vena caval occlusions, the correlation coefficient was 0.96 +/- 0.05 (mean +/- SD). The slope of the end-systolic pressure-volume relationship was not significantly altered either by a moderate resistive afterload induced by angiotensin II infusion, or by a moderate increase in preload produced by dextran, but was increased from 4.7 +/- 2.3 to 6.5 +/- 2.2 mm Hg/ml (P less than 0.05) in response to the positive inotropic stimulus of dobutamine. The volume intercept at zero end-systolic pressure was unaffected by dextran or dobutamine, but was decreased from 12 +/- 8 to 5 +/- 11 ml (P less than 0.01) by angiotensin II infusion, indicating a leftward shift of the end-systolic pressure-volume relationship.(ABSTRACT TRUNCATED AT 250 WORDS)
In vivo 31P nuclear magnetic resonance measurements in canine heart using a catheter-coil.
Authors: Kantor H L , Briggs R W , Balaban R S
Published: June 2012

We have developed a new method of obtaining high resolution 31P nuclear magnetic resonance spectra from canine heart without the need for major surgery. This is done by passing an elliptical nuclear magnetic resonance receiver coil through a peripheral blood vessel into the right or left ventricle. This technique enables spectra to be obtained from a defined region of myocardium in less than 7 minutes (for the right ventricle) with a signal:noise ratio of greater than 9:1. With this catheter-coil, useful cardiac metabolic information will be obtainable, not only from specified regions of the heart, but also from various layers of myocardium.
Voltage-dependent block of calcium channel current in the calf cardiac Purkinje fiber by dihydropyridine calcium channel antagonists.
Authors: Sanguinetti M C , Kass R S
Published: June 2012

We have investigated the mechanisms of blockade of calcium channel current by the dihydropyridines, e.g. nisoldipine, nitrendipine, and nicardipine. Membrane current was recorded in isolated calf Purkinje fibers using a two-microelectrode voltage-clamp technique, and voltage protocols were designed to identify voltage- and use-dependent block by these compounds systematically. Our results show that calcium channel blockade by dihydropyridine derivatives is strongly modulated by membrane potential. Block is more pronounced when current is measured from depolarized holding potentials, but in contrast to verapamil, this voltage-dependent block occurs in the absence of repetitive depolarizations. Use-dependent block by dihydropyridines is observed at pulse frequencies greater than 1 Hz. Our results suggest that dihydropyridines bind preferentially to the inactivated state of the calcium channel, and that the development of use-dependent block is related to the ionization constants of the compounds. Furthermore, binding is approximately one thousand times stronger to inactivated channels than to resting channels. This state-dependent difference in binding affinities may account for the previously reported contrast between electrophysiological and binding data for these compounds.
Vasopressin causes endothelium-dependent relaxations of the canine basilar artery.
Authors: Katusic Z S , Shepherd J T , Vanhoutte P M
Published: June 2012

The effect of synthetic 8-arginine vasopressin (vasopressin) was studied in isolated canine basilar, left circumflex coronary, and femoral arteries of the dog. Vascular rings with and without endothelium were suspended for isometric tension recording in physiological salt solution. The removal of the endothelium was confirmed by the absence of relaxations induced by either thrombin (basilar arteries) or acetylcholine (coronary and femoral arteries). In the basilar artery, vasopressin induced concentration-dependent inhibition of myogenic tone. In basilar and coronary arteries, the hormone caused concentration-dependent relaxations during contractions evoked by prostaglandin F2 alpha. In femoral arteries, vasopressin caused contraction. After removal of the endothelium, the inhibitory responses to vasopressin were abolished in basilar arteries and significantly reduced in left circumflex coronary arteries. The contractions of femoral arteries were not affected by endothelium removal. The V1-vasopressinergic antagonist d(CH2)5Tyr(Me)AVP prevented the inhibitory response to vasopressin, but did not alter endothelium-dependent relaxations of basilar arteries caused by adenosine diphosphate. These results demonstrate that the endothelial cells mediate relaxation induced by vasopressin via specific V1-vasopressinergic receptors.
Temporal changes in he sympathetic-parasympathetic interactions that occur in the perfused canine atrium.
Authors: Furukawa Y , Levy M N
Published: June 2012

In the isolated, blood-perfused, canine right atrium, stimulation of the intramural autonomic nerves evoked negative chronotropic and inotropic responses. The responses were not maintained at a constant level during tonic neural stimulation, but they tended to drift back toward their control levels. These time-dependent changes in the cardiac responses were more pronounced the higher the frequency of stimulation. After the beta-adrenergic receptors were blocked in half of the preparations, the negative cardiac responses to autonomic neural stimulation were more pronounced, but the time dependency of those responses was less. After the muscarinic receptors were blocked in the other half of the preparations, only positive responses to neural stimulation were observed. These responses faded significantly at a high stimulation frequency (30 Hz), but not at a lower frequency (5 Hz). The cardiac responses to combined autonomic neural stimulation were substantially more negative than the algebraic sum of the individual responses to sympathetic and parasympathetic stimulation. The extent of this interaction was most pronounced near the beginning of stimulation, but it became less pronounced as the stimulation progressed. Hence, the cardiac sympathetic-parasympathetic interactions change appreciably with time during a continuous train of autonomic neural stimulation.
Significance of quiescent smooth muscle migration in the injured rat carotid artery.
Authors: Clowes A W , Schwartz S M
Published: June 2012

Cellular accumulation in the intima of injured artery has generally been attributed to smooth muscle cell proliferation. Since smooth muscle cells in normal artery are found mainly in the media, migration of smooth muscle cells into the intima has been considered a necessary prerequisite for subsequent myointimal thickening. The nondividing medial cells would appear to have no role in the reparative process. We have investigated in the rat ballooned carotid the possibility that nondividing cells might also contribute to injury-induced intimal thickening. All proliferating smooth muscle cells were labeled by 3H-thymidine given by continuous intraperitoneal infusion. The amounts of 3H-thymidine used were not toxic and did not inhibit smooth muscle cell proliferation. Autoradiograms performed on histological cross-sections showed a progressive decrease in the fraction of unlabeled cells at 3, 7, and 14 days after carotid injury. However, the actual number of nondividing cells remained constant. The calculated growth fraction for the 14-day period was 40%. A substantial number of unlabeled cells was observed in the intima. These data have led us to conclude that only a small fraction of smooth muscle cells in an artery proliferate in response to the injury stimulus, and do so shortly after injury, or not at all. Furthermore, nondividing, as well as proliferating smooth muscle cells, can migrate and contribute, in a substantial way, to the increase in intimal smooth muscle cell number.
Possible mechanisms of ventricular arrhythmias elicited by ischemia followed by reperfusion. Studies on isolated canine ventricular tissues.
Authors: Ferrier G R , Moffat M P , Lukas A
Published: June 2012

The purpose of this study was to develop an isolated tissue model in which arrhythmic activity could be generated in response to conditions encountered in ischemia followed by reperfusion, and in which intracellular recordings could be used to identify and study arrhythmogenic mechanisms. Isolated canine Purkinje fiber-papillary muscle preparations were superfused with modified Tyrode's solutions. Tissues were exposed to conditions observed in ischemia (hypoxia, acidosis, elevated lactate, zero substrate for 40 minutes). Superfusion with Tyrode's solution of "normal" composition was then reinstituted. Transmembrane recordings from Purkinje and muscle tissues were made, using standard microelectrode techniques. Ischemic conditions caused loss of membrane potential, shortened action potentials, depressed excitability, and progressive bidirectional conduction block between muscle and Purkinje tissues. Spontaneous activity, probably reentrant in origin, was observed. Return to nonischemic conditions resulted in a multiphasic sequence of responses in Purkinje fibers: prompt hyperpolarization, progressive depolarization to unresponsiveness, and final repolarization to control. The depolarization phase was accompanied by oscillatory afterpotentials which initiated extrasystoles. Final repolarization included a phase of automaticity at low membrane potentials, during which Purkinje tissue functioned as a parasystolic focus. Elevation of potassium concentration to 10 mM during the ischemic period did not alter the sequence of electrophysiological events during ischemic conditions or upon reperfusion. This study demonstrates that ischemia followed by reperfusion elicits an orderly sequence of electrophysiological events which may constitute important mechanisms of arrhythmia in vivo.