bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracellular pH of canine subendocardial Purkinje cells surviving in 1-day-old myocardial infarcts.
Authors: Dresdner K P , Kline R P , Wit A L
Published: June 2012

A large reduction of intracellular potassium activity in depolarized subendocardial Purkinje fibers 24 hours after coronary artery ligation is accompanied by a much smaller increase in intracellular sodium activity. Similar intracellular ionic changes also occur during acute ischemia in ventricular muscle and are consistent with mechanisms based on intracellular acidification, which is known to occur in acutely ischemic muscle. To determine if canine subendocardial Purkinje cells 24 hours after myocardial infarction are also acidic, their intracellular pH, surface pH, and maximum diastolic potential (MDP) were measured with double-barrel pH-sensitive microelectrodes and compared with control fibers in noninfarcted hearts. In 12 mM bicarbonate Tyrode's solution (5% CO2-95% O2), the average intracellular pH was not significantly different (p greater than 0.25) for normal tissue (6.83 +/- 0.08, SD, MDP = -83.5 +/- 3.2 mV), for depolarized Purkinje fibers in infarct preparations during the first hour of superfusion (6.88 +/- 0.11, MDP = -47.8 +/- 11.8 mV), and for partially recovered Purkinje fibers in infarcts averaged over the third to sixth hours of superfusion (6.85 +/- 0.12, MDP = -74.5 +/- 9.6 mV). In 24 mM bicarbonate Tyrode's solution, infarct intracellular pH during both the first hour of superfusion (7.08 +/- 0.13, MDP = -57.6 +/- 15.7 mV) and during the third to sixth hours of superfusion (7.06 +/- 0.15, MDP = -76.5 +/- 9.6 mV) was significantly alkaline (p less than 0.0005) compared with average control pH (6.92 +/- 0.12, MDP = 82.1 +/- 3.7 mV). In 24 mM bicarbonate Tyrode's solution, the intracellular pH did vary with MDP (0.0032 pH units/mV). During superfusion of normal Purkinje fibers with hypoxic Tyrode's solution, intracellular pH acidified by 0.22 pH units as they depolarized. Therefore, intracellular acidification does not seem to be a cause of the depolarization of subendocardial Purkinje cells 24 hours after myocardial infarction.
Fractal nature of regional myocardial blood flow heterogeneity.
Authors: Bassingthwaighte J B , King R B , Roger S A
Published: June 2012

Spatial variation in regional flows within the heart, skeletal muscle, and in other organs, and temporal variations in local arteriolar velocities and flows is measurable even with low resolution techniques. A problem in the assessment of the importance of such variations has been that the observed variance increases with increasing spatial or temporal resolution in the measurements. This resolution-dependent variance is now shown to be described by the fractal dimension, D. For example, the relative dispersion (RD = SD/mean) of the spatial distribution of flows for a given spatial resolution, is given by: RD(m) = RD(mref).[m/mref]1-Ds where m is the mass of the pieces of tissue in grams, and the reference level of dispersion, RD(mref), is taken arbitrarily to be the RD found using pieces of mass mref, which is chosen to be 1 g. Thus, the variation in regional flow within an organ can be described with two parameters, RD(mref) and the slope of the logarithmic relationship defined by the spatial fractal dimension Ds. In the heart, this relation has been found to hold over a wide range of piece sizes, the fractal Ds being about 1.2 and the correlation coefficient 0.99. A Ds of 1.2 suggests moderately strong correlation between local flows; a Ds = 1.0 indicates uniform flow and a Ds = 1.5 indicates complete randomness.
Slow recovery of excitability and the Wenckebach phenomenon in the single guinea pig ventricular myocyte.
Authors: Delmar M , Michaels D C , Jalife J
Published: June 2012

The cellular mechanisms of Wenckebach periodicity were investigated in single, enzymatically dissociated guinea pig ventricular myocytes, as well as in computer reconstructions of transmembrane potential of the ventricular cell. When depolarizing current pulses of the appropriate magnitude were delivered repetitively to a well-polarized myocyte, rate-dependent activation failure was observed. Such behavior accurately mimicked the Wenckebach phenomenon in cardiac activation and was the consequence of variations in cell excitability during the diastolic phase of the cardiac cycle. The recovery of cell excitability during diastole was studied through the application of single test pulses of fixed amplitude and duration at variable delays with respect to a basic train of normal action potentials. The results show that recovery of excitability is a slow process that can greatly outlast action potential duration (i.e., postrepolarization refractoriness). Two distinct types of subthreshold responses were recorded when activation failure occurred: one was tetrodotoxin- and cobalt-insensitive (type 1) and the other was sensitive to sodium-channel blockade (type 2). Type 1 responses, which were commonly associated with the typical structure of the Wenckebach phenomenon (Mobitz type 1 block), were found to be the result of the nonlinear conductance properties of the inward rectifier current, IK1. Type 2 sodium-channel-mediated responses were associated with the so-called "millisecond Wenckebach." These responses may be implicated in the mechanism of Mobitz type 2 rate-dependent block. Single-cell voltage-clamp experiments suggest that variations in excitability during diastole are a consequence of the slow deactivation kinetics of the delayed rectifier, IK. Computer simulations of the ventricular cell response to depolarizing current pulses reproduced very closely all the response patterns obtained in the experimental preparation. It is concluded that postrepolarization refractoriness and Wenckebach periodicity are properties of normal cardiac excitable cells and can be explained in terms of the voltage dependence and slow kinetics of potassium outward currents. The conditions for the occurrence of intermittent activation failure during diastole will depend on the frequency and magnitude of the driving stimulus.
Cardiac anaphylaxis. Complement activation as an amplification system.
Authors: del Balzo U , Polley M J , Levi R
Published: June 2012

Complement is activated, and C3a and C5a anaphylatoxins are generated during hypersensitivity reactions clinically associated with cardiopulmonary collapse. The administration of C3a or C5a to nonsensitized isolated guinea pig hearts mimics the events caused by antigen challenge of sensitized hearts (i.e., cardiac anaphylaxis) in the absence of complement. Thus, complement-derived anaphylatoxins may participate in immediate hypersensitivity reactions in which the heart is a target organ. To assess the contribution of complement activation and anaphylatoxin generation to cardiac dysfunction, we have elicited anaphylaxis in isolated guinea pig hearts in the presence of complement and found that the ensuing dysfunction is markedly enhanced. This amplification is most likely attributable to anaphylatoxin formation because 1) inactivation of C3 or selective C3 depletion, i.e., the loss of the component responsible for the formation of the anaphylatoxins C3a and C5a, prevents complement-induced exacerbation of cardiac anaphylaxis, whereas reconstitution with C3 and C5, or even only C3, restores it; in fact, the greater the C3 content at the time of antigen challenge, the more intense the anaphylactic crisis; and 2) the severity of cardiac anaphylaxis is markedly reduced by preexposure to C3a, and this reduction is directly related to the dose of C3a injected and to the amount of endogenous cardiac histamine depleted by C3a before antigen challenge. Complement-derived anaphylatoxins appear to promote the same mediator release that has been initiated by the antigen-antibody reaction; thus, complement activation functions as an amplification system in cardiac anaphylaxis.
Inhibition of Na-Ca exchange by general anesthetics.
Authors: Haworth R A , Goknur A B , Berkoff H A
Published: June 2012

General anesthetics, typically octanol, were found to inhibit the influx of calcium in isolated sodium-loaded adult rat heart cells, using 45Ca, quin 2, or indo 1. Inhibition by octanol, like inhibition by sodium, was competitive with calcium. Octanol and sodium together inhibited calcium influx synergistically. At physiological levels of extracellular calcium and sodium, the EC50 was 177 +/- 37 microM for octanol and 48 +/- 5 microM for decanol. These values are threefold to fourfold larger than those reported to cause 50% loss of righting reflex in tadpoles, a measure of their anesthetic effectiveness. We conclude that general anesthetics inhibit Na-Ca exchange at the sarcolemma. We suggest that octanol inhibits like sodium, and the synergism stems from the cooperativity of sodium inhibition at the binding and regulatory sites of the exchanger. Insofar as Na-Ca exchange may regulate inotropy, the inhibition of Na-Ca exchange by general anesthetics could contribute to their negative inotropic effect.
Ca2+ uptake by cardiac sarcoplasmic reticulum from patients with idiopathic dilated cardiomyopathy.
Authors: Movsesian M A , Bristow M R , Krall J
Published: June 2012

We measured Ca2+ uptake by sarcoplasmic reticulum prepared from left ventricular myocardium obtained from six nonfailing human hearts and nine excised hearts from patients with class IV idiopathic dilated cardiomyopathy. Ca2+ uptake had a Vmax of 593 +/- 82 nmol/mg-min, a K0.5 of 0.68 +/- 0.07 microM, and an nHill of 1.7 +/- 0.1 in the nonfailing hearts. The corresponding values in the excised failing hearts were 593 +/- 36 nmol/mg-min, 0.63 +/- 0.03 microM, and 1.6 +/- 0.1. The beta-receptor density in crude sarcolemma prepared from left ventricular myocardium was 110.0 +/- 15.3 fmol/mg in the unmatched donors and 52.1 +/- 4.5 fmol/mg in the excised failing hearts. These results suggest that abnormal Ca2+ handling in idiopathic dilated cardiomyopathy in humans is not the result of any intrinsic alteration of Ca2+ uptake by sarcoplasmic reticulum.
Amantadine-induced afterpotentials and automaticity in guinea pig ventricular myocytes.
Authors: Hiraoka M , Hirano Y , Kawano S , Fan Z , Sawanobori T
Published: June 2012

The ionic mechanisms of amantadine-induced changes in membrane potential and automatic activity in guinea pig ventricular myocytes were studied using the suction-pipette whole-cell clamp method. While 25-100 microM amantadine decreased the action potential amplitude and duration, 200 and 400 microM amantadine lengthened the action potential duration and decreased the maximum diastolic potential with an appearance of diastolic depolarization and automaticity. In the presence of 25-100 microM amantadine, the preparations developed an afterpotential due to incomplete repolarization and a delayed afterdepolarization that eventually brought about triggered automaticity. The former type of afterpotential was abolished by tetrodotoxin (TTX) and the latter by Co2+. Spontaneous activity from the diastolic depolarization was also abolished by Co2+ but not by Cs+. Amantadine suppressed the calcium current to as much as half of the control at the concentrations used (25-200 microM). The drug also produced a depression of the inward rectifier K+ current. The outward current showing time-dependent decay was activated at the plateau voltages by concentrations lower than 100 microM, whereas the delayed outward K+ current was depressed by the drug in a concentration-dependent manner at more positive potentials. Amantadine activated the TTX-sensitive and TTX-insensitive inward currents on repolarization from depolarized states, without producing the transient inward current. These results indicate that the amantadine-induced diastolic depolarization and afterpotentials are caused by changes in multiple ionic currents and that, therefore, the drug can be used as a unique model for the study of arrhythmogenesis.
Changes in phosphoinositide turnover in isolated guinea pig hearts stimulated with isoproterenol.
Authors: Edes I , Solaro R J , Kranias E G
Published: June 2012

The incorporation of 32Pi into phospholamban, troponin I, phosphatidylinositols, and inositol trisphosphates was studied in Langendorff-perfused guinea pig hearts stimulated with isoproterenol. Hearts were perfused with Krebs-Henseleit buffer containing [32P]Pk and freeze-clamped at different times during the positive inotropic response. Exposure of the hearts to 0.1 microM isoproterenol for up to 1 minute was associated with significant (up to threefold) increases in phospholamban and troponin I phosphorylation, but there was no significant increase in 32P incorporation into phospholipids. However, longer exposure (2 minutes or more) to isoproterenol was associated with increases in the degree of 32P labeling of phosphatidylinositols and phosphatidic acid. Examination of 32P labeling of inositol trisphosphates in the same hearts revealed that the radioactivity associated with these compounds decreased with time. The decreases were significant at times of exposure of 2 minutes or longer to beta-adrenergic stimulation. The tissue levels of the inositol 1,4,5-trisphosphate isoform were also measured in hearts perfused with isoproterenol for 3 minutes, and they were found to be significantly lower compared with values obtained in control hearts. The effects of isoproterenol on 32P incorporation into phospholipids and proteins were observed in the presence of prazosin, and they were completely abolished by the beta-receptor blocker propranolol. Examination of the phosphoinositide-specific phospholipase C activity in the perfused hearts revealed that isoproterenol stimulation was associated with a decrease in the membrane-associated enzymatic activity at physiological calcium concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Change of residual strains in arteries due to hypertrophy caused by aortic constriction.
Authors: Fung Y C , Liu S Q
Published: June 2012

The stress and strain that remain in an organ when the external load is removed are called residual stress and strain. They can be revealed by cutting up the organ in such a way as to reveal the zero-stress configuration. The function of the organ depends on the residual strain. For a blood vessel, the zero-stress configuration is very different from that of the no-load condition, and it changes over time when the physical stress acting on the vessel is changed. Data on rat aorta are presented. Physical changes were obtained by constricting the aorta at the celiac trunk level with a band of metal. Banding causes an increase of blood pressure and hypertrophy of the vessel in the upper body and a transient decrease of blood pressure in the lower body. If the aorta is cut transversely into rings and each ring is cut radially, it will open up into a noncircular arc, which may be characterized by its opening angle. It is shown that the opening angle varies systematically along the aorta and that it changes significantly together with changes of blood pressure and hypertrophy. In the ascending aorta, the opening angle increased from 171 degrees and to 214 degrees in 4 days after banding, then decreased gradually to an asymptotic value of 126 degrees in 40 days. At other sections, the swing of opening angle is smaller. The implications are discussed.
Significance of myocardial alpha- and beta-adrenoceptors in catecholamine-induced cardiac hypertrophy.
Authors: Zierhut W , Zimmer H G
Published: June 2012

The role of alpha- and beta-adrenoceptors in the development of catecholamine-induced cardiac hypertrophy in vivo was investigated. Rats received a constant intravenous infusion of norepinephrine or sodium chloride (control) for 3 days. The norepinephrine infusion was combined with the alpha-blocker prazosin, the beta-blocker metoprolol, or both blockers. For modulation of the work load of the heart, the calcium channel blocker verapamil was added to the norepinephrine infusion. A further group of animals was treated with the alpha-adrenergic stimulator norfenephrine, which also was combined with prazosin or verapamil. Norepinephrine induced significant increases in mean aortic pressure, left ventricular dP/dtmax, heart rate, and total peripheral resistance. The left ventricular weight/body weight ratio was significantly elevated and was accompanied by an increase in the RNA concentration and the RNA/DNA ratio. Prazosin as well as metoprolol partially antagonized the increase in left ventricular weight and RNA concentration, whereas simultaneous prazosin and metoprolol treatment prevented the norepinephrine-induced alterations. Although combination of norepinephrine with verapamil resulted in considerable reduction of all functional parameters, the development of cardiac hypertrophy and the elevated RNA/DNA ratio were not significantly influenced. Stimulation of alpha-receptors with norfenephrine elicited an increase in total peripheral resistance and in left ventricular weight, which was abolished by prazosin. Verapamil did not affect the norfenephrine-induced cardiac hypertrophy, although it normalized essentially all functional parameters. Thus, the rapid development of cardiac hypertrophy in the norepinephrine model seems to be directly mediated by stimulation of myocardial alpha- and beta-adrenoceptors rather than by hemodynamic changes.
Abnormal subendocardial blood flow in pressure overload hypertrophy is associated with pacing-induced subendocardial dysfunction.
Authors: Nakano K , Corin W J , Spann J F , Biederman R W , Denslow S , Carabello B A
Published: June 2012

To detect the functional significance of subendocardial hypoperfusion in the pressure-overloaded left ventricle, we studied subendocardial and subepicardial function and subendocardial and subepicardial blood flow simultaneously in seven dogs with left ventricular hypertrophy (left ventricle/body weight ratio, 7.2 g/kg) produced by chronic aortic banding. Seven normal dogs served as controls. Subendocardial and subepicardial segment lengths were measured by ultrasonic dimension gauges, and myocardial blood flow was measured with radioactive microspheres. Atrial pacing (180-200 beats/min for 5 minutes) was used to produce a chronotropic stress. In dogs with left ventricular hypertrophy, the subendocardial blood flow failed to increase during pacing compared with the baseline state (1.21 +/- 0.17 vs. 1.22 +/- 0.17 ml/min/g). Subendocardial shortening fraction deteriorated with pacing stress (before pacing, 30.6 +/- 3.9%; after pacing, 24.2 +/- 3.7%; p less than 0.001). In controls, subendocardial blood flow increased from 1.32 +/- 0.19 to 1.80 +/- 0.19 ml/min/g during pacing, and shortening fraction was preserved (before pacing, 25.5 +/- 3.9%; after pacing, 25.9 +/- 3.3%). Subepicardial blood flow in dogs with hypertrophy increased from 1.54 +/- 0.24 to 2.32 +/- 0.34 ml/min/g, and subepicardial shortening fraction was maintained (before pacing, 10.4 +/- 1.0%; after pacing, 10.5 +/- 1.2%) as it was in controls (subepicardial blood flow, from 1.27 +/- 0.18 to 2.12 +/- 0.17 ml/min/g; shortening fraction, from 16.6 +/- 2.5% to 15.5 +/- 2.2%). We conclude that, with pacing stress in pressure-overload hypertrophy, subendocardial blood flow failed to increase. This abnormality corresponded with a deterioration in subendocardial contractile function.
Activation patterns in healed experimental myocardial infarction.
Authors: Kadish A , Balke C W , Levine J F , Moore E N , Spear J F
Published: June 2012

The maximum amplitude of vector loops formed by summing orthogonally recorded bipolar electrograms has been shown to reflect the direction of activation in cardiac muscle. To investigate whether components of vector loops could provide information about different activation directions in local areas of myocardium, we correlated "instantaneous vectors" with isochronal activation patterns in an in vitro preparation of experimental myocardial infarction. In thirteen 3 mm x 3 mm regions studied (from 11 tissues), at least 16 microelectrode impalements with a minimum density of 0.8 mm between sites were made. In seven situations in which notched, irregular, and prolonged duration electrograms were present, vector loops pointed in the same general direction throughout their entire time course. In these preparations, microelectrode impalements demonstrated only a single major direction of activation. In five of six areas in which multidirectional vector loops were present, two or more separate local directions of activation corresponded to the directions of the vector loop. Instantaneous vectors were then used to analyze propagation patterns in vivo in 10 animals with 2-4-week-old experimental myocardial infarction. Of 150 sites in the 10 animals, 13% contained more than one major local direction of activation. In 11 markedly abnormal sites, electrograms were recorded during pacing from four sites around the recording probe. When comparing electrogram characteristics from the four sites, a mean difference of 5.9 mV in electrogram amplitude and 19.1 msec in electrogram duration (coefficient of variation, 27% for amplitude and 22% for duration) was found. In only two of the 11 sites was it found that the same number of activation directions occurred from all pacing sites. We conclude: 1) Instantaneous components of vector loops accurately represent local directions of cardiac activation at differing times. 2) Most areas of experimental myocardial infarction have only one major direction of activation despite the presence of abnormal electrograms. 3) In some regions, however, two major local directions of activation can be identified within a relatively local area. 4) Geometric activation patterns in experimental myocardial infarction are markedly dependent on initial activation direction.
Correlation between cytosolic free calcium, contracture, ATP, and irreversible ischemic injury in perfused rat heart.
Authors: Steenbergen C , Murphy E , Watts J A , London R E
Published: June 2012

The relations between ATP depletion, increased cytosolic free calcium concentration [( Cai]), contracture development, and lethal myocardial ischemic injury, as evaluated by enzyme release, were examined using 19F nuclear magnetic resonance to measure [Cai] in 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid (5F-BAPTA)-loaded perfused rat hearts. Total ischemia at 37 degrees C was induced in beating hearts, potassium-arrested hearts, magnesium-arrested hearts, and hearts pretreated with 0.9 microM diltiazem to reduce but not abolish contractility. In the beating hearts, time-averaged [Cai], which is intermediate between the systolic and the basal [Cai], was 544 +/- 74 nM. In contrast, in the potassium- and magnesium-arrested hearts, the time-averaged values are lower than in beating hearts (352 +/- 88 nM for potassium arrest, 143 +/- 22 nM for magnesium arrest). During ischemia, ATP depletion, contracture, and a rise in [Cai] are delayed by cardiac arrest, but all occur more rapidly in the potassium-arrested hearts than in the magnesium-arrested hearts. The diltiazem-treated hearts were generally similar to the magnesium-arrested hearts in their response to ischemia. Under all conditions, contracture development was initiated after tissue ATP had fallen to less than 50% of control; invariably, there was a progressive rise in [Cai] during and following contracture development. Reperfusion with oxygenated perfusate shortly after peak contracture development resulted in a return of [Cai] to its preischemic level, resynthesis of creatine phosphate, no significant enzyme release, and no substantial loss of 5F-BAPTA from the heart. The data demonstrate that an increase in [Cai] precedes lethal myocardial ischemic injury. This rise in [Cai] may accelerate the depletion of cellular ATP and may directly contribute to the development of lethal ischemic cell injury.
Cellular mechanism of the functional refractory period in ventricular muscle.
Authors: Ramza B M , Tan R C , Osaka T , Joyner R W
Published: June 2012

A premature action potential elicited in ventricular muscle during the functional refractory period of a preceding action potential requires an increased stimulus intensity for successful propagation. We measured the cellular basis for these relative decreases in tissue excitability during the recovery phase by performing parallel experiments on rabbit left papillary muscle and isolated rabbit ventricular cells in addition to conducting theoretical studies with numerical simulations of action potential initiation. For each experimental preparation, the pacing protocol consisted of a train of 10 stimuli (S1) at an S1-S1 interval of 500 msec with a premature stimulus (S2) of variable S1-S2 intervals following the tenth S1 action potential. The stimulus threshold for initiation of an S2 action potential (I2) was then measured as a function of the time of occurrence of the S2 stimulus relative to the time of 95% repolarization of the tenth S1 action potential (stimulus delay [SD] time). In the tissue preparation, the I2 increased sharply for SD times less than 0 msec to a value that was 100% above the S1 stimulus threshold for SD time = -5 +/- 2.4 msec (n = 8). Similar experiments on the isolated ventricular cell showed no increases in I2 as a function of SD time but rather significant decreases in both the action potential amplitude (APA) and the maximum rate of rise of the action potential upstroke (Vmax) of the S2 action potential. The APA and Vmax for the S2 action potential were decreased to 50% of the S1 action potential values for SD time = -5.2 +/- 2.1 msec and SD time = 0.3 +/- 1.6 msec, respectively (n = 8). Both parameters reached 100% recovery by SD time = 10 msec. These results and our numerical simulations are consistent with the hypothesis that the decreases in tissue excitability that occur with premature stimulation have a cellular mechanism as a result of a decrease in cellular responsiveness (APA, Vmax) rather than an intrinsic decrease in cellular excitability.
Changes of atrial natriuretic peptide and its messenger RNA with development and regression of cardiac hypertrophy in renovascular hypertensive rats.
Authors: Matsubara H , Yamamoto J , Hirata Y , Mori Y , Oikawa S , Inada M
Published: June 2012

We assessed the changes in atrial natriuretic peptide (ANP) and its messenger RNA (mRNA) levels in atria and ventricles in relation to hemodynamic factors during antihypertensive treatments in two-kidney, one-clip renovascular hypertensive rats (RHRs). Hypertension of 10-week duration caused a twofold increase in the left ventricular weight/body weight ratio, a significant increase in left ventricular end-diastolic pressure, and an eightfold increase in left ventricular ANP mRNA levels in RHRs, as compared with the levels in control rats. Uninephrectomy or 4 weeks of treatment with the converting enzyme inhibitor enalapril reduced the blood pressure to the control level, with the complete reversal of left ventricular hypertrophy, left ventricular end-diastolic pressure, and ANP mRNA levels. Four weeks of treatment with the arterial vasodilator hydralazine significantly, but not completely, reduced the high blood pressure, but it did not influence left ventricular hypertrophy, end-diastolic pressure, and ANP mRNA levels. The increased ANP synthesis observed in the right ventricles of RHRs also reverted to the control level by uninephrectomy or enalapril treatment, but not by hydralazine, with a time course similar to that of left ventricular ANP. In addition, uninephrectomy caused the left and right ventricular ANP and ANP mRNA levels of RHRs to fall to the levels of control rats as early as 1 week, despite persistent left ventricular hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)
Two stable levels of diastolic potential at physiological K+ concentrations in human ventricular myocardial cells.
Authors: McCullough J R , Chua W T , Rasmussen H H , Ten Eick R E , Singer D H
Published: June 2012

Cells in many specimens of human ventricle can exhibit either of two stable levels of diastolic potential (DP) when exposed to 4 mM K+ in vitro (i.e., -78 +/- 4 mV or -45 +/- 5 mV, mean +/- SEM). In this report we show that the DP of some partially depolarized human ventricular cells developed a sustained 25-35 mV hyperpolarization (n = 28) when bath K+ concentration (K+b) was raised from 4 to 7 mM. On return of K+b to 4 mM, the DP of most, but not all, of these cells returned to the original depolarized levels. In other cells, the transition between the two levels of DP occurred at variable K+b ranging from 1 to 20 mM. We investigated the ionic mechanism(s) underlying the shifts between the two levels of potential by studying the K+ dependence of the DP in partially depolarized cells in 22 specimens of human ventricle. DP hyperpolarized an average of 25.6 mV (from -44.4 +/- 1.3 to -70.0 +/- 1.3 mV; n = 25) when K+b was increased from 4 to 7 mM. Intracellular K+ activity, determined by K+-selective microelectrodes, was within the range of normal reported for other mammalian species (106.7 +/- 4.4 mM in 4 mM K+; n = 22) and was unaffected by increasing K+b to 7 mM (111.7 +/- 6.6 mM; n = 6). Ba2+ (0.05 mM), a blocker of the inward rectifying K+ current, reversibly prevented the hyperpolarization, whereas acetylstrophanthidin (9 microM) failed to inhibit it. These results suggest that the hyperpolarization was due to a K+-dependent increase in K+ permeability and that electrogenic sodium pumping did not contribute significantly to the process. The ionic basis of the depolarization from a hyperpolarized level of DP also was investigated. Decreasing bath Na+ concentration and exposure to 30 microM tetrodotoxin did not prevent the depolarization. However, the depolarization could be inhibited by 2 mM Mn2+. These findings suggest that the depolarization may have been due to a Mn2+-sensitive inward current.
Effect of cellular uncoupling by heptanol on conduction in infarcted myocardium.
Authors: Spear J F , Balke C W , Lesh M D , Kadish A H , Levine J L , Moore E N
Published: June 2012

Experiments were performed in vitro on six normal thin ventricular epicardial tissue strips and 10 strips removed from the infarcted regions of dogs 21-60 days after experimental myocardial infarction. Conduction was evaluated by mapping activation sequences at 40-45 sites over an area of 1 x 2 cm during pacing at a basic cycle length of 2,000 msec. The amplitude and length of recorded electrograms were also determined at each site. After control recordings, heptanol, which increases gap junctional resistance, was added to the tissue bath at concentrations ranging between 0.2 and 1.0 mM. In contrast to its effect on normal tissues, heptanol caused 75 of 260 previously active sites in the infarcted tissues to become inactive. The affected sites were located in areas of very slow conduction and/or adjacent to areas of preexisting conduction block. In addition, heptanol decreased the length and degree of fractionation of electrograms recorded in slowly conducting regions of the infarcted tissues. The magnitude of the decrease in electrogram length following heptanol was related to the degree of electrogram abnormality during control as reflected in the ratio of electrogram length to amplitude. Heptanol shortened electrograms by causing local conduction block, which eliminated some components of the fractionated electrograms. In an additional eight epicardial strips removed from the infarcted region, 0.5 mM heptanol had only a slight effect (10.7% decrease) on the maximum rate of membrane depolarization. Thus, heptanol does not act primarily by way of depressing the fast inward current. We conclude from heptanol's effects on conduction and electrogram characteristics that slow and dissociated conduction in the infarcted region is due to an abnormality in gap junctional distribution between surviving cells and/or an abnormality in individual gap junctional function.
Impact of carbon monoxide on cardiopulmonary dysfunction after smoke inhalation injury.
Authors: Sugi K , Theissen J L , Traber L D , Herndon D N , Traber D L
Published: June 2012

With the inhalation of smoke, there are both cardiopulmonary changes and elevated levels of carbon monoxide (CO). We hypothesize that these changes in cardiopulmonary function are the result of a histotoxic hypoxia associated with CO poisoning. This hypothesis was tested in chronically instrumented sheep (n = 19). Piezoelectric crystals were attached to the left ventricle for the measurement of its external minor and major diameters in addition to wall thickness. A pressure transducer was placed in the left ventricle via the apex. The caudal-mediastinal lymph node was also cannulated. After a five-day recovery period, six sheep (smoke group) were insufflated with four series of 16 breaths (700 ml/breath) of cotton smoke, and five sheep (control group) were insufflated with air using a modified bee smoker (smoke group: COHb, 90 +/- 6%; control group: COHb, 6 +/- 1%). Eight sheep (CO group) were ventilated with 2% CO in air to reach a COHb of 90% (COHb, 92 +/- 1%). In the smoke group, lung lymph flow reached 42 +/- 10 ml/hr at 24 hours after smoke insufflation (baseline, 6 +/- 1 ml/hr). The maximum elastance of the left ventricle (end-systolic pressure-volume ratio), a sensitive index of myocardial contractility, was significantly decreased from a baseline of 6.5 +/- 0.9 to 3.3 +/- 0.7 mm Hg/ml. In the control and CO group, neither lung lymph flow nor maximum elastance varied from the baseline value. We conclude that the cardiopulmonary dysfunction after smoke inhalation does not occur after a similar exposure to CO. Initial CO poisoning alone is not a causative factor of cardiopulmonary dysfunction after smoke inhalation.
Exercise-induced subendocardial dysfunction in dogs with left ventricular hypertrophy.
Authors: Hittinger L , Shannon R P , Kohin S , Manders W T , Kelly P , Vatner S F
Published: June 2012

The effects of treadmill exercise on regional myocardial blood flow and function were examined in 10 adult, conscious dogs with left ventricular hypertrophy (LVH) induced by aortic banding in puppies, which resulted in a left ventricular (LV) weight/body weight ratio of 8.5 +/- 0.3. Data were compared with results from eight control dogs with an LV weight/body weight ratio of 4.9 +/- 0.2. At rest, LV systolic and end-diastolic pressures were significantly greater (p less than 0.01), and mean arterial pressure was significantly less (p less than 0.05) in LVH dogs. Mean myocardial blood flow (control dogs, 0.98 +/- 0.11 ml/min/g; LVH dogs, 1.16 +/- 0.06 ml/min/g) and the transmural blood flow distribution at baseline, as assessed by endocardial/epicardial blood flow ratio (control, 1.35 +/- 0.12; LVH, 1.21 +/- 0.09), were similar in the two groups. During exercise to a target heart rate (240 beats/min), LVH dogs demonstrated greater (p less than 0.01) increases in LV systolic and end-diastolic pressures. In control dogs, as expected, exercise augmented velocity of circumferential fiber shortening (16 +/- 9%) and shortening fraction (15 +/- 5%), but in LVH dogs, exercise reduced the velocity of circumferential fiber shortening (-14 +/- 6%) and shortening fraction (-17 +/- 5%). Exercise also increased full wall thickening (35 +/- 5%), subendocardial wall thickening (66 +/- 10%), and subepicardial wall thickening (44 +/- 9%) in control dogs. In LVH dogs, exercise increased subepicardial wall thickening (31 +/- 9%) and reduced subendocardial wall thickening (-40 +/- 7%); full wall thickening did not change (-11 +/- 9%). This was associated with a fall in endocardial/epicardial flow ratio to 0.72 +/- 0.05 (p less than 0.01) in LVH dogs. The subendocardial dysfunction persisted late into recovery, at a time when the transmural blood flow distribution had returned to baseline; this occurrence suggested myocardial stunning. Thus, in dogs with LVH, selective subendocardial hypoperfusion and profound selective depression in subendocardial wall thickening are observed during exercise. The subendocardial dysfunction persisted into recovery despite resolution of the perfusion abnormality.
Diameter change and pressure-red blood cell velocity relations in coronary microvessels during long diastoles in the canine left ventricle.
Authors: Kanatsuka H , Ashikawa K , Komaru T , Suzuki T , Takishima T
Published: June 2012

The objective of this study was to determine whether coronary vascular resistance remains constant during long diastoles and whether critical closure of arterial microvessels occurs at zero-flow pressure. For this purpose, we directly measured internal diameters and red blood cell velocities in arterial and venous coronary microvessels during long diastoles under maximal vasodilation. The epicardial coronary microcirculation was viewed in anesthetized, open-chest mongrel dogs through an intravital microscope equipped with a newly developed floating objective. Coronary microvascular diameters and red blood cell velocities were measured with high-speed cinematography. During maximal vasodilation (150 micrograms/kg body wt i.v. dilazep), long diastoles were induced by vagal nerve stimulation. Internal diameters of all small arteries and arterioles (n = 12) gradually declined with decreasing aortic pressure during long diastoles, and the reduction of the diameter was greatest when aortic pressure was less than 35 mm Hg. The mean internal diameter (88.8 +/- 52.2 microns) at minimal aortic pressure (19.2 +/- 6.4 mm Hg) was significantly less than that at an aortic pressure of 100 mm Hg (116.2 +/- 68.5 microns, p less than 0.01). The internal diameters of small veins and venules remained nearly constant during long diastoles. When red blood cell progression in coronary microvessels stopped at the nadir of aortic pressure, all arterial coronary microvessels remained open; that is, there was no evidence of "critical closure."(ABSTRACT TRUNCATED AT 250 WORDS)
Changes in intracellular calcium during mechanical alternans in isolated ferret ventricular muscle.
Authors: Lab M J , Lee J A
Published: June 2012

Alternans in heart is important as pulsus alternans in cardiac failure and electrophysiological alternans in myocardial ischemia. The explanation of this phenomenon is still unclear. We attempted to investigate the cellular mechanisms of alternans by measuring intracellular free calcium concentration [( Ca2+]i) with the photoprotein aequorin in isolated ferret papillary muscles. Tension and length were also recorded simultaneously. Transient mechanical alternans lasting five to 20 contractions could be reliably induced in this preparation by following a 30-second rest period with stimulation at a fast rate (2-4 Hz). Production of sustained mechanical alternans, which lasted longer than 20 contractions and could persist for several hundred contractions, required additional interventions, consisting of a lower temperature (25 degrees C), a lower external calcium concentration (1 mM), and a lower pH (6.91) than control conditions (0.33-0.5 Hz, 30 degrees C, 2 mM Ca2+, pH 7.36). Transient mechanical alternans was associated with transient in-phase alternation of aequorin light and, hence, [Ca2+]i. Sustained mechanical alternans was associated with sustained in-phase alternation of aequorin light as well as incomplete relaxation of tension. However, when muscles were switched from isometric to unloaded isotonic contraction, relaxation between stimuli was complete but contraction and the aequorin light signal continued to alternate. The addition of 10 mM caffeine or 10 microns ryanodine abolished transient and sustained mechanical alternans and also abolished the associated alternation of aequorin light. Commensurate with the action of ryanodine, which allows the sarcoplasmic reticulum to reaccumulate calcium to a limited extent after a period of rapid stimulation, sustained mechanical alternans sometimes reappeared in an attenuated form 30 to 50 contractions after the addition of ryanodine. These results demonstrate that incomplete muscle relaxation between beats need not be present for alternans to occur, and support the hypothesis that alternans is caused by intracellular calcium cycling involving the sarcoplasmic reticulum.
Thromboxane A2 and peptidoleukotrienes contribute to the myocardial ischemia and contractile dysfunction in response to intracoronary infusion of complement C5a in pigs.
Authors: Ito B R , Roth D M , Engler R L
Published: June 2012

Intracoronary infusions of activated complement C5a result in myocardial ischemia, contractile dysfunction, and leukocyte accumulation. The hypothesis was tested that the generation of the coronary vasoconstrictors, thromboxane A2 and the 5-lipoxygenase leukotrienes (LTC4 and LTD4), contributes to the C5a-induced decrease in coronary blood flow and contractile function. The left anterior descending coronary artery in anesthetized swine was cannulated and servo pump-perfused with arterial blood at constant pressure and measured flow. Regional subendocardial contractile function was assessed with sonomicrometry. The interventricular vein was cannulated for sampling of coronary venous blood for leukocyte count. The responses in left anterior descending coronary artery blood flow and percent segment shortening to intracoronary infusions of LTC4 (1 microgram), LTD4 (1 microgram), thromboxane agonist U46619 (7.5 micrograms), and C5a (500 ng) were assessed before and after 1) LTD4/LTE4 receptor blockade with leukotriene receptor blocker LY171883 (10 mg/kg i.v.) (n = 5), 2) thromboxane A2/prostaglandin H2 receptor blockade with thromboxane receptor blocker BM13505 (2 mg/kg i.v.) (n = 5), and 3) combined thromboxane and leukotriene receptor blockade (n = 5). In the absence of receptor blockade, intracoronary C5a decreased coronary flow (50-60%) and regional segment function (60-70%) compared with the preinfusion levels. This was accompanied by a fall in coronary venous blood leukocyte levels by 5-6 x 10(6) cells/ml in the absence of alterations in arterial blood leukocyte count. Intracoronary injections of LTD4, LTC4, or U46619 also resulted in prompt decreases in coronary blood flow (50-60%) and segment function (70-80%) from preinfusion levels. Leukotriene receptor blockade with LY171883 abolished these responses to LTD4 and LTC4. Administration of LY171883 also attenuated (p less than 0.05) the myocardial response to C5a; coronary flow and segment function decreased by approximately 28% from preinfusion levels. Thromboxane receptor blockade with BM13505 eliminated the response in coronary flow and segment function to intracoronary U46619. Similar to LY171883, administration of BM13505 blunted (p less than 0.05) the C5a-induced decreases in coronary flow and contractile function, which fell by approximately 20-25% from the preinfusion level. After the combined LTD4/LTE4 receptor and thromboxane A2/prostaglandin H2 receptor blockade, intracoronary C5a resulted in little change in both coronary blood flow and segment shortening. In contrast to the flow and function effects, the C5a-induced myocardial leukocyte extraction was not decreased by leukotriene and/or thromboxane receptor blockade.(ABSTRACT TRUNCATED AT 400 WORDS)
Effects of intracellular acidosis on [Ca2+]i transients, transsarcolemmal Ca2+ fluxes, and contraction in ventricular myocytes.
Authors: Kohmoto O , Spitzer K W , Movsesian M A , Barry W H
Published: June 2012

We examined the effects of intracellular acidosis produced by washout of NH4Cl on [Ca2+]i transients (indo-1 fluorescence), cell contraction (video motion detector), and 45Ca and 24Na fluxes in cultured chick embryo ventricular myocytes. Exposure of cells to 10 mM NH4Cl produced intracellular alkalosis (pH 7.6), and subsequent washout resulted in a transient acidosis (pH 6.5). Exposure to 10 mM NH4Cl slightly decreased [Ca2+]i transients but increased the amplitude of cell contraction. Subsequent washout of NH4Cl initially increased diastolic [Ca2+]i and decreased the peak positive and negative d[Ca2+]i/dt, while the amplitude of cell contraction was markedly decreased. Subsequently, peak systolic [Ca2+]i increased with partial recovery of contraction. A similar increase in [Ca2+]i and decrease in contraction after washout of NH4Cl was observed in single paced adult guinea pig ventricular cells. Acidosis decreased 45Ca uptake by sarcoplasmic reticulum vesicles isolated from chick embryo ventricle. However, the [Ca2+]i increase caused by intracellular acidosis was also observed in the presence of 10 mM caffeine, suggesting that altered sarcoplasmic reticulum handling of calcium is not the only mechanism involved. Intracellular acidosis only slightly increased total 24Na uptake under these conditions, an effect resulting from the combination of a stimulation of amiloride-sensitive sodium influx (Na(+)-H+ exchange) and inhibition of sodium influx via Na(+)-Ca2+ exchange, manifested by a significant decrease in 45Ca efflux. Further support for a lack of involvement of an increased [Na+]i in the observed increase in [Ca2+]i during acidosis was low-sodium, nominal 0-calcium extracellular solution, an experimental condition that minimizes the possible effects of Na(+)-H+ exchange and Na(+)-Ca2+ exchange. We conclude that the [Ca2+]i increase caused by intracellular acidosis in cultured ventricular cells is primarily due to changes in [Ca2+]i buffering and [Ca2+]i extrusion, rather than to an increase in transsarcolemmal calcium influx. Intracellular acidosis also markedly decreases the sensitivity of the contractile elements to [Ca2+]i in cultured chick embryonic and adult guinea pig ventricular myocytes.
Importance of endogenous angiotensin II in the cardiovascular responses to sympathetic stimulation in conscious rabbits.
Authors: Isaacson J S , Reid I A
Published: June 2012

Pharmacological evidence indicates that angiotensin (Ang II) converting enzyme inhibitors attenuate cardiovascular responses to sympathetic stimulation. To investigate the physiological significance of this attenuation, the pressor and heart rate responses to bilateral carotid occlusion (BCO) were studied before and after administration of captopril and again during Ang II replacement in conscious, aortic nerve-sectioned rabbits with chronically implanted carotid occluders. In the control period, BCO produced increases (p less than 0.05) in mean arterial pressure (MAP) and heart rate (HR) of 37.3 +/- 3.0 mm Hg and 21.7 +/- 5.4 beats/min from baseline values of 79.1 +/- 2.5 mm Hg and 255.4 +/- 16.7 beats/min. Captopril (5 mg/kg i.v.) markedly reduced (p less than 0.05) both the pressor (10.2 +/- 2.6 mm Hg) and HR (5.0 +/- 4.0 beats/min) responses to BCO, in parallel with a decrease in plasma Ang II of 75%. Infusion of a subpressor dose of Ang II (5-25 ng/kg/min i.v.) increased plasma Ang II to precaptopril levels and fully restored (p less than 0.05) the pressor (33.0 +/- 5.7 mm Hg) and HR (19.8 +/- 7.7 beats/min) responses to BCO. In two additional series of experiments, the mechanism of the effects of captopril and Ang II were investigated. In the first series, cardiac baroreflex curves (pulse interval versus MAP) were generated by increasing or decreasing blood pressure with phenylephrine or nitroprusside (5-20 micrograms/kg/min i.v.). The slope of the linear region of the curve (2.9 msec/mm Hg) was not changed significantly by captopril treatment (3.1 msec/mm Hg) or Ang II replacement (3.2 msec/mm Hg), indicating that cardiac baroreflex sensitivity was not altered by blockade of the renin-angiotensin system. In the second series, the effect of captopril on the pressor response to exogenous norepinephrine (0.1-2.5 micrograms/kg/min i.v.) was tested. The response was reduced by less than 40%, indicating only a modest postsynaptic component to the action of captopril. These results provide physiological evidence for an important action of endogenous Ang II in facilitating the cardiovascular responses to sympathetic stimulation in conscious rabbits. This facilitation is not due to an action upon the baroreflex per se but results, at least in part, from a presynaptic action of Ang II.