bluuebunny/crossref_metadata_2025 huggingface dataset:
Two components of use-dependent block of Na+ current by disopyramide and lidocaine in guinea pig ventricular myocytes.
Authors: Sunami A , Fan Z , Nitta J , Hiraoka M
Published: June 2012

We studied the kinetics of the use-dependent block of the Na+ current (INa) by disopyramide and lidocaine. INa was recorded from isolated guinea pig ventricular myocytes by using the whole-cell patch-clamp technique. The use-dependent block of INa by disopyramide with 20- and 200-msec depolarizing pulses developed in two exponential functions. The degree of the use-dependent block and the amplitude of the fast (Af) and slow (As) components with the short (20-msec) pulse protocol were comparable to those with the long (200-msec) pulse protocol. When pH was raised from 7.3 to 8.0, disopyramide increased Af without a change in As. At pH 6.5, INa block developed with a single exponential function revealing only the slow component. The fast and slow components of INa block by disopyramide could be explained by binding of the uncharged and charged forms, respectively, to the activated state of the channel. Development of INa block by lidocaine also was expressed by two exponentials at all pulse durations (5-200 msec). As pulse durations were prolonged or holding potentials were depolarized, the degree of the use-dependent block and Af increased. When pH was lowered to 6.5, the short pulse produced only the slow component, whereas the long pulse caused two exponentials with decreased Af and increased As. Internal application of QX-314, a permanently charged lidocaine analogue, produced a single exponential block of INa with a very slow onset rate.(ABSTRACT TRUNCATED AT 250 WORDS)
Postnatal maturation of excitation-contraction coupling in rat ventricle in relation to the subcellular localization and surface density of 1,4-dihydropyridine and ryanodine receptors.
Authors: Wibo M , Bravo G , Godfraind T
Published: June 2012

To better understand excitation-contraction coupling in cardiac muscle, we investigated the main Ca2+ channels involved in that process in adult and neonatal rat ventricle. Voltage-dependent (L-type) Ca2+ channels and sarcoplasmic reticulum Ca2+ release channels were labeled by means of [3H] (+)-PN200-110 and [3H]ryanodine, respectively. The number of [3H]ryanodine binding sites (per gram tissue) increased more than that of [3H] (+)-PN200-110 binding sites over the postnatal period (2.1-fold versus 1.35-fold, respectively). After equilibration of microsomal fractions in density gradient, ryanodine receptors were characterized by a heavy distribution pattern that did not change appreciably between days 1 and 30 after birth. In neonatal tissue, 1,4-dihydropyridine receptors were found mainly in low-density subfractions, together with other sarcolemmal constituents, whereas in adult tissue, they were recovered predominantly in high-density subfractions, together with ryanodine receptors. Thus, after birth, and in parallel with the development of T tubules, there was a progressive concentration of L-type Ca2+ channels in junctional structures of high equilibrium density, where they were situated close to the Ca2+ release channels of the sarcoplasmic reticulum. In adult ventricle, L-type channels were, on an average, threefold more abundant in T tubules than in external sarcolemma. In parallel mechanical studies, we found that the inhibitory action of ryanodine on systolic contraction was much more pronounced in adult than in neonatal right ventricle, and that, conversely, neonatal tissue was more sensitive that adult tissue to inhibitors of L-type channels. We conclude that, in view of the presumed mechanism of Ca2+ release from the sarcoplasmic reticulum, that is, Ca(2+)-induced Ca2+ release, the predominant localization in adult rat ventricle of the major Ca2+ entry pathway in the vicinity of the Ca2+ release pathway is of great functional significance. Furthermore, owing to the relative stoichiometry of Ca2+ entry and Ca2+ release channels in junctional structures (about 1:9), a physical link between these channels is not likely to be involved in the modulation of Ca2+ release from the sarcoplasmic reticulum in cardiac muscle.
Coronary microvascular resistance in hypertensive cats.
Authors: Kanatsuka H , Lamping K G , Eastham C L , Marcus M L , Dellsperger K C
Published: June 2012

Chronic systemic hypertension has been shown to alter the distribution of vascular resistance in many microvascular beds. The purposes of this study were to assess the effects of chronic systemic hypertension on the pressure distribution in the coronary microcirculation and to determine the microvascular site where coronary vascular resistance is increased. Cats were made hypertensive using a one-kidney, one-wrap model (Page model). A servonulling system was used to directly measure pressures in the epimyocardial microvessels of the beating left ventricle in normotensive and hypertensive cats. In chronically hypertensive cats, mean arterial pressure was 153 +/- 5 mm Hg compared with 98 +/- 3 mm Hg in normotensive cats (p less than 0.05). Left ventricular mass was increased approximately 34% in hypertensive cats (9.4 +/- 0.3 versus 7.0 +/- 0.3 g, p less than 0.05). Myocardial perfusion measured using radiolabeled microspheres was not different between hypertensive and normal cats. Coronary vascular resistance of the left ventricle was increased in hypertensive cats (0.90 +/- 0.08 versus 0.66 +/- 0.05 mm Hg x min x 100 g/ml, p less than 0.05). Microvascular pressures were measured in three groups of microvessels: small, less than 200 microns; medium, 200-300 microns; and large, greater than or equal to 300 microns. Mean microvascular pressures of large, medium, and small arterial microvessels in hypertensive cats were 144 +/- 8, 127 +/- 6, and 115 +/- 7 mm Hg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Ionic currents activated during hyperpolarization of single right atrial myocytes from cat heart.
Authors: Wu J Y , Vereecke J , Carmeliet E , Lipsius S L
Published: June 2012

Whole-cell recording techniques were used on single right atrial myocytes to study the ionic currents that may be responsible for the diverse diastolic voltage characteristics of atrial tissue. Ionic currents were activated by hyperpolarizing voltage pulses negative to -30 mV. In general, four different types of cells were identified based primarily on the ionic currents elicited during hyperpolarization. The first cell type exhibited an inward current that decayed with time at more negative voltages, reversed near the potassium equilibrium potential, inwardly rectified at more positive voltages, increased in elevated extracellular potassium, and was blocked by 3 mM barium or 10 mM cesium. This current was identified as the potassium current iK1. A second cell type exhibited a time-dependent inward current that increased at more negative voltages, had an activation range between -50 and -110 mV, had a reversal potential of -26 mV, and was blocked by 3 mM cesium. This current was identified as an if current. A third cell type exhibited an inward current that initially decayed and then became more inward with time. Barium (3 mM) abolished the initial inward current and revealed a time-dependent increasing inward current that was blocked by 3 mM cesium. This current was composed of both the iK1 and if currents. A fourth cell type exhibited only small time-independent leak currents in response to hyperpolarization. These results indicate that individual cells within the right atrium are electrophysiologically heterogeneous with respect to the types of ionic channels present in their sarcolemmal membranes. This specialization in ionic currents partially explains the diverse diastolic voltage characteristics and functional properties of atrial tissue.
Cellular distribution of phosphodiesterase isoforms in rat cardiac tissue.
Authors: Bode D C , Kanter J R , Brunton L L
Published: June 2012

We have resolved multiple forms of cyclic nucleotide phosphodiesterase (PDE) in whole rat ventricle and in isolated rat ventricular myocytes by use of anion-exchange high-performance liquid chromatography. One major form, the soluble calmodulin-stimulated PDE, is apparently absent from isolated myocytes. We discern four peaks of PDE activity (designated A-D in the order of their elution) in a soluble fraction obtained from whole rat ventricle. Peak A is stimulated twofold to threefold by the addition of calcium and calmodulin (Ca2+/CalM) and preferentially hydrolyzes cGMP over cAMP (in the presence of Ca2+/CalM, KmcGMP = 1.5 microM, KmcAMP = 17 microM). Peak B has similar affinities for both cAMP and cGMP (half-maximum velocities achieved at 30 microM substrate) and demonstrates positive cooperativity with cAMP but not with cGMP. The hydrolysis of cAMP by peak B is stimulated by cGMP at substrate concentrations up to 20 microM; the maximum effect is seen at 1 microM cAMP (25-fold stimulation by 3 microM cGMP). This pattern of stimulation by cGMP results from two kinetic changes: an increase in the enzyme's apparent affinity for cAMP (apparent KmcAMP decreases from 33 to 11 microM) and the abolition of positive cooperativity. Peaks C and D selectively hydrolyze cAMP, are not stimulated by Ca2+/CalM or cGMP, and differ in their affinities for substrate (peak C, apparent KmcAMP = 7.2 microM; peak D, 0.44 microM). In addition, peak D is much more sensitive than peak C to inhibition by cGMP, cilostamide, rolipram, and milrinone. Ro20-1724 is a slightly more potent inhibitor of peak D than of peak C. Peak D appears to consist of two different enzyme activities, one inhibited by cGMP, cilostamide, and cardiotonic drugs and the other potently inhibited by rolipram. In contrast to whole ventricle, the soluble fraction of isolated rat ventricular myocytes lacks peak A. Three major peaks in myocytes are entirely analogous to peaks B, C, and D of whole ventricle in terms of the NaCl concentration at which they elute, substrate affinities, and stimulation or inhibition by various drugs and effectors. We conclude that the soluble Ca2+/CalM-stimulated PDE in whole rat ventricle is present in nonmyocyte cells.
Circus movement atrial flutter in the canine sterile pericarditis model. Differential effects of procainamide on the components of the reentrant pathway.
Authors: Schoels W , Yang H , Gough W B , el-Sherif N
Published: June 2012

To evaluate the mechanisms of action of procainamide on the components of the reentrant pathway, drug-induced changes in activation patterns, effective refractory periods (ERPs), and stimulation thresholds were analyzed in nine dogs with sterile pericarditis and sustained atrial flutter. Activation maps were based on 127 close bipolar recordings from a special "jacket" electrode. From the control map, 22 +/- 2 sites covering the slow zone and the normal zone of the reentrant circuit were selected to measure ERPs and thresholds. The excitable gap was estimated from the longest ERP during pacing at the tachycardia cycle length. During atrial flutter, epicardial activation proceeded as a single wave around an arc of functional conduction block in the proximity of the atrioventricular (AV) ring or around a combined functional/anatomic obstacle, with the arc being contiguous with one of the venae cavae. An area of slow conduction, which accounted for 53 +/- 15% of the revolution time within 35 +/- 15% of the total length of the reentrant pathway, was bordered by the arc of block and the AV ring or a caval vein and the AV ring, respectively. Procainamide (5-10 mg/kg i.v.) prolonged the cycle length of atrial flutter from 144 +/- 17 to 190 +/- 24 msec (p less than 0.05) and then terminated the arrhythmia in all studies. The increase in cycle length was due to an increase in conduction time in the slow zone by 37 +/- 11 msec (86 +/- 17% of the total cycle length increase). During the last reentrant beat, conduction failed in the slow zone, with the arc of block joining the AV ring. At termination, procainamide had prolonged conduction time, stimulation threshold, and ERP in the normal zone by 11 +/- 18%, 40 +/- 80%, and 5 +/- 15%, respectively, compared with 51 +/- 16%, 86 +/- 93%, and 14 +/- 21%, respectively, in the slow zone (p less than 0.05 for all three parameters). The duration of the excitable gap did not change significantly. We conclude that procainamide preferentially affected the slow zone of single loop reentrant circuits. The drug terminated circus movement atrial flutter without abolishing the excitable gap, and its effect on conduction seemed the major determinant of the antiarrhythmic action.
Effect of positive inotropic agents on myosin isozyme population and mechanical activity of cultured rat heart myocytes.
Authors: Rupp H , Berger H J , Pfeifer A , Werdan K
Published: June 2012

To examine whether catecholamines have a direct effect on myosin heavy chain expression of heart myocytes or whether they act via an altered work load, myocytes from neonatal rat hearts were cultured in thyroid hormone-free media containing various positive inotropic and chronotropic agents. The velocity and frequency of contraction of the myocytes were monitored using an optoelectronic system. After 3-5 days of culture, myosin isozyme populations, cellular cAMP content, and 2-deoxy-D-glucose uptake of the myocytes were determined. Compared with myocytes cultured in the absence of inotropic agents (32.6 +/- 3.5% V1), the proportion of myosin V1 was significantly (p less than 0.05) increased in the case of 1 microM isoproterenol (48.2 +/- 5.9% V1), 1 microM forskolin (57.1 +/- 11.7% V1), and 1 mM dibutyryl cAMP (79.1 +/- 2.0% V1). Dibutyryl cAMP increased V1 to a similar level as 30 nM triiodothyronine did (70.2 +/- 13.0% V1). Only a small increase was observed in myocytes cultured in the presence of 10 microM phenylephrine (40.4 +/- 8.4% V1), 10 microM ouabain (40.6 +/- 11.9% V1), or 10 microM Bay K 8644 (40.7 +/- 11.7% V1). The agents with a marked effect on myosin heavy chain expression resulted in a higher cAMP content; isoproterenol and forskolin also stimulated 2-deoxy-D-glucose uptake. All agents resulted in a higher velocity of contraction; with the exception of ouabain, frequency of contraction was also increased. A change in Ca2+ concentration in the medium from 1.3 to 2.4 mM resulted in a small increase in V1 (40.7 +/- 5.2% V1) but had the same effect on contraction velocity as dibutyryl cAMP did. Furthermore, 10 nM isoproterenol also increased V1 in myocytes that were arrested with 10 microM verapamil. The increase in V1 in the case of dibutyryl cAMP, isoproterenol, and forskolin is thus most probably not a correlate of the increased mechanical activity but of the high cellular cAMP content.
Inhibitory role of the coronary arterial endothelium to alpha-adrenergic stimulation in experimental heart failure.
Authors: Main J S , Forster C , Armstrong P W
Published: June 2012

The role of the endothelium in regulating coronary alpha-adrenergic tone was evaluated in isolated coronary arterial rings from dogs with and without pacing-induced congestive heart failure (CHF). The maximal contractile response to methoxamine was attenuated approximately 43% (p less than 0.05) in both intact and denuded CHF rings compared with control. Conversely, norepinephrine-induced contractions were diminished 58% in intact CHF vessels and 39% in denuded CHF vessels (p less than 0.05). Denudation did not alter responses to methoxamine but significantly (p less than 0.05) augmented the tension generated by norepinephrine in both control (1.7-fold) and CHF (2.4-fold) arteries. In both intact control and CHF coronary arteries, norepinephrine elicited rapid, transient relaxations that preceded slow, sustained contractions; the initial relaxation phase was endothelium dependent, because denudation eliminated the response. Relaxations to the selective alpha 2-adrenoceptor agonist BHT 920 were also dependent on the presence of an endothelium. At peak CHF, endothelium-dependent relaxations to norepinephrine and BHT 920 were enhanced, whereas relaxations to nitroglycerin and acetylcholine were unaltered. The data suggest that alpha-adrenergic tone in canine coronary arteries is diminished by pacing-induced CHF because of a decrease in alpha 1-adrenoceptor-mediated constriction and an enhanced capacity of the endothelium to antagonize the direct vascular smooth muscle response of norepinephrine through endothelium-dependent, alpha 2-adrenoceptor-mediated relaxations.
Cytochrome P-450-dependent vasodilator responses to arachidonic acid in the isolated, perfused kidney of the rat.
Authors: Oyekan A O , McGiff J C , Quilley J
Published: June 2012

Pretreatment of phenylephrine (0.5 microM)-preconstricted, isolated perfused kidneys of the male rat with indomethacin (2.8 microM) or BM 13.177 (20 microM) abolished the vasoconstrictor response to arachidonic acid (AA), uncovering a vasodilator response. BW 755C (25 microM), a dual cyclooxygenase/lipoxygenase inhibitor, did not modify the vasodilator effect of AA, whereas 5,8,11,14-eicosatetraynoic acid (10 microM), which blocks all pathways of AA metabolism, abolished AA-induced vasodilation, thus suggesting the involvement of nonlipoxygenase AA metabolites. Clotrimazole (0.7 microM) and 7-ethoxyresorufin (1 microM), both considered to be specific inhibitors of the cytochrome P-450 monooxygenase enzymes, inhibited the vasodilator effect, suggesting that AA-induced renal vasodilation is mediated by one or more cytochrome P-450-derived AA metabolites. None of these interventions affected the vasodilator responses to acetylcholine (100 ng) and nitroprusside (1 microgram). Denudation of the endothelium with CHAPS (10 mg/l) reduced the vasodilator responses to AA, suggesting a requirement of an intact endothelium, whereas inhibition of guanylate cyclase with methylene blue (10(-4) M) was without effect, suggesting that cGMP was not involved in the vasodilator response to AA. The AA-induced renal vasodilation was accompanied by the generation of biologically active material or materials released into the renal effluent, which relaxed endothelium-intact and endothelium-denuded rings of isolated aorta and mesenteric and celiac arteries of the rabbit. These results suggest that in the rat kidney, AA is metabolized by endothelial cytochrome P-450-dependent enzymes to vasodilator metabolites.
Dispersion of refractoriness in canine ventricular myocardium. Effects of sympathetic stimulation.
Authors: Opthof T , Misier A R , Coronel R , Vermeulen J T , Verberne H J , Frank R G , Moulijn A C , van Capelle F J , Janse M J
Published: June 2012

In 18 dogs on total cardiopulmonary bypass, the average interval between local activations during artificially induced ventricular fibrillation (VF interval) was measured from extracellular electrograms, simultaneously recorded from up to 32 ventricular sites. VF intervals were used as an index of local refractoriness, based on the assumption that during ventricular fibrillation, cells are reexcited as soon as they have recovered their excitability. In support of this, microelectrode recordings in two hearts during ventricular fibrillation did not show a diastolic interval between successive action potentials. Refractory periods determined at a basic cycle length of 300 msec with the extrastimulus method correlated well with VF intervals measured at the same sites. Thus, this technique allows assessment of spatial dispersion of refractoriness during brief interventions such as sympathetic stimulation. The responses to left, right, and combined stellate ganglion stimulation varied substantially among individual hearts. This was observed both in dogs with an intact (n = 12) and decentralized (n = 6) autonomic nervous system. Individual ventricular sites could show effects of both left and right stellate ganglion stimulation (42% of tested sites) or show effects of left-sided stimulation only (31%) or right-sided stimulation only (14%). In 13% of sites, no effects of stellate stimulation were observed. Apart from these regional effects, the responses could be qualitatively different; that is, within the same heart, the VF interval prolonged at one site but shortened at another in response to the same intervention, although shortening was the general effect and prolongation the exception. Whenever sites responded to stellate ganglion stimulation with a shortening of VF interval, this shortening was approximately 10% for left, right, or combined stimulation, whether the autonomic nervous system was intact or decentralized. In six of 12 hearts in the intact group, there was a distinct regional effect of left stellate ganglion stimulation; in the other six hearts, the effects were distributed homogeneously over the ventricles. In three hearts, the effect of left stellate ganglion stimulation was strongest in the posterior wall, and in the other three hearts, in the anterior wall. The effects of right stellate ganglion stimulation were restricted to the anterior or lateral part of the left ventricle. Dispersion of VF intervals increased after left and combined stellate ganglion stimulation in the intact group and after right stellate ganglion stimulation in the decentralized group, but not significantly in every heart. This points to a marked individual variation with regard to the effects of sympathetic stimulation on electrophysiological properties of the heart.
A unified model of atrioventricular nodal conduction predicts dynamic changes in Wenckebach periodicity.
Authors: Talajic M , Papadatos D , Villemaire C , Glass L , Nattel S
Published: June 2012

The atrioventricular (AV) node responds in a complex fashion to changes in activation rate. A variety of approaches have been used to explain these dynamic AV nodal responses, but none has been able to account fully for AV nodal behavior. Three specific rate-dependent properties of the AV node have been described: 1) time-dependent recovery after excitation, 2) an effect of short cycles to advance recovery ("facilitation"), and 3) a gradual slowing of conduction in response to sustained, high-frequency activation ("fatigue"). We hypothesized that a model incorporating quantitative descriptors of all three processes might be able to account for a wide variety of AV nodal behaviors. Quantitative descriptors of AV nodal recovery, facilitation, and fatigue were developed based on AV nodal conduction changes during selective pacing protocols in seven autonomically blocked dogs. These descriptors were incorporated into a set of mathematical equations that define AV nodal conduction of any beat based on activation history. The equations were then applied to predict pacing-induced Wenckebach periodicity in each dog. Experimental data were obtained after nine to 19 step decreases in atrial cycle length into the Wenckebach zone in each animal. Observed behaviors included complex patterns of block, a progressive increase in the level of block over 5 minutes of rapid pacing, and periods of alternating patterns of block. The model accurately predicted the onset of AV block at each cycle length, the relation between conduction ratio and cycle length as a function of time, and the changing patterns of Wenckebach periodicity during sustained atrial pacing. All three terms of the model equation (describing recovery, facilitation, and fatigue) were essential to account fully for the observed behaviors. Elimination of AV nodal fatigue from the model resulted in failure to account for time-dependent changes in Wenckebach patterns, whereas exclusion of facilitation led to consistent overestimation of the degree of AV block at each cycle length. We conclude that a mathematical model incorporating terms to describe recovery, facilitation, and fatigue accurately predicts a wide range of Wenckebach-type behavior and that complex conduction patterns of the AV node can be fully accounted for by simple functional AV nodal properties.
Carotid sinus baroreceptor reflex in dogs with experimental heart failure.
Authors: Wang W , Chen J S , Zucker I H
Published: June 2012

We have previously demonstrated a decrease in baroreceptor discharge sensitivity in dogs with experimental heart failure. In the present study, we determined the sensitivity of the carotid sinus baroreceptor reflex in dogs with pacing-induced heart failure. The carotid sinus baroreceptor reflex sensitivity was determined by pressurizing one carotid sinus with all other baroreceptor and cardiopulmonary receptor inputs removed. The data were analyzed by plotting carotid sinus pressure-mean arterial pressure curves and carotid sinus pressure-renal sympathetic nerve activity curves in the two groups of dogs. The peak arterial pressure during carotid hypotension was significantly depressed in dogs with heart failure compared with normal dogs (107.1 +/- 5.7 versus 139.8 +/- 7.0 mm Hg, p less than 0.001). Mean arterial pressure range, renal sympathetic nerve activity range, and peak slope were significantly decreased in the heart-failure group. To determine if this depression was completely due to depression of baroreceptor discharge per se, or to alterations in central or end-organ responsiveness, similar experiments were performed by stimulating the carotid sinus nerve and evaluating frequency, voltage, and duration of stimulation on the resultant mean arterial pressure and renal sympathetic nerve activity. As was the case with carotid sinus pressurization, electrical stimulation caused a significantly smaller change in mean arterial pressure in heart-failure dogs compared with the normal dogs. However, there was no significant difference between normal and heart-failure dogs for the renal sympathetic nerve activity-electrical stimulation curves. These data strongly suggest that the depressed carotid sinus baroreceptor reflex in heart failure is not solely the result of depressed baroreceptor responsiveness but may be related to poor end-organ responses and normal central control of renal sympathetic outflow.
Beneficial effects of alpha 1-adrenoceptor activity on myocardial stunning in dogs.
Authors: Kitakaze M , Hori M , Sato H , Iwakura K , Gotoh K , Inoue M , Kitabatake A , Kamada T
Published: June 2012

This study was undertaken to elucidate whether alpha-1 adrenoceptor activity is beneficial to contractile dysfunction during reperfusion after a brief period of ischemia (stunned myocardium) in 54 open-chest dogs. Contractile dysfunction assessed by fractional shortening (FS) was observed 3 hours after the onset of reperfusion following 15 minutes of complete occlusion of the left anterior descending coronary artery. Pretreatment with prazosin (4 micrograms/kg/min i.c.) further deteriorated contractile dysfunction compared with the untreated condition (12.7 +/- 0.6% versus 6.9 +/- 0.4% with prazosin treatment, p less than 0.001). Conversely, alpha 1-adrenoceptor agonists, methoxamine (1.0 microgram/kg/min i.c.) and norepinephrine (0.24 microgram/kg/min i.c.) with rauwolscine and propranolol, significantly attenuated contractile dysfunction (FS in the methoxamine-treated group, 17.3 +/- 0.3%, p less than 0.001 versus the untreated group; FS in the norepinephrine-treated group, 18.0 +/- 0.9%, p less than 0.05 versus 13.6 +/- 1.1% in the propranolol group). Both adenosine release and hyperemic coronary flow response during the early reperfusion period were significantly attenuated in the prazosin-treated group, and both were enhanced in the alpha 1-adrenoceptor stimulation groups. These results suggest that beneficial effects of alpha 1-adrenoceptor activity may be due to the enhanced release of adenosine. To test the cause-effect relation between the extent of adenosine release and contractile dysfunction during reperfusion, 8-phenyltheophylline was infused to block adenosine receptors in the methoxamine-treated group. The treatment with 8-phenyltheophylline completely abolished (FS, 7.4 +/- 0.3%) the beneficial effect of the enhanced adenosine release by alpha 1-adrenoceptor stimulation. Furthermore, in the prazosin-treated group, adenosine (9 micrograms/kg/min) was additionally infused into the left anterior descending coronary artery 5 minutes before and 2 hours after the onset of reperfusion. Both hyperemic coronary flow and contractile dysfunction (FS, 17.3 +/- 0.3%) recovered to the levels of the alpha 1-adrenoceptor stimulation groups. However, treatment with papaverine could not prevent deleterious effects of prazosin despite the fact that comparable hyperemic flow was obtained. Instead, lactate production up to 10 minutes after the onset of reperfusion was significantly larger (p less than 0.01) despite augmented contractile function in the prazosin-treated and the 8-phenyltheophylline with methoxamine-treated groups compared with the untreated group. The electron microscopic examination revealed no irreversible myocardial injury with and without pharmacological interventions. Thus, we conclude that alpha 1-adrenoceptor activity can reduce the magnitude of myocardial stunning and that its cellular mechanism is due to enhanced adenosine release by alpha 1-adrenoceptor activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Dual effect of serotonin on growth of bovine pulmonary artery smooth muscle cells in culture.
Authors: Lee S L , Wang W W , Moore B J , Fanburg B L
Published: June 2012

We have previously reported that serotonin (5-hydroxytryptamine [5HT]) alters cultured bovine pulmonary artery smooth muscle cell (SMC) configuration through two different regulatory mechanisms. We now report that 5HT also regulates SMC growth through these same two mechanisms--a stimulatory event initiated intracellularly and inhibition of growth resulting from a cell surface action. 5HT (1 microM) plus 0.1 mM iproniazid (a 5HT metabolic inhibitor) produced a severalfold stimulation of DNA synthesis (as measured by [3H]thymidine incorporation) of SMCs after a 17-24-hour incubation with only a slight elevation of cellular cAMP. This stimulatory effect responded synergistically with other growth factors including platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor and was effectively reversed by 5HT uptake inhibition. It was not produced by 5-hydroxyindoleacetic acid, a metabolite of 5HT. In the presence of 1 microM 5HT plus 0.1 mM isobutylmethylxanthine (IBMX), cAMP was elevated eightfold, dendritic formation occurred, and [3H]thymidine labeling of SMCs was inhibited. Inhibition of labeling by [3H]thymidine was mimicked by other agents that elevated cellular cAMP (10 microM histamine, 1 microM isoproterenol plus 0.1 mM IBMX, and 10 microM forskolin) and by 1 mM dibutyryl cAMP. This inhibitory effect was not blocked by either inhibition of 5HT uptake or 5HT-receptor antagonists ketanserin (5HT2); methiothepin, spiperone, and mianserin (5HT1/5HT2); and 3-tropanyl-indole-3-carboxylate and 3-tropanyl-3,5-dichlorobenzoate (5HT3). However, similar to 5HT, the 5HT1A agonist, (+/-)-8-hydroxy-(+/-)-2-dipropylamino-8-hydroxy-1,2,3, 4-tetrahydronaphthalenehydrobromide, in association with IBMX, produced an elevation in cAMP and inhibition of labeling by [3H]thymidine. 5HT, in the presence of either iproniazid or IBMX, did not alter [Ca2+]i, indicating that [Ca2+]i was not a signal for either of these actions.(ABSTRACT TRUNCATED AT 250 WORDS)
Doppler and electromagnetic comparisons of instantaneous aortic flow characteristics in primates.
Authors: Spencer K T , Lang R M , Neumann A , Borow K M , Shroff S G
Published: June 2012

Assessment of the pulsatile mechanical behavior of the coupled left ventricle and the peripheral arterial circulation requires accurate estimation of instantaneous aortic flow. Before the availability of Doppler technologies, this could only be achieved by invasive techniques. The purpose of this study was to assess the accuracy of Doppler-based measurement of instantaneous aortic blood flow and waveform morphology throughout ventricular ejection when compared with an established invasive method. Accordingly, data from electromagnetic flow and continuous-wave aortic Doppler recordings were simultaneously acquired and compared in five monkeys over a wide range of flows generated by intravenous infusions of the beta-adrenoceptor agonist dobutamine and the alpha-receptor agonist methoxamine. Instantaneous aortic pressure was measured using a high-fidelity micromanometer-tipped catheter placed in the ascending aorta. Excellent correlations were noted for stroke volume, cardiac output, left ventricular ejection time, maximal flow velocity, and maximal rate of change of flow velocity (dQ/dtmax). When compared with electromagnetic flows, continuous-wave aortic Doppler had significantly lower times to maximal flow velocity and dQ/dtmax. Frequency domain analysis indicated that both the magnitude and phase were within +/- 6% up to the third harmonic. Instantaneous comparison disclosed that during early systole (up to 10% of ejection) Doppler was higher than electromagnetic flow rate by 11 +/- 19% (p less than 0.05). At 20-30% of systolic ejection, electromagnetic flow rates were slightly higher than Doppler (5 +/- 4% at 20% of ejection, p less than 0.001 and 2 +/- 3% at 30% of ejection, p less than 0.05). From 40% of ejection to the end of systole, flow rates using both techniques were virtually identical.(ABSTRACT TRUNCATED AT 250 WORDS)
Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction.
Authors: Vanoli E , De Ferrari G M , Stramba-Badiale M , Hull S S , Foreman R D , Schwartz P J
Published: June 2012

The interest for the antifibrillatory effect of vagal stimulation has been largely limited by the fact that this concept seemed restricted to acute experiments in anesthetized animals. To explore the potentially protective role of vagal stimulation in conscious animals we developed a chronically implantable device to be placed around the cervical right vagus. An anterior myocardial infarction was produced in 161 dogs; 1 month later an exercise stress test was performed on the 105 survivors. Toward the end of the test the circumflex coronary artery was occluded for 2 minutes. Fifty-nine (56%) dogs developed ventricular fibrillation and, before this test was repeated, were assigned either to a control group (n = 24) or to be instrumented with the vagal device (n = 35). Five dogs were excluded because of electrode malfunction. Compared with the heart rate level attained after 30 seconds of occlusion during exercise in the control test, vagal stimulation led to a decrease of approximately 75 beats/min (from 255 +/- 33 to 170 +/- 36 beats/min, p less than 0.001). In the control group 22 (92%) of 24 dogs developed ventricular fibrillation during the second exercise and ischemia test. By contrast, during vagal stimulation ventricular fibrillation occurred in only 3 (10%) of the 30 dogs tested and recurred in 26 (87%) during an additional exercise and ischemia test in the control condition (p less than 0.001 versus the vagal stimulation test; internal control analysis). Combined analysis of the tests performed in the control condition showed that ventricular fibrillation was reproducible in 48 (89%) of the 54 dogs tested. The protective effect of vagal stimulation was also significant in the group comparison analysis and even after exclusion of those four dogs in which ventricular fibrillation was not reproducible (92% versus 11.5%, control versus vagal stimulation, p less than 0.001). When heart rate was kept constant by atrial pacing, the vagally mediated protection was still significant (p = 0.015) as five (55%) of nine dogs survived the test. This study shows that vagal stimulation, performed shortly after the onset of an acute ischemic episode in conscious animals with a healed myocardial infarction, can effectively prevent ventricular fibrillation. This striking result seems to depend on multiple mechanisms having a synergistic action. The decrease in heart rate is an important but not always essential protective mechanism. The electrophysiological effects secondary to the vagally mediated antagonism of the sympathetic activity on the heart are likely to play a major role.
Paradoxically decreased aortic wall stiffness in response to vitamin D3-induced calcinosis. A biphasic analysis of segmental elastic properties in conscious dogs.
Authors: Cabrera Fischer E I , Armentano R L , Levenson J , Barra J G , Morales M C , Breitbart G J , Pichel R H , Simon A
Published: June 2012

We studied the aortic elastic behavior in response to vitamin D3-induced accelerated calcinosis in conscious dogs chronically instrumented with a pressure microtransducer and a pair of ultrasonic diameter dimension gauges in the upper descending thoracic aorta. The two functional phases of the elastic segmental properties of the aorta in vivo were discriminated by computation on a beat-by-beat basis from the phasic pressure-diameter (P-D) hysteresis loops in basal conditions and during the transient state of a wide range of pressures obtained mechanically (aortic occlusion) or pharmacologically (angiotensin bolus). The overall P-D curve formed by all P-D hysteresis loops was comprised of two linear relations according to a model that assumes that only elastin is stretched at lower pressures, whereas both elastin and collagen are stretched at higher pressures. The slope of the first linear portion of the P-D curve was considered as the elastin P-D elastic modulus, and the slope of the curve obtained by subtraction between the P-D curve and the extrapolation of the elastin straight line was assumed to be the collagen P-D elastic modulus. After vitamin D3-induced calcinosis, the elastin elastic modulus was unaffected, whereas the collagen elastic modulus decreased significantly during occlusion maneuvers (58.6%, p less than 0.01) and during bolus injections of angiotensin (37.2%, p less than 0.05). The collagen elastic modulus correlated with the serum calcium concentration (r = -0.65, p less than 0.001) and with the aortic pulse pressure (r = 0.51, p less than 0.01), and this relation persisted at constant heart rate. Histopathologic analysis evidenced calcium-depositing elastic lamina, focal disappearance of collagen, and rupture of elastic fibers. The present study shows that accelerated, severe, experimental calcinosis-inducing calcium deposition inside the large artery walls is accompanied by a clear-cut paradoxical reduction in arterial rigidity that is mainly due to functional and structural modification of collagen elasticity.
Measurement of endothelial cytosolic calcium concentration and nitric oxide production reveals discrete mechanisms of endothelium-dependent pulmonary vasodilatation.
Authors: Archer S L , Cowan N J
Published: June 2012

Nitric oxide is an endothelium-derived relaxing factor. Conversion of L-arginine to nitric oxide follows mediator-induced elevation of endothelial cytosolic calcium concentration. However, not all endothelium-dependent vasodilatation is caused by endothelium-derived relaxing factor, and few studies have correlated changes in vascular tone with measurement of free cytosolic calcium concentration or nitric oxide. The effects of three endothelium-dependent vasodilators (acetylcholine, bradykinin, and A23187) on vascular tone and nitric oxide production were studied in proximal rat pulmonary artery rings. Changes in free cytosolic calcium concentration and nitric oxide production were also studied in bovine pulmonary artery endothelial cells. A23187 and bradykinin caused pulmonary vasodilatation, nitric oxide production, and elevation of endothelial calcium concentrations. Although acetylcholine caused endothelium-dependent vasodilatation, it reduced free cytosolic calcium concentration and failed to increase nitric oxide levels. Acetylcholine-induced dilatation was partially inhibited by meclofenamate but was unaffected by ouabain. Acetylcholine, unlike bradykinin and A23187, does not act through a nitric oxide-dependent mechanism in the rat pulmonary vasculature.
Effect of left atrial filling pressure on the activity of specific myosin isozymes in rat heart.
Authors: Kato N S , Weisberg A , Winegrad S
Published: June 2012

One of the fundamental properties of cardiac muscle is the increase in force generated and work performed with a rise in the resting length of the tissue. There are data to indicate that length-dependent responses of electromechanical coupling and calcium binding by troponin are part of the basis for the pressure-volume relation in the heart. In this study, the contribution of changes in the functional properties of the contractile proteins independent of modification in electromechanical coupling has been examined. Isolated working hearts containing either a mixture of myosin heavy chain (MHC) isozymes (alpha[fast] and beta [slow]) or exclusively the fast MHC have been subjected to left atrial filling pressures (LAPs) between 5 and 20 cm H2O. After 40 minutes at a given LAP, the heart was quickly frozen. The relative activities of calcium- and actin-activated ATPase of V1 and V3 myosin, containing alpha- and beta-MHC, were measured in cryostatic sections of the heart by quantitative histochemistry under conditions for which the concentration of calcium would not be limiting. In hearts containing both isozymes of myosin, the relative enzymatic activity of each isozyme of myosin varied with LAP. At low LAP, V1 was primarily responsible for the enzymatic activity, but as LAP increased the relative contribution of V1 decreased and that of V3 increased. The change in the calcium- and actin-activated activities of the enzyme with change in LAP occurred within 5 minutes and was reversible. In spite of the apparent substitution of enzymatic activity of V3 for V1, total myosin ATPase activity did not decline, but instead remained constant.(ABSTRACT TRUNCATED AT 250 WORDS)
Ethanol acutely and reversibly suppresses excitation-contraction coupling in cardiac myocytes.
Authors: Danziger R S , Sakai M , Capogrossi M C , Spurgeon H A , Hansford R G , Lakatta E G
Published: June 2012

We used adult rat cardiac myocytes to examine the acute effects of 0.1-5.0% (vol/vol) ethanol (ETOH) on 1) the cytosolic [Ca2+] (Cai) transient measured as the change in indo 1 fluorescence at 410/490 nm and contraction elicited by electrical stimulation of single cells and 2) the sarcoplasmic reticulum (SR) Ca2+ content in cell suspensions. During stimulation at 1 Hz, clinically relevant ETOH correlations (0.1-0.15% [vol/vol]) caused a 10-15% decrease in the contraction amplitude, measured by myocyte edge tracking, without decreasing the Cai transient that initiates contraction. At higher ETOH concentrations (1-5% [vol/vol]), ETOH caused profound contractile depression and also reduced the magnitude of the Cai transient. These effects were reversed within minutes of ETOH washout. Addition of norepinephrine (10 microM) to the bathing solution or an increase in bathing [Ca2+] in the continued presence of ETOH could also reverse its effects. The relation of the amplitude of the Cai transient to the contraction amplitude measured across a range of bathing [Ca2+] was shifted by ETOH, such that for a given Cai transient a marked reduction in contraction amplitude occurred. In unstimulated myocyte suspensions, ETOH (1-5% [vol/vol]) caused a concentration-dependent depletion of SR Ca2+ content, manifested as a diminution in the Cai increase elicited by caffeine in the presence of extracellular EGTA and no added Ca2+. Thus, in rat cardiac myocytes a reduction in the myofilament Ca2+ response, possibly due to a decrease in myofilament Ca2+ sensitivity, is a mechanism for contractile depression due to clinically relevant ETOH concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Diminished tolerance of prehypertrophic, cardiomyopathic Syrian hamster hearts to Ca2+ stresses.
Authors: Hano O , Lakatta E G
Published: June 2012

Although abnormal myocardial calcium homeostasis in the cardiomyopathic hamster (CMH) has been documented in the hypertrophic stage of the disease, the Ca2+ tolerance before the hypertrophic stage has not been investigated. We studied isovolumic contractile function in response to a variety of Ca2+ stresses including increases in perfusate [Ca2+] (Cao), the Ca2+ channel agonist Bay K 8644, and alpha- or beta-adrenergic agonists of isolated perfused hamster hearts from 24-45-day-old male CMH, BIO 14.6 strain, and age- and sex-matched F1B strain controls. The coronary flow at a constant perfusion pressure did not differ between two groups at baseline or after any Ca2+ stress. At a Cao of 1.0 mM, neither end-diastolic pressure (EDP) nor developed pressure (DP) nor half relaxation time (RT1/2) during stimulation at 1-3 Hz differed between the two groups; as Cao was increased up to 10 mM, CMH hearts showed a lower threshold for the occurrence of a Ca2+ overload profile: EDP and RT1/2 increased to a greater, and DP to a lesser, extent in CMH than in control hearts. To determine whether calcium influx via Ca2+ channels mediates the lower threshold for Ca2+ overload in CMH hearts, we measured resting pressure and scattered laser light intensity fluctuation (SLIF) in unstimulated hearts. Prior studies have shown that SLIF is generated by microscopic tissue motion caused by diastolic spontaneous sarcoplasmic reticulum Ca2+ release and that SLIF amplitude reflects the extent of cell and sarcoplasmic reticulum Ca2+ loading. The Ca(2+)-dependent increase in resting pressure in unstimulated hearts was highly correlated with an increase in SLIF, and this relation was steeper in CMH than in control hearts. CMH hearts also showed a reduced threshold for the occurrence of a Ca2+ overload profile in response to the adrenergic receptor agonists and the Ca2+ channel agonist during electrical stimulation in a Cao of 2.0 mM: maximum DP achieved with each agonist was significantly less and the dose-response curves to each agonist were shifted leftward in CMH versus control hearts. In CMH hearts EDP began to increase at a significantly lower concentration of each agonist, and the maximum extent of increase in EDP in response to all agonists was significantly enhanced compared with control hearts. In response to beta-adrenergic or Ca2+ channel agonists, neither resting pressure nor SLIF in unstimulated hearts increased in control or in CMH hearts. In contrast, in response to alpha-adrenergic stimulation, both SLIF and resting pressure increased to a greater extent in CMH than in control hearts.(ABSTRACT TRUNCATED AT 400 WORDS)
Cardiac cycle length modulates cardiovascular regulation that is dependent on previous beat contraction history.
Authors: Slinker B K
Published: June 2012

Previous studies of the beat-to-beat regulation of left ventricular performance in the intact cardiovascular system have shown that the performance of the left ventricle on any one beat is influenced by the mechanical events of the previous beat, so-called previous beat contraction history. The general hypothesis investigated in this study is that previous beat contraction history occurs because of the perturbation of one or more biochemical processes with time courses that are long relative to one cardiac cycle. If this is true, then previous beat contraction history should depend on the interval between beats and, therefore, should extend beyond the previous beat to two, or even three, previous beats as heart rate is increased. Hemodynamic responses to random preload and afterload changes were measured in 11 anesthetized open-chest dogs on right heart bypass at three paced heart rates. Multiple linear regression was used to analyze these hemodynamic sequences and identify variables from the previous one, two, or three beats that were important in the mechanical history dependence of left ventricular function. The results of this analysis showed that under baseline conditions, all 11 hearts showed one beat of history dependence, with only two of 11 hearts showing a dependence on the previous two or three beats. At the highest heart rate, all 11 hearts still showed one beat of history dependence, but 10 of 11 hearts showed two beats of history dependence, and four of 11 showed three beats of history dependence (p less than 0.05). A general framework for the mechanism underlying these findings, which relates previous beat contraction history to the interval-dependent mechanical restitution phenomenon, is proposed and discussed.