bluuebunny/crossref_metadata_2025 huggingface dataset:
Subcellular distribution of high-affinity type IV cyclic AMP phosphodiesterase activity in rabbit ventricular myocardium: relations to the effects of cardiotonic drugs.
Authors: Kithas P A , Artman M , Thompson W J , Strada S J
Published: June 2012

Rabbit ventricular myocardium contains distinct cytosolic and particulate cyclic AMP (cAMP) phosphodiesterase activities that exhibit characteristics ascribed to a high-affinity type IV cAMP phosphodiesterase activity found in several tissues. The particulate activity associated with sarcoplasmic reticulum vesicles has an apparent Km for cAMP of about 0.3 microM and a Vmax of 2.45 +/- 0.55 nmol/min/mg. Cyclic GMP (cGMP) inhibits hydrolysis measured at 0.25 microM cAMP with an IC50 value of 0.28 microM. In comparison, a ventricular cytosolic high-affinity cAMP phosphodiesterase activity obtained by anion exchange chromatography (Peak III) has an apparent Km of 0.93 microM and a Vmax of 17 +/- 1 nmol/min/mg. Hydrolysis of 0.25 microM cAMP by this cytosolic activity is weakly inhibited by cGMP with an IC50 value of 142 microM. Particulate enzyme activity is 60-fold more sensitive to inhibition by milrinone than is the cytosolic form (Ki = 0.18 versus 11 microM, respectively); the pyridazinone imazodan is a 12-fold more potent inhibitor of the particulate activity than of the cytosolic form (Ki = 1.5 versus 18 microM, respectively). Inhibition of both cytosolic and particulate enzyme activities appears competitive in nature. Solubilization of particulate activity did not significantly alter its affinity for substrate or sensitivity to inhibition by cGMP. In the presence of a submaximally activating concentration of forskolin (0.4 microM), selective phosphodiesterase inhibitors potentiated the activation of protein kinase in isolated ventricular septal slices. Under these conditions, changes in cAMP-dependent protein kinase activity ratios correlated more closely with contractile responses than did changes in intracellular content of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
Role of adenosine in coronary vasodilation during exercise.
Authors: Bache R J , Dai X Z , Schwartz J S , Homans D C
Published: June 2012

This study examined the hypothesis that increases in myocardial blood flow during exercise are mediated by adenosine-induced coronary vasodilation. Active hyperemia associated with graded treadmill exercise and coronary reactive hyperemia were examined in chronically instrumented awake dogs during control conditions, after intracoronary infusion of adenosine deaminase (5 units/kg/min for 10 minutes), and after adenosine receptor blockade with 8-phenyltheophylline. Both adenosine deaminase and 8-phenyltheophylline caused a rightward shift of the dose-response curve to intracoronary adenosine; 8-phenyltheophylline was significantly more potent than adenosine deaminase. Adenosine deaminase caused a 33 +/- 7 to 39 +/- 3% decrease in reactive hyperemia blood flow following coronary occlusions of 5-20 seconds duration, respectively, while 8-phenyltheophylline produced a 40 +/- 6 to 62 +/- 8% decrease in reactive hyperemia. Increasing myocardial oxygen consumption during treadmill exercise was associated with progressive increase of coronary blood flow. Neither adenosine deaminase nor 8-phenyltheophylline attenuated the increase in coronary blood flow or the decrease of coronary vascular resistance during exercise. Neither agent altered the relation between myocardial oxygen consumption and coronary blood flow. Thus, although both adenosine deaminase and 8-phenyltheophylline antagonized coronary vasodilation in response to exogenous adenosine and blunted coronary reactive hyperemia, neither agent impaired coronary vasodilation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support a substantial role for adenosine in mediating coronary vasodilation during exercise.
Role of sarcoplasmic reticulum in arterial contraction: comparison of ryanodines's effect in a conduit and a muscular artery.
Authors: Ashida T , Schaeffer J , Goldman W F , Wade J B , Blaustein M P
Published: June 2012

Ryanodine interferes with sarcoplasmic reticulum function in various types of muscle; in vascular smooth muscle, it can inhibit contractions that depend on sarcoplasmic reticulum calcium release, probably by depleting the sarcoplasmic reticulum calcium store. We tested ryanodine and calcium channel blockers (verapamil, diltiazem, and nitrendipine) on small rings of rat thoracic aorta (RA) and bovine tail artery (BTA) to determine the relative contributions of sarcoplasmic reticulum calcium release and gated calcium entry to contractions induced by norepinephrine, caffeine, and 100 mM K depolarization. Ryanodine blocked caffeine contractions in both tissues and attenuated norepinephrine responses (by 52% in RA, 14% in BTA) but minimally altered potassium contractions. Calcium channel blockers almost completely abolished potassium contractions and reduced norepinephrine contractions (by 45% in RA, 82% in BTA) but hardly affected caffeine responses. The blocking effects of ryanodine and calcium channel antagonists on the norepinephrine responses were additive. Ryanodine had no effect on baseline tension in the standard media; however, when calcium extrusion via Na-Ca exchange was inhibited by low external sodium (0-calcium, low-sodium solution), tension increased progressively after introduction of ryanodine. This indicates that the sarcoplasmic reticulum calcium released by ryanodine then accumulated in the cytosol and activated contraction; restoration of external sodium caused prompt relaxation. The smaller effects of caffeine and ryanodine in BTA indicate that sarcoplasmic reticulum plays a less important role in calcium control in this tissue, with gated calcium entry dominating. These functional findings are correlated with electron-microscopic evidence that BTA has about 60% less sarcoplasmic reticulum than does RA. Ryanodine appears to be a useful tool for determining the functional relevance of sarcoplasmic reticulum for contraction in different arterial smooth muscles.
Impaired fibrinolysis-inducing capacity for postinjury phenotype of cultivated human arterial and human atherosclerotic intimal smooth muscle cells.
Authors: Björkerud S
Published: June 2012

Impaired fibrinolysis is believed to promote atherosclerosis and contribute to myocardial infarction. The major triggering factor for fibrinolysis is vascular tissue plasminogen activator (t-PA), and the aim of this study was to evaluate the capacity of human arterial smooth muscle cells (SMC) for induction of fibrinolysis. SMC were plated on labeled fibrin gels, and lysis was measured as release of label. Fibrinolytic capacity was dependent on the phenotypic state of SMC. The "multilayered phenotype" to which SMC modulate after cellular injury had a much lower fibrinolysis-inducing capacity than the more ordinary "monolayered" SMC type. Fibrinolysis was mediated by activation of plasminogen. In long-term experiments under conditions imitating thrombolysis, platelet-derived growth factor promoted fibrinolysis indirectly by increase of SMC number, and a direct effect on cellular production of t-PA was not detected. SMC from atherosclerotic intima had a much lower capacity for induction of fibrinolysis than cells from adjacent nonatherosclerotic intima. SMC also displayed several structurally detectable interactions with the fibrin substratum, such as organization of the gel by means of extension of numerous filamentous processes and contraction and wrinkling of the gel. In conclusion, human arterial SMC in vitro induce fibrinolysis by activation of plasminogen. This capacity is dependent on phenotype and lowered for SMC from atherosclerotic intima, suggesting impairment after arterial injury and in atherosclerosis.
Improved distribution of regional oxygenation in denervated ischemic dog myocardium.
Authors: Acad B A , Joselevitz-Goldman J , Scholz P M , Weiss H R
Published: June 2012

The role of the adrenergic nervous system in the response to coronary artery occlusion has been examined using surgical and chemical denervation techniques. Experiments were conducted on four groups of dogs (n = 18): 1) untreated controls; 2) intrapericardial denervation immediately prior to coronary ligation; 3) surgical denervation 2 weeks prior to the experiment; and 4) chemical sympathectomy 5 days prior to the experiment with 6-hydroxydopamine (50 mg/kg). Small artery and vein O2 saturations were obtained microspectrophotometrically and combined with radioactive microsphere blood flow determinations to calculate regional myocardial O2 consumption in open chest dogs. Denervation significantly reduced the preocclusion heart rate from 165 +/- 16 beats/min in the control to 114 +/- 13 in the chronic surgically denervated and to 137 +/- 15 in the chemically sympathectomized groups. After 2 hours of occlusion, the O2 consumption and flow were similar in the nonischemic area except for lower values in the surgically denervated group. Total coronary blood flow and O2 consumption in the occluded regions were not significantly affected by chronic denervation. However, significant elimination of areas with low venous O2 saturation (less than 20%) were found in the ischemic myocardium of the chronically denervated groups as compared with the control or with the acutely denervated dogs. The mean venous O2 saturation was found to be significantly higher in all regions of these two groups as compared with the control. The O2 extraction was also lowered. Thus, chronic denervation reduced microregional heterogeneity of oxygenation in the ischemic myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
Neurogenic histaminergic vasodilation in canine skeletal muscle: mediation by alpha 2-adrenoceptor stimulation.
Authors: Camazine B , Shannon R P , Guerrero J L , Graham R M , Powell W J
Published: June 2012

This study examines the neurogenic effect of alpha 2-adrenoceptor stimulation on skeletal muscle vascular resistance and its relation to the level of background sympathetic activity. The isolated, separately perfused, neurally intact canine gracilis muscle preparation was used since it permits deliberate and quantifiable alterations in background sympathetic activity, as measured by skeletal muscle vascular resistance. Systemic intravenous UK-14304, a highly selective alpha 2-adrenoceptor agonist, produced a precipitous, neurogenic vasodilation that lowered vascular resistance below the subsequently denervated resistance, thus indicating that an active vasodilation was involved. The overall magnitude of the vasodilation was much greater in animals that had been hemorrhaged to elevate background sympathetic activity than in animals that had been transfused to lower background activity. The neurogenic vasodilation was unaffected by baroreceptor and cardiopulmonary receptor denervation and by prior cholinergic-receptor blockade of the gracilis muscle. Prior H1- and H2-histaminergic-receptor blockade, on the other hand, eliminated the active vasodilation but not a vasodilation down to the subsequently denervated resistance. Prior alpha 1-adrenoceptor blockade lowered resistance down to the subsequently denervated resistance and greatly attenuated the active vasodilation. The present study demonstrates that withdrawal of sympathetic activity by alpha 2-adrenoceptor stimulation produces an active vasodilation resulting from histamine release in skeletal muscle as well as a passive vasodilation resulting from lysis of peripheral vasoconstrictor tone.
Augmented expression of atrial natriuretic polypeptide gene in ventricles of spontaneously hypertensive rats (SHR) and SHR-stroke prone.
Authors: Arai H , Nakao K , Saito Y , Morii N , Sugawara A , Yamada T , Itoh H , Shiono S , Mukoyama M , Ohkubo H
Published: June 2012

Tissue levels of atrial natriuretic polypeptide (ANP) and ANP messenger RNA (mRNA) in the atrium and ventricle were measured simultaneously in spontaneously hypertensive rats (SHR) and its substrain, SHR-stroke prone (SHRSP), and these levels were compared with those in control Wistar-Kyoto rats (WKY). At 27 weeks of age with established hypertension and ventricular hypertrophy, ANPmRNA levels in ventricles from SHR and SHRSP were markedly increased, and total contents of ventricular ANPmRNA in SHR and SHRSP were approximately 50% and 250%, respectively, of the corresponding atrial contents. However, levels and total contents of atrial ANPmRNA in SHR and SHRSP were similar to those of WKY, and the total content of ventricular ANPmRNA in WKY was only 6% of the content of atrial ANPmRNA. ANP concentrations in ventricles of SHR and SHRSP were increased in association with the augmentation of ANPmRNA levels. During the prehypertensive stage at 6 weeks of age, slight increases in levels and total contents of ANPmRNA and ANP in the ventricle were observed only in SHRSP. These results demonstrate that the expression of the ANP gene is markedly augmented in ventricles of SHR and SHRSP, especially of SHRSP, at the stage of established hypertension and ventricular hypertrophy, and they also suggest that these genetically hypertensive rats are one of the best animal models to investigate the biosynthesis, storage, and secretion of ventricular ANP.
Effects of alloxan-induced diabetes on ischemia-reperfusion injury in rabbit hearts.
Authors: Vogel W M , Apstein C S
Published: June 2012

Hearts from rabbits with 8-16 weeks of alloxan-diabetes were compared with hearts from normal rabbits to determine whether diabetic myocardium is more sensitive to ischemic injury. In isolated buffer-perfused hearts, left ventricular developed pressure, diastolic pressure, time to peak pressure (TTPP), time to half-maximal relaxation (RT1/2), and positive and negative dP/dt were measured during generation of left ventricular filling curves before and after 90 minutes of low-flow ischemia. Hearts from diabetic rabbits (blood glucose, 384 +/- 28 mg/dl, mean +/- 95% confidence limits) had left ventricular developed and diastolic pressures similar to normal hearts but exhibited significant increases in TTPP and RT1/2 with decreased positive and negative dP/dt. Left ventricular chamber volume relative to heart mass was greater in diabetic than in normal hearts. Recovery of developed pressure after ischemia was similar in normal (41 +/- 16%) and diabetic hearts (47 +/- 13%). In diabetic hearts during recovery from ischemia, TTPP and R1/2 remained increased compared with normal hearts, with positive and negative dP/dt decreased compared with normal hearts, in proportion to the preischemic differences. After ischemia, high-energy phosphates were depleted to the same extent in normal and diabetic rabbits. In coronary ligation experiments, histochemically determined infarct size in diabetic rabbits after 30 minutes occlusion and 24 hours reperfusion was similar to that in normal rabbits when adjusted for a significantly smaller heart weight and a correspondingly smaller anatomic risk region in the diabetic animals. Thus, despite characteristic abnormalities of mechanical function in diabetic hearts, the severity of injury after ischemia with reperfusion was normal for diabetic hearts.
Pertussis toxin-treated dog: a whole animal model of impaired inhibitory regulation of adenylate cyclase.
Authors: Fleming J W , Hodges T D , Watanabe A M
Published: June 2012

We have shown previously that stimulation of high-affinity GTP hydrolysis and inhibition of adenylate cyclase activity by muscarinic agonists are mediated by pertussis toxin (IAP) substrates (Gi and Go) in canine cardiac sarcolemma. We have now used the pertussis toxin-treated dog as a whole animal model in which Gi- and Go-mediated biochemical mechanisms can be studied. Mongrel dogs were injected intravenously with IAP 48 hours prior to death and isolation of left ventricular sarcolemma. Treatment of the animal in vivo with the toxin prevented subsequent in vitro IAP-catalyzed [32P]ADP-ribosylation of substrates in cardiac, erythrocytic, and renal cortical plasma membranes, suggesting that ADP-ribosylation occurred in vivo from endogenous substrate. Consistent with our previous results obtained by treating sarcolemma in vitro with IAP, muscarinic receptor-mediated stimulation of high-affinity GTP hydrolysis and inhibition of GTP-activated adenylate cyclase activity were attenuated in sarcolemma purified from the toxin-treated animals. Proximal to adenylate cyclase, guanine nucleotide regulation of muscarinic receptor affinity for agonists was also abolished in membranes from the toxin-treated animals. In addition, the ability of oxotremorine to attenuate GTP regulation of stimulation of adenylate cyclase activity by magnesium ions was abolished in sarcolemma from the IAP-treated dogs. Thus, cardiac sarcolemma isolated from the IAP-treated animals displayed biochemical characteristics of an adenylate cyclase system in which inhibitory regulatory pathways had been attenuated. The cardiac biochemical studies and the in vivo ADP-ribosylation of noncardiac IAP substrates also suggests considerable potential use of this model in the physiological and biochemical study of regulatory mechanisms mediated by GTP-binding proteins in other systems.
Rates of glycolysis and glycogenolysis during ischemia in glucose-insulin-potassium-treated perfused hearts: A 13C, 31P nuclear magnetic resonance study.
Authors: Hoekenga D E , Brainard J R , Hutson J Y
Published: June 2012

The effects of 11.7 mM glucose, insulin, and potassium (GIK) on metabolism during ischemia were investigated in the perfused guinea pig heart using magnetic resonance spectroscopy. Intracellular metabolites, primarily glycogen and glutamate, were labeled with 13C by addition of [1-13C]glucose to the perfusate during a normoxic, preischemic period. 13C and 31P NMR spectroscopy was used to observe the metabolism of 13C-labeled metabolites simultaneously with high-energy phosphorus metabolites and pH. The extent of acidosis and the rate and amount of labeled lactate accumulation during ischemia were the same in control (3 mM glucose + insulin) and GIK-treated hearts. In contrast, the rate of labeled glycogen mobilization during ischemia in GIK-treated hearts was one third the rate observed in control hearts. These observations suggest that GIK decreased the rate of glycogenolysis during ischemia without affecting the rate of glycolysis. We propose that glucose contributed as a glycolytic substrate to a greater extent during ischemia in GIK-treated hearts than in hearts perfused with 3 mM glucose and insulin. The glycogen-sparing effect of GIK demonstrated in these studies could delay the onset of ischemic damage in a clinical setting by prolonging the availability of glycolytic substrate necessary for production of high-energy phosphate.
A computer study of the relation between chamber mechanical properties and mean pressure-mean flow of the left ventricle.
Authors: Negroni J A , Lascano E C , Pichel R H
Published: June 2012

Computer simulation of left ventricular contraction was used to analyze the mean left ventricular pressure-mean flow relation with changes of parameter values: end-diastolic volume, contractile state, internal resistance, characteristic resistance, capacitance, end-diastolic stiffness, and heart rate and with changes of experimental conditions: filling kinetics (constant atrial pressure as opposed to constant end-diastolic volume) and coronary perfusion pressure (constant or varying with atrial pressure, i.e., self-perfused). The chamber mechanical properties used in the simulation were defined in terms of a modified purely elastic behavior model with a flow-dependent resistive component. Computed results showed that at constant end-diastolic volume and constant ventricular perfusion pressure the mean pressure-mean flow relation was linear, except for changes in internal resistance where a cubic fit of points was more appropriate. In these conditions, parameter variations in the accepted linear relation produced changes in the slope and mean pressure axis intercept. Imposition of changes in experimental conditions gave rise to nonlinear mean pressure-mean flow relations. The results indicate that with elastic-resistive chamber mechanical properties as a starting point, the experimental conditions would be responsible for the different shapes of the mean pressure-mean flow relation obtained in isolated heart experiments. However, a more complete description of chamber properties (such as the addition of a deactivation component) could also give rise to nonlinear pump function graphs.
Effect of adenosine on histamine release and atrioventricular conduction during guinea pig cardiac anaphylaxis.
Authors: Heller L J , Regal J F
Published: June 2012

Anaphylactic events occurring in cardiac tissue can result in severe metabolic imbalances. The present study addresses the question of whether adenosine, produced in response to this stress, influences either the antigen-antibody-induced alterations in cardiac function or the release of histamine, which is known to be one of the important mediators of the anaphylactic reaction. Isolated hearts of passively sensitized guinea pigs were perfused at constant flow in a Langendorff preparation with physiological salt solution. Under control conditions, antigen challenge evoked a rapid transient release of histamine, an increase in coronary vascular resistance and beating rate, and an increase followed by a decrease in left ventricular systolic pressure. The antigen-induced transient increase in adenosine release from 0.26 +/- 0.07 to 4.66 +/- 0.48 nmol/min/g was associated with a 75 +/- 9% increase in the PR interval in all hearts and atrioventricular blocks in six of 17 hearts. Antigen challenge was also conducted in the presence of theophylline, 8-(4-sulfophenyl) theophylline (SP-T), erythro-9-(2-hydroxy-3-nonyl) adenosine hydrochloride (EHNA), or exogenous adenosine. The major findings were that 1) the antigen-induced prolongation of the PR interval was attenuated by the adenosine receptor blockers theophylline (to 23 +/- 6%) and SP-T (to 15 +/- 4%); 2) the incidence of antigen-induced atrioventricular blocks tended to be decreased by theophylline (to three of 10 hearts) and SP-T (to zero of seven hearts) and to be increased by the adenosine deaminase inhibitor, EHNA (to six of 10 hearts); 3) none of the interventions had major influences upon antigen-induced alterations in vascular resistance, atrial automaticity, or systolic pressure; and 4) EHNA and adenosine both significantly increased adenosine levels before anaphylaxis and also enhanced the total histamine release induced by antigen challenge from a control value of 2,321 +/- 244 ng/g to 3,424 +/- 307 ng/g and 4,298 +/- 616 ng/g, respectively. We conclude from our data that increases in levels of endogenous adenosine during cardiac anaphylaxis may contribute to the development of atrioventricular conduction delays and blocks and that increases in levels of adenosine before antigen challenge may increase the amount of histamine released during cardiac anaphylactic reactions.
Nodal myosin distribution in the bovine heart during prenatal development: an immunohistochemical study.
Authors: Gorza L , Thornell L E , Schiaffino S
Published: June 2012

A novel type of cardiac myosin heavy chain, immunologically related to the myosin isoforms expressed during skeletal muscle development, has recently been described in sinoatrial and atrioventricular nodal fibers of the adult bovine heart (Gorza et al, J Cell Biol 1986; 102:1758-1766). The tissue-specific expression of this myosin type has been utilized in the present study to investigate the differentiation of nodal fibers during cardiac development. In 4-6-week-old bovine embryos, reactivity for nodal myosin was observed in a cluster of cardiac fibers in the sinus venosus wall, corresponding to the sinoatrial node primordium and in a number of fibers localized in the left atrial wall, especially in proximity to vascular orifices, possibly corresponding to the postulated left-sided sinoatrial node. In contrast, reactivity for nodal myosin was not detected in the atrioventricular node until 12 weeks of gestation. Before this stage, fibers reactive for nodal myosin were also seen scattered in the left atrial wall and interatrial septum, raising the possibility that atrioventricular nodal fibers may derive from the left-sided sinoatrial node. Reactivity for nodal myosin was never seen in normal atrial and ventricular myocardium, nor in the ventricular conduction tissue, indicating that nodal myosin does not represent a primordial myosin form, but is rather a specific marker of a distinct muscle cell lineage.
Opiate receptor-mediated decrease in renal nerve activity during hypotensive hemorrhage in conscious rabbits.
Authors: Morita H , Nishida Y , Motochigawa H , Uemura N , Hosomi H , Vatner S F
Published: June 2012

Effects of hemorrhage on renal nerve activity and of subsequent opiate receptor blockade with naloxone were studied in conscious rabbits. Mean arterial pressure remained constant at 77 +/- 2 mm Hg through 17 +/- 2 ml/kg hemorrhage, while renal nerve activity increased by 159 +/- 16%. After 25 +/- 1 ml/kg hemorrhage, mean arterial pressure fell by 42 +/- 3 mm Hg, and renal nerve activity decreased below the prehemorrhagic control level by 41 +/- 15%. Bolus injection of naloxone (3 mg/kg i.v.) increased mean arterial pressure to 79 +/- 2 mm Hg, not significantly different from the prehemorrhagic control level. Renal nerve activity increased by 171 +/- 28%, comparable to the peak increase during nonhypotensive hemorrhage. On a different day, hemorrhage was repeated, and phenylephrine was infused during the subsequent hypotension. Phenylephrine increased mean arterial pressure to the prehemorrhagic control level. With increasing mean arterial pressure, renal nerve activity increased from its level during hypotensive hemorrhage and recovered toward the prehemorrhagic control level (-26 +/- 11%), but it did not return to the peak value reached during nonhypotensive hemorrhage. To further examine the blocking effects of naloxone on changes in mean arterial pressure and renal nerve activity induced by exogenous opiate peptides, methionine-enkephalin was injected both in the control state and after treatment with naloxone. A bolus injection of methionine-enkephalin (10 micrograms/kg) decreased mean arterial pressure (-8.1 +/- 2.0 mm Hg) and renal nerve activity (-95 +/- 1%). Pretreatment with naloxone (0.5 mg/kg) effectively blocked this depressor effect and reduction in renal nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Atrioventricular nodal accommodation in isolated guinea pig hearts: physiological significance and role of adenosine.
Authors: Jenkins J R , Belardinelli L
Published: June 2012

The progressive prolongation of atrioventricular node (AVN) conduction time to a new steady-state value caused by sudden and maintained increases in atrial rate is the most common form of AV nodal accommodation. This study was undertaken to 1) characterize AV nodal accommodation in isolated perfused guinea pig hearts, 2) investigate the influence of potential modulators of this phenomenon such as acetylcholine and adenosine, and 3) determine the physiological significance of AV nodal accommodation on cardiac function. Beat-by-beat changes in AVN conduction time caused by single- or multiple-step increases in atrial pacing rate were measured during control conditions and in the presence of atropine (1 microM), propranolol (1 microM), and the adenosine antagonist BW-A1433 (1 microM). BW-A1433 was the only intervention that significantly reduced the cumulative and frequency-dependent prolongation of AVN conduction time but this was only observed at atrial cycle lengths less than or equal to 170 msec. In addition, BW-A1433 shortened the Wenckebach cycle length from 163 +/- 2 to 153 +/- 2 during normoxia and from 172 +/- 3 to 164 +/- 4 during mild hypoxia. In contrast, dipyridamole (1 microM), an adenosine uptake blocker, markedly accentuated the AVN conduction time prolongation, accentuated the AV block associated with fast atrial rates, and significantly increased the Wenckebach cycle length. These effects of dipyridamole were prevented and antagonized by BW-A1433 and adenosine deaminase. When O2 supply was limited and at the same time demand increased secondary to fast atrial pacing, the rate of adenosine release increased from a control of 125 +/- 27 to 580 +/- 54 pmol/min/g. This was accompanied by a significant prolongation in AVN conduction time that invariably progressed to AV block. Once AV block occurred, O2 consumption decreased, O2 supply-to-demand ratio improved and the rate of adenosine release dropped to 310 +/- 61 pmol/min/g. Reversal of the AV block with adenosine antagonists resulted in a decrease in O2 supply-to-demand ratio and a severalfold increase in the rate of adenosine release. In this feedback system, adenosine signals the imbalance between O2 supply and demand, causes AV block and, thus, reduces demand to compensate for the limited O2 supply. On the other hand, adenosine deaminase and antagonists act as "error signals" by attenuating the effect of adenosine, whereas dipyridamole enhances the "gain" of the system by potentiating the effects of adenosine.(ABSTRACT TRUNCATED AT 400 WORDS)
Defects in sarcolemmal Ca2+ transport in hearts due to induction of calcium paradox.
Authors: Makino N , Panagia V , Gupta M P , Dhalla N S
Published: June 2012

Na+-Ca2+ exchange and Ca2+-pump activities were studied in sarcolemmal vesicles isolated from rat hearts subjected to "calcium paradox" on perfusion with Ca2+-free medium followed by reperfusion with medium containing 1.25 mM Ca2+. Perfusion of hearts with Ca2+-free medium for 5 minutes did not affect the Na+-dependent Ca2+ uptake, ATP-dependent Ca2+ uptake, or Ca2+-stimulated ATPase activities in sarcolemma. Reperfusion of the Ca2+-deprived hearts with medium containing Ca2+ for 1-2 minutes increased Na+-dependent Ca2+ uptake, whereas reperfusion for 5-10 minutes decreased Na+-dependent Ca2+ uptake in sarcolemmal vesicles. Both ATP-dependent Ca2+ uptake and Ca2+-stimulated ATPase activities in sarcolemma were depressed on reperfusion of Ca2+-deprived hearts for 2-10 minutes. Reperfusion of Ca2+-deprived hearts for 5 minutes, which failed to generate contractile force, resulted in contracture without any recovery of the contractile force development. These changes in sarcolemmal Ca2+ transport and contractile function were prevented when hearts were perfused with Ca2+-free medium either in the presence of low sodium (35 mM) or at a low temperature (21 degrees C) before starting the reperfusion. No alterations in the purity of the preparation or permeability of sarcolemmal vesicles with respect to Na+ or Ca2+ were detected in hearts perfused with Ca2+-free medium or on reperfusion with medium containing calcium. The results indicate abnormalities in sarcolemmal Na+-Ca2+ exchange and Ca2+-pump mechanisms on reperfusion of Ca2+-deprived hearts with medium containing Ca2+, and such changes may partly account for the occurrence of intracellular Ca2+ overload during the development of calcium paradox.
Catheter-mediated electrical ablation: the relation between current and pulse width on voltage breakdown and shock-wave generation.
Authors: Bardy G H , Coltorti F , Stewart R B , Greene H L , Ivey T D
Published: June 2012

Voltage waveform breakdown is characteristic of barotraumatic shock-wave generation during electrical catheter ablation of cardiac arrhythmias. The purpose of this investigation was to avoid barotrauma by defining, in vitro, the limits of pulse amplitude and pulse width for rectangular constant-current pulses that do not result in voltage breakdown and subsequently to determine what pulsing frequency is safe for use when high-energy trains of pulses are used. Electric pulses were delivered with a variable waveform modulator with a wide dynamic range and bandwidth capable of delivering pulses of 30-10,000-mu sec duration with amplitudes of up to 25 A. Cathodal pulses were delivered to a 6F catheter immersed in fresh anticoagulated bovine blood warmed to 37 degrees C to stimulate the milieu of a catheter in the chambers of the human heart. The maximum pulse amplitude that could be delivered without incurring voltage waveform breakdown varied inversely with pulse duration. Pulses of 30 mu sec broke down at currents above 24 A (2,500 V). Pulses of 10,000-mu sec duration broke down at 1 A (250 V). The maximum safely delivered energy for a single pulse was 2.5 J for pulses of 80-120 mu sec. Peak power for single pulses was maximum at 50-55 kW with 30-50-mu sec pulses. Charge delivery for single pulses was maximized at 9 mC with long, 10,000-mu sec duration pulses. To deliver an electrical pulse with energy significantly greater than 2.5 J without incurring voltage breakdown, trains of pulses were delivered where each pulse in the train had previously been shown to be free of voltage breakdown.(ABSTRACT TRUNCATED AT 250 WORDS)
Diminished cardiac hypertrophy and muscle performance in older compared with younger adult rats with chronic atrioventricular block.
Authors: Walford G D , Spurgeon H A , Lakatta E G
Published: June 2012

The combined effect of advancing age and hemodynamic overload on cardiac muscle function has received little attention. In male, Sprague-Dawley rats, we studied the interaction of chronic atrioventricular heart block induced by transvenous electrocautery for 4-12 months (mean, 7 months) and age at study (12, 19 +/- 0.7, and 24 +/- 0.2 months) on cardiac hypertrophy and muscle function compared with age-matched, sham-operated controls. Hypertrophy was determined by the ratio of heart weight to tibial length. Muscle function was first determined from the mechanical variables of the isometric contraction of an excised, thin, left ventricular trabecular muscle bathed at 29 degrees C under a variety of calcium concentrations and stimulation patterns. Then, in the same muscles after disruption of membranes with Triton X-100, the force-pCa curve of the myofibrils was obtained. No hypertrophy occurred with aging in the control group, but alteration in hypertrophy with age occurred in the block group such that the youngest animals with block had the most hypertrophy (170%) and the oldest animals with block the least hypertrophy (120%). The tension developed by cardiac muscle and the duration of the isometric contraction were not affected by age in the control group but were significantly affected by age in the block group. The young animals with block had a markedly prolonged contraction duration and almost twice the developed tension compared with the older animals with block or with controls. The age-related difference in muscle contraction duration in the block group was associated with, and may have only been secondary to, the age-related difference in the extent of cardiac hypertrophy. For developed tension, the age-related difference in the block group could not be explained by differences in the extent of cardiac hypertrophy. Rather, this difference was attributable to both an increased myofibrillar force-generating capacity in the young block and to an impairment in excitation-contraction coupling in the old block. The results show that during long-term block, age exerted not only a significant effect on the extent of cardiac hypertrophy but also an independent effect on the developed tension of cardiac muscle.
Structural and reactivity alterations of the renal vasculature of spontaneously hypertensive rats prior to and during established hypertension.
Authors: Smeda J S , Lee R M , Forrest J B
Published: June 2012

The renal vasculature of Wistar Kyoto spontaneously hypertensive rats (SHR), prior to (4-5 week) and during established hypertension (21 week) and those of age-matched Wistar Kyoto normotensive rats (WKY) were morphometrically and pharmacologically studied. Under dilated conditions, the vascular resistances (RVR) of the isolated kidneys of young and adult SHR were similar to WKY. Morphometric measurements of renal vasculature indicated that the cross-sectional area of the intima and adventitia and its subcomponents were similar in adult SHR and WKY. With the exception of the preglomerular arterioles, all the renal arteries of adult SHR exhibited elevated cross-sectional quantities of total media, medial smooth muscle cells (SMCs), and extracellular space. Analysis of the SMCs indicated the presence of increased numbers of SMC layers and/or an increase in the SMC volume-to-surface area ratio in arteries sampled from adult SHR. Vascular contraction produced by infusing norepinephrine, BaCl2, angiotensin II, or by stimulating the renal nerves elevated the RVR to a greater degree in adult SHR than in WKY. The sensitivity of the renal vasculature to the various contractile agents was similar in adult SHR and WKY. When compared with WKY, prehypertensive SHR also exhibited increased cross-sectional quantities of arterial media and elevated amplitudes of RVR change in response to norepinephrine and renal nerve stimulation. However, the vascular contractile sensitivity to norepinephrine was reduced. Our results indicate that renovascular wall thickening and the hypercontractile reactivity associated with such a change precedes hypertension in SHR. In prehypertensive SHR, elevations in RVR might be counterbalanced by a decreased norepinephrine sensitivity. An increase in the norepinephrine contractile sensitivity and further vascular thickening with age could elevate the RVR and establish hypertension.
Coiled perimysial fibers of papillary muscle in rat heart: morphology, distribution, and changes in configuration.
Authors: Robinson T F , Geraci M A , Sonnenblick E H , Factor S M
Published: June 2012

The morphology, distribution, and configuration of coiled perimysial fibers of rat heart papillary muscle were studied. Methods included bright-field light microscopy of silver-stained sections, scanning and transmission electron microscopy, and differential interference contrast light microscopy of unfixed and unstained specimens. Coiled fibers, elliptical in cross section, are arranged in a branched network that diverges from the muscle-tendon junction and is continuous throughout the length of the muscle and into the ventricle wall. Most fibers range in diameter from less than 1 micron to 10 micron and are parallel with the long axis of the muscle, although branching is common and oblique orientations are seen. Several myocytes are associated with each coiled perimysial fiber. Constituent fibrils (diameter, 40-50 nm) occur in bundles twisted within the fiber. Small satellite elastic fibers are parallel to the collagen fiber axes. Stereo analysis of the coiled perimysial fibers reveals helical configurations, as opposed to planar waviness, that become less convoluted or even straighten as the resting muscle is stretched. Calculations based on cross-sectional areas of fibers, changes in fiber configurations, and tensile moduli reported for collagen fibers of other tissues show that the potential tensile strength of the network of coiled perimysial fibers is sufficient to contribute significantly to the mechanical properties of papillary muscle. Detailed evaluations of possible roles of the coiled perimysial collagen fiber system as a function of passive stretch and contraction in ventricular wall, as well as in papillary muscle, warrant further study.
Ca2+ transients in perfused hearts revealed by gated 19F NMR spectroscopy.
Authors: Marban E , Kitakaze M , Chacko V P , Pike M M
Published: June 2012

Gated acquisition of 19F nuclear magnetic resonance spectra from perfused ferret hearts loaded with the fluorinated Ca2+ indicator 5,5'-F2-BAPTA allows direct quantitation of the cyclical changes in the intracellular free Ca2+ concentration ([Ca2+]i) that underlie contraction in intact hearts. [Ca2+]i increased from approximately 200 nM in diastole to approximately 1 microM or higher in early systole. Although the 19F spectra that report [Ca2+]i changed dramatically and reproducibly during the cardiac cycle, no changes were detectable in gated phosphorus spectra. We exploited the ability to control the coronary arterial flow of our hearts to investigate the mechanism of the fall in contractility that results from a decrease in perfusion even when the flow suffices to sustain normal high energy phosphate concentrations. Under these conditions, the amplitude of Ca2+ transients falls markedly along with the decline in pressure. This down-regulation of Ca2+ transients constitutes a novel protective mechanism that minimizes energy demand during low-flow ischemia.
Developmental changes in the expression of rabbit left ventricular troponin T.
Authors: Anderson P A , Moore G E , Nassar R N
Published: June 2012

We examined cardiac troponin T (TnT) isoform expression in rabbit left ventricular myocardium at three different stages of postnatal development. Using sodium dodecyl sulfate gel electrophoresis (PAGE), we resolved five isoforms: TnT1, TnT2, TnT3, TnT4, and TnT5. TnT1 had the slowest electrophoretic mobility and TnT5 the fastest. The predominant isoforms were TnT2, TnT3, and TnT4. The relative amounts of TnT2, TnT3, TnT4, and TnT5 were examined in myocardium from three age-groups: 3 days (Group 1), 21-22 days (Group 2), and 99-109 days (Group 3). The amount of TnT2 relative to the total amount of TnT (determined by the ratio of the areas under the densitometric curves) decreased significantly (p less than 0.01) with age from 42 +/- 4% in Group 1 to 25 +/- 3% in Group 3. In contrast, the relative amount of TnT4 increased with age from 23 +/- 2% in Group 1 to 33 +/- 4% in Group 3 (p less than 0.01). The relative amounts of the other two isoforms change biphasically with development: TnT3 decreased from Group 1 to Group 2 and increased from Group 2 to Group 3. TnT5, a minor isoform, increased from Group 1 to Group 2 and decreased from Group 2 to Group 3. These developmental changes in troponin T expression may account for some of the maturational changes observed in the physiological and biochemical properties of the myocardium.
Xenon handling in the liver: red cell capacity effect.
Authors: Goresky C A , Schwab A J , Rose C P
Published: June 2012

Xenon, despite its lack of chemical reactivity, associates preferentially with red cells in blood. To characterize the effect of this and the nature of xenon-tissue interaction in the liver, multiple indicator dilution studies were performed in the anesthetized normal dog through portal vein injection and hepatic vein collection of anaerobic blood samples. Two experimental runs were carried out in each animal, one at the prevailing hematocrit and the other at reduced hematocrit after bleeding and replacement with dextran. For comparison, the injection mixtures contained labeled red blood cells (a vascular reference), sucrose (an interstitial space reference), and labeled water (which freely enters liver cells), as well as labeled xenon. At the higher hematocrit, the labeled xenon curves generally rose earlier, peaked higher, and decayed more quickly than the labeled water curve; at the lower hematocrit, the xenon curve was delayed and diminished in magnitude in relation to the labeled water curves. Analysis of the curve shapes indicated that xenon, like labeled sucrose and water, underwent delayed wave flow-limited distribution. With knowledge of the red cell plasma partition coefficient (2.89 ml/ml), it was possible to both account for the change in form of the xenon curves with hematocrit and to use the data to estimate the liver cell tissue plasma xenon partition coefficient. Values averaged 1.93 ml/ml liver space, or 1.79 ml/g, and did not change significantly from first to second runs. Theoretical analysis indicated that flow cannot be estimated from xenon downslopes.
Substance P induces a cardiovascular defense reaction in the rat: pharmacological characterization.
Authors: Unger T , Carolus S , Demmert G , Ganten D , Lang R E , Maser-Gluth C , Steinberg H , Veelken R
Published: June 2012

In this study in conscious rats, we tested the hypothesis that substance P, a central pressor peptide and a potential transmitter substance of pain pathways, could be involved in the cardiovascular defense reaction that is typically associated with unpleasant sensory stimuli. The hemodynamic responses to centrally administered substance P were pharmacologically characterized. The increases in blood pressure and heart rate after intracerebroventricular injections of substance P were accompanied by mesenteric and renal vasoconstriction and hind limb vasodilation (pulsed-Doppler flow probes). The pressor and vasoconstrictor responses were attenuated by peripheral alpha 1-adrenoceptor blockade with prazosin but were not influenced by blockade of vascular vasopressin receptors with d(CH2)5Tyr(Me) arginine vasopressin (AVP). Cardiac beta 1-adrenoceptor blockade with metoprolol abolished the tachycardic and reduced the pressor responses. Substance P-induced hind limb vasodilation was not sensitive to intravenous atropine but was largely prevented by peripheral beta 2-adrenoceptor blockade with ICI 118,551. Thus, the substance P-induced pressor effects are mediated by alpha 1-adrenergic sympathetic vasoconstriction and beta 1-adrenergic cardiac stimulation, whereas the hind limb vasodilation is mainly due to beta 2-adrenergic stimulation. Substance P dose-dependently (0.01-10 micrograms i.c.v.) released oxytocin but not vasopressin or adrenocorticotropic hormone (ACTH) from the pituitary gland. High doses reduced basal ACTH levels. Together with the hemodynamic responses, a behavioral arousal reaction was observed, which included increased locomotion, grooming, scratching, and skin biting. Our results demonstrate that a neuropeptide can induce classic cardiovascular defense reaction.(ABSTRACT TRUNCATED AT 250 WORDS)
Intracoronary infusion of prostaglandin I2 attenuates arterial baroreflex control of heart rate in conscious dogs.
Authors: Panzenbeck M J , Tan W , Hajdu M A , Zucker I H
Published: June 2012

Prostaglandin I2 (PGI2) is known to stimulate ventricular C fiber receptors resulting in a Bezold-Jarisch-like reflex. Also, cardiac receptor stimulation is known to interact with the expression of arterial baroreflexes. Therefore, experiments were performed to determine the effects of left circumflex coronary artery infusion of PGI2 on the baroreflex control of heart rate in conscious instrumented dogs. Dogs were instrumented chronically with an aortic catheter for the measurement of mean aortic pressure, hydraulic occluder cuffs on the descending aorta and inferior vena cava, a left ventricular catheter for the measurement of left ventricular pressure and heart rate, and a nonocclusive catheter in the left circumflex coronary artery. At the time of experimentation, arterial pressure was altered randomly in steps by partially inflating the occluders. Mean arterial pressure-heart curves (baroreflex curves) were constructed by fitting the data to a logistic curve by nonlinear regression. PGI2 infused into the left circumflex coronary artery at doses of 10, 20, and 50 ng/kg/min caused significant (p less than 0.05) inhibition of the maximum heart rate, heart rate range, and maximum slope of the curve compared to the control baroreflex curve obtained during intracoronary infusion of PGI2 vehicle. PGI2 had no significant effect on the minimum heart rate during hypertension. Since PGI2 is known to stimulate left ventricular receptors, these effects were most likely produced via stimulation of cardiac receptors. In additional experiments using beta 1-blockade with metoprolol or cholinergic blockade with atropine methyl bromide, it was shown that PGI2 attenuates baroreflex-mediated tachycardia by preventing parasympathetic withdrawal completely and by attenuating sympathetic stimulation by approximately 50%.(ABSTRACT TRUNCATED AT 250 WORDS)