bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardial contractile depression from high-frequency vibration is not due to increased cross-bridge breakage
Authors: Campbell Kenneth B. , Wu Yiming , Kirkpatrick Robert D. , Slinker Bryan K.
Published: December 2017

Experiments were conducted in 10 isolated rabbit hearts at 25°C to test the hypothesis that vibration-induced depression of myocardial contractile function was the result of increased cross-bridge breakage. Small-amplitude sinusoidal changes in left ventricular volume were administered at frequencies of 25, 50, and 76.9 Hz. The resulting pressure response consisted of a depressive response [ΔPd( t), a sustained decrease in pressure that was not at the perturbation frequency] and an in-frequency response [ΔP f ( t), that part at the perturbation frequency]. ΔPd( t) represented the effects of contractile depression. A cross-bridge model was applied to ΔP f ( t) to estimate cross-bridge cycling parameters. Responses were obtained during Ca2+ activation and during Sr2+ activation when the time course of pressure development was slowed by a factor of 3. ΔPd( t) was strongly affected by whether the responses were activated by Ca2+ or by Sr2+. In the Sr2+-activated state, ΔPd( t) declined while pressure was rising and relaxation rate decreased. During Ca2+ and Sr2+ activation, velocity of myofilament sliding was insignificant as a predictor of ΔPd( t) or, when it was significant, participated by reducing ΔPd( t) rather than contributing to its magnitude. Furthermore, there was no difference in cross-bridge cycling rate constants when the Ca2+-activated state was compared with the Sr2+-activated state. An increase in cross-bridge detachment rate constant with volume-induced change in cross-bridge distortion could not be detected. Finally, processes responsible for ΔPd( t) occurred at slower frequencies than those of cross-bridge detachment. Collectively, these results argue against a cross-bridge detachment basis for vibration-induced myocardial depression.
Preconditioning and adenosine in I/R-induced leukocyte-endothelial cell interactions
Authors: Kubes Paul , Payne Derrice , Ostrovsky Lena
Published: December 2017

Recently, it was reported that preconditioning reduced leukocyte adhesion following ischemia-reperfusion (I/R). We further examined the effects of preconditioning and adenosine not only on neutrophil adhesion but also on neutrophil rolling and vascular dysfunction. Intravital microscopy revealed a decrease in neutrophil rolling velocity; a profound increase in neutrophil rolling, adhesion, and microvascular dysfunction; and a reduction in venular shear rates associated with 60 min ischemia and 60 min reperfusion in the feline mesentery. Preconditioning (5 min ischemia/10 min reperfusion) prevented subsequent I/R-induced slow neutrophil rolling, neutrophil adhesion, and microvascular dysfunction but did not affect the flux of rolling neutrophils. Adenosine deaminase A1and A2adenosine-receptor antagonists had only minor effects on the preconditioning responses. Pretreatment of vessels with exogenous adenosine reduced neutrophil adhesion and microvascular permeability and improved neutrophil rolling velocity and shear forces associated with I/R, but the flux of rolling neutrophils was not affected. Finally, in vitro experiments revealed that adenosine had absolutely no direct effect on neutrophil-endothelial cell interactions. In conclusion, our data suggest that adenosine plays only a minor role in preconditioned vessels and that adenosine per se may not directly affect neutrophil-endothelial cell interactions.
Vasomotor responses in chronically hyperperfused and hypoperfused rat mesenteric arteries
Authors: Pourageaud Fabrice , De Mey Jo G. R.
Published: December 2017

We evaluated the reactivity of small arteries after remodeling induced by elevated or reduced blood flow. In 6-wk-old rats, every other first-order side branch of the superior mesenteric artery was ligated near the bifurcation of second-order branches. Four weeks after surgery, vessels that had been exposed to high flow (HF) or low flow (LF) were isolated and mounted in a pressure myograph at 100 mmHg and were compared with vessels from sham-operated rats (Sham). In HF: 1) basal lumen diameter was increased; 2) sensitivity to norepinephrine, arginine vasopressin, and perivascular nerve stimulation was not modified; 3) maximal constrictor responses (Δ diameter) to these stimuli and 125 mM K+ were increased; and 4) sensitivity and maximal dilator responses to sodium nitroprusside, acetylcholine, and flow were not modified. In LF: 1) basal diameter was reduced; 2) sensitivity to constrictor stimuli was not altered; 3) maximal responses to all vasoconstrictors except arginine vasopressin were reduced; and 4) sensitivity but not maximal dilator responses to sodium nitroprusside and acetylcholine was reduced. During acute flow-induced dilatations, lower shear stress was maintained in HF (48 ± 7 dyn/cm2) than in Sham (63 ± 10 dyn/cm2), but no shear stress regulation was observed in LF. These observations indicate that arterial structural responses to altered blood flow are accompanied by modified reactivity of the arterial smooth muscle, which entails changes in responsiveness to neurogenic and endothelium-dependent stimuli.
Inhibition of myocardial glucose uptake by cGMP
Authors: Depre Christophe , Gaussin Vinciane , Ponchaut Sylvie , Fischer Yvan , Vanoverschelde Jean-Louis , Hue Louis
Published: December 2017

Guanosine 3′,5′-cyclic monophosphate (cGMP), a second messenger of nitric oxide (NO), regulates myocardial contractility. It is not known whether this effect is accompanied by a change in heart metabolism. We report here the effects of 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP), a cGMP analog, on regulatory steps of glucose metabolism in isolated working rat hearts perfused with glucose as the substrate. When glucose uptake was stimulated by increasing the workload, addition of the cGMP analog totally suppressed this stimulation and accelerated net glycogen breakdown. 8-BrcGMP did not affect pyruvate dehydrogenase activity but activated acetyl-CoA carboxylase, the enzyme that produces malonyl-CoA, an inhibitor of long-chain fatty acid oxidation. To test whether glucose metabolism could also be affected by altering the intracellular concentration of cGMP, we perfused hearts with NG-nitro-l-arginine methyl ester (l-NAME), an inhibitor of NO synthase, or with S-nitroso- N-acetylpenicillamine (SNAP), a NO donor. Perfusion withl-NAME decreased cGMP and increased glucose uptake by 30%, whereas perfusion with SNAP resulted in opposite effects. None of these conditions affected adenosine 3′,5′-cyclic monophosphate concentration. Limitation of glucose uptake by SNAP or 8-BrcGMP decreased heart work, and this was reversed by adding alternative oxidizable substrates (pyruvate, β-hydroxybutyrate) together with glucose. Therefore, increased NO production decreases myocardial glucose utilization and limits heart work. This effect is mediated by cGMP, which is thus endowed with both physiological and metabolic properties.
Step baroreflex response in awake patients undergoing carotid surgery: time- and frequency-domain analysis
Authors: Landesberg Giora , Adam Dan , Berlatzky Yacov , Akselrod Solange
Published: December 2017

Step baroreceptor stimulation can provide an insight into the baroreflex control mechanism, yet this has never been done in humans. During carotid surgery under regional anesthesia, a step increase in baroreceptor stimulation occurs at carotid declamping immediately after removal of the intra-arterial atheromatous plaque. In 10 patients, the R-R interval and systolic and diastolic blood pressures (BP) were continuously recorded, and signals obtained within the time window from 10 min before until 10 min after carotid declamping were analyzed. Mean ± SD time signals, power spectra, and transfer and coherence functions before and after declamping were calculated. Immediately after carotid declamping, both heart rate (HR) and BP declined in an exponential-like manner lasting 10.3 ± 5.9 min, and their power spectra increased in the entire frequency range. Transfer function magnitude and coherence functions between BP and HR increased predominantly in the midfrequency region (∼0.1 Hz), with no change in phase function. Thus, in carotid endarterectomy patients, step increase in baroreceptor gain elicits a prolonged decline in HR and BP. Frequency analyses support the notion that the baroreflex control mechanism generates the midfrequency HR and BP variability, although other frequency regions are also affected.
Multiple effects of KPQ deletion mutation on gating of human cardiac Na+channels expressed in mammalian cells
Authors: Chandra Rashmi , Starmer C. Frank , Grant Augustus O.
Published: December 2017

Several aspects of the effect of the KPQ deletion mutation on Na+channel gating remain unresolved. We have analyzed the kinetics of the early and late currents by recording whole cell and single-channel currents in a human embryonic kidney (HEK) cell line (HEK293) expressing wild-type and KPQ deletion mutation in cardiac Na+channels. The rate of inactivation increased three- to fivefold between −40 and −80 mV in the mutant channel. The rate of recovery from inactivation was increased twofold. Two modes of gating accounted for the late current: 1) isolated brief openings with open times that were weakly voltage dependent and the same as the initial transient and 2) bursts of opening with highly voltage-dependent prolonged open times. Latency to first opening was accelerated, suggesting an acceleration of the rate of activation. The ΔKPQ mutation has multiple effects on activation and inactivation. The aggregate effects may account for the increased susceptibility to arrhythmias.
Mechanism of volume adaptation in the awake early pregnant rat
Authors: Verkeste Carla M. , Slangen Brigitte F. M. , Dubelaar Marie-Louise , Van Kreel Bernard K. , Peeters Louis L. H.
Published: December 2017

The objective of the present study was to determine whether the increase in plasma volume (PV) during pregnancy is established by fluid retention or by a shift within the extracellular fluid volume (ECFV) from the interstitium toward the intravascular compartment. To this end, we simultaneously measured total body water (TBW), ECFV, and PV together with the hematocrit (Hct) and plasma osmolality 4, 8, and 12 days postsurgery in chronically instrumented pregnant (P) and nonpregnant (NP) rats. The P rats were instrumented with a catheter in the femoral artery on day 1 postconception. In the NP group, neither TBW nor ECFV and PV had changed consistently on days 8 and 12 postsurgery relative to day 4. In contrast, in the P animals, TBW, ECFV, and PV had increased by 16, 24, and 20%, respectively, by day 12 relative to day 4. To evaluate whether PV had increased in concert with an overall rise in TBW or as a result of a fluid shift at the cost of the interstitial fluid volume, we calculated the relative size of each fluid compartment on three consecutive measurement sessions. In the NP group, TBW, presented as percentage of maternal weight (%MW) as well as ECFV (%TBW) and PV (%ECFV) had not changed consistently throughout the measurement period. In the P animals, TBW (%MW) was slightly higher on day 12 compared with day 4, but ECFV (%TBW) and PV (%ECFV) had not changed significantly. Finally, in the NP group, Hct had not changed, whereas, in the P animals, Hct was 10% lower on days 8 and 12 compared with day 4. Plasma osmolality did not change consistently in either group during the course of the experimental period. The gradual synchronous increase in all fluid compartments, without consistent change in their relative distribution, suggests that, in normal rat pregnancy, PV expansion is primarily achieved by fluid retention rather than by a redistribution of the ECFV.
Inhibition of nitric oxide synthesis increases venular permeability and alters endothelial actin cytoskeleton
Authors: Baldwin Ann L. , Thurston Gavin , Al Naemi Hamda
Published: December 2017

Inhibition of nitric oxide (NO) synthesis using N G-nitro-l-arginine methyl ester (l-NAME) or N G-monomethyl-l-arginine (l-NMMA) increases venular permeability in the rat mesentery (I. Kurose, R. Wolf, M. B. Grisham, T. Y. Aw, R. D. Specian, and D. N. Granger. Circ. Res. 76: 30–39, 1995), but the cellular mechanisms of this response are not known. This study was performed to determine whether such venular leaks are associated with changes in the endothelial actin cytoskeleton. In anesthetized Sprague-Dawley rats, the microvasculature of a mesenteric window was perfused with buffered saline, with or without 10−5M l-NAME,l-NMMA, or the inactive enantiomer N G-nitro-d-arginine methyl ester for 3 or 30 min. FITC-albumin was added to the perfusate for the last 3 min. The vasculature was perfusion fixed, stained for filamentous actin and for mast cells, and viewed microscopically. In control preparations, venules showed few FITC-albumin leaks and the endothelial actin cytoskeleton consisted of a peripheral rim along the cell-cell junctions. Preparations treated withl-NAME orl-NMMA showed significantly more leakage, the actin rims in leaky venules were discontinuous, and short, randomly oriented fibers appeared within the cells. In nonleaky venules, the peripheral actin rims sometimes contained small, equally spaced discontinuities not seen in control preparations. Although a mast cell stabilizer was used, 27–70% of the mast cells were degranulated in the presence ofl-NMMA. Thus inhibition of NO synthesis alters the endothelial cytoskeleton and increases albumin leakage from mesenteric venules, either directly or indirectly via the involvement of mast cells.
Subcellular properties of [Ca2+]itransients in phospholamban-deficient mouse ventricular cells
Authors: Hüser Jörg , Bers Donald M. , Blatter Lothar A.
Published: December 2017

The regulatory protein phospholamban exerts a physiological inhibitory effect on the sarcoplasmic reticulum (SR) Ca2+ pump that is relieved with phosphorylation. We have studied the subcellular properties of intracellular Ca2+([Ca2+]i) transients in ventricular myocytes isolated from wild-type (WT) and phospholamban-deficient (PLB-KO) mice. In PLB-KO myocytes, steady-state twitch [Ca2+]itransients revealed an accelerated relaxation and the occurrence of highly localized failures of Ca2+release. The acceleration of SR Ca2+ uptake caused an increase in SR Ca2+ load with the frequent occurrence of spontaneous [Ca2+]iwaves and Ca2+ sparks. [Ca2+]iwaves in PLB-KO cells showed a marked decrease in spatial width and more frequently appeared to abort. Local Ca2+ release events (Ca2+ sparks) were larger and more variable in amplitude and [Ca2+]ideclined faster in PLB-KO myocytes. Increased local buffering and reduction in the refractoriness of SR Ca2+ release caused by the increased SR pump rate led to an overall enhancement of local [Ca2+]igradients and inhomogeneities in the [Ca2+]idistribution during spontaneous Ca2+ release, [Ca2+]iwaves, and excitation-contraction coupling.
Estrogen diminishes postischemic hydroxyl radical production
Authors: McHugh Nansie A. , Merrill Gary F. , Powell Saul R.
Published: December 2017

Reperfusion of blood flow to an ischemic myocardium is imperative to survival; ironically, it may also manifest several pathophysiological conditions. The most important of these are reperfusion arrhythmias and tissue injury and/or death. The mechanisms involved in reperfusion arrhythmias remain to be fully elucidated; however, increasing evidence indicates that reperfusion-induced arrhythmias are a free radical-mediated phenomenon. Acute administration of conjugated equine estrogen to dogs attenuates ischemia- and reperfusion-induced arrhythmias. The cardioprotective effect of estrogens in postmenopausal women is well documented, and recent studies suggest that estrogens possess strong antioxidant properties, with equine estrogens most potent. In this study we show that administration of conjugated equine estrogen to fully anesthetized dogs abolishes the burst of ⋅ OH radicals typically produced on reperfusion of the myocardium. This indicates that estrogen might attenuate reperfusion-induced ventricular arrhythmias by virtue of its antioxidant properties, suggesting a novel cardioprotective effect of the hormone.
Oxygen induces electromechanical coupling in arteriolar smooth muscle cells: a role for L-type Ca2+ channels
Authors: Welsh Donald G. , Jackson William F. , Segal Steven S.
Published: December 2017

We tested whether O2-induced vasomotor responses of arterioles correspond to changes in membrane potential ( E m) of cells in the arteriolar wall. The cheek pouches of anesthetized male hamsters were prepared for intravital microscopy and intracellular recording. Microelectrodes containing Lucifer yellow dye were used to label smooth muscle cells (SMC) or endothelial cells (EC) during arteriolar responses to O2. During low-[Formula: see text] superfusion (∼20 Torr; arteriolar diameter 55 ± 2 μm), E m of SMC and EC averaged −37 and −36 mV, respectively. High-[Formula: see text] superfusion (∼150 Torr) depolarized SMC (to −15 ± 1 mV) with vasoconstriction (to 24 ± 2 μm) and diameter cycled with E m of SMC during vasomotion. In contrast, the E m of EC did not change with [Formula: see text] nor during vasomotion, yet E m depolarized by 21 ± 2 mV when the extracellular K+ concentration ([K+]o) was raised to 55 mM. Superfusion with diltiazem (10 μM) or nifedipine (1 μM) abolished vasomotor and electrical responses to[Formula: see text] in SMC but did not eliminate depolarizations to elevated [K+]o. We conclude that, under physiological conditions, electrical and mechanical responses of arteriolar SMC to changes in[Formula: see text] are mediated through L-type Ca2+ channels without corresponding electrical activity in EC.
Left atrial systolic and diastolic function accompanying chronic rapid pacing-induced atrial failure
Authors: Hoit Brian D. , Shao Yanfu , Gabel Marjorie
Published: December 2017

The objective of this study was to examine the hypothesis that long-term, rapid atrial pacing produces a model of atrial systolic and diastolic dysfunction but does not alter ventricular function. Eight dogs were atrially paced at 400 beats/min (3:1–5:1 ventricular response) for 6 wk and subsequently instrumented with left atrial (LA) and left ventricular (LV) sonomicrometers and micromanometers. Data were compared with those from six sham-operated controls at matched heart rates and mean LA pressures of 10 mmHg. Dogs with rapid pacing had slightly greater LA volume (10.3 ± 4.0 vs. 7.9 ± 4.4 ml) and reduced ejection fraction (2.2 ± 1.4 vs. 13.0 ± 4.0, P < 0.05), systolic ejection rate (0.3 ± 0.1 vs. 2.8 ± 1.2 vol/s, P < 0.05), and reservoir fraction (0.07 ± 0.04 vs. 0.35 ± 0.06, P < 0.05) compared with controls. LA diastolic chamber stiffness was greater after rapid atrial pacing than before (stiffness constant k c, 5.7 ± 2.3 vs. 3.4 ± 0.6, P < 0.05), and the ratio of transesophageal echo-determined pulmonary venous systolic to diastolic integrated flow (a measure of relative reservoir to conduit function of the LA) was less in rapidly paced dogs compared with control dogs (0.41 ± 0.19 vs. 0.68 ± 0.23, P < 0.05). In contrast, rapid atrial pacing did not influence LV systolic performance or lusitropy, because the LV pressure time derivative and the time constant of LV relaxation were similar in both groups. In this model of isolated atrial myopathy, increased atrial stiffness and enhanced conduit function compensate for impaired atrial booster pump and reservoir functions.
Attenuation of postischemic reperfusion injury in striated skin muscle by diaspirin-cross-linked Hb
Authors: Pickelmann Sven , Nolte Dirk , Leiderer Rosmarie , Schütze Elke , Messmer Konrad
Published: December 2017

Hemoglobin-based oxygen carriers have been suggested to enhance the formation of oxygen free radicals, especially under conditions of ischemia-reperfusion (I/R), in which activation and adhesion of leukocytes play a pivotal role for propagation of reperfusion injury. This study investigates the effects of the hemoglobin-based oxygen carrier diaspirin-cross-linked hemoglobin (DCLHb) in an I/R model of hamster striated skin muscle. The dorsal skinfold chamber model in the awake Syrian golden hamster was used for analysis of the microcirculation and local tissue [Formula: see text]in striated skin muscle utilizing the technique of intravital fluorescence microscopy and a multiwire platinum surface (Clark type) electrode. Measurements were made before 4 h of pressure-induced ischemia and at 0.5, 2, and 24 h of reperfusion. Animals were treated with 5 ml/kg body wt of either 10% DCLHb ( n = 8), 6% Dextran 60 (Dx-60; 60 kDa, n = 8), or 0.9% NaCl ( n = 7), which was given intravenously 15 min before reperfusion. In animals treated with DCLHb or Dx-60, a significant decrease of leukocytes rolling along and sticking in postcapillary venules, associated with a recovery of functional capillary density and red blood cell velocity, was observed compared with saline-treated controls. In the early reperfusion period (0.5 h), DCLHb and Dx-60 efficiently restored local tissue[Formula: see text], whereas tissue[Formula: see text] decreased from 18.3 ± 1.9 to 15.3 ± 5.3 mmHg in 0.9% NaCl-treated animals. Electron microscopic analysis of the postischemic tissue at 24 h of reperfusion revealed markedly reduced tissue damage in animals treated with DCLHb compared with Dx-60 or isotonic saline. These results indicate that DCLHb attenuates postischemic reperfusion injury of striated skin muscle, presumably through alterations of leukocyte-endothelial cell interactions.
Transmural heterogeneity of action potentials andI to1 in myocytes isolated from the human right ventricle
Authors: Li Gui-Rong , Feng Jianlin , Yue Lixia , Carrier Michel
Published: December 2017

Limited information is available about transmural heterogeneity in cardiac electrophysiology in man. The present study was designed to evaluate heterogeneity of cardiac action potential (AP), transient outward K+ current ( I to1) and inwardly rectifying K+ current ( I K1) in human right ventricle. AP and membrane currents were recorded using whole cell current- and voltage-clamp techniques in myocytes isolated from subepicardial, midmyocardial, and subendocardial layers of the right ventricle of explanted failing human hearts. AP morphology differed among the regional cell types. AP duration (APD) at 0.5–2 Hz was longer in midmyocardial cells (M cells) than in subepicardial and subendocardial cells. At room temperature, observed I to1, on step to +60 mV, was significantly greater in subepicardial (6.9 ± 0.8 pA/pF) and M cells (6.0 ± 1.1 pA/pF) than in subendocardial cells (2.2 ± 0.7 pA/pF, P < 0.01). Slower recovery of I to1 was observed in subendocardial cells. The half-inactivation voltage of I to1 was more negative in subendocardial cells than in M and subepicardial cells. At 36°C, the density of I to1 increased, the time-dependent inactivation and reactivation accelerated, and the frequency-dependent reduction attenuated in all regional cell types. No significant difference was observed in I K1 density among the regional cell types. The results indicate that M cells in humans, as in canines, show the greatest APD and that a gradient of I to1 density is present in the transmural ventricular wall. Therefore, the human right ventricle shows significant transmural heterogeneity in AP morphology and I to1properties.
Vulnerability to arrhythmias during social stress in rats with different sympathovagal balance
Authors: Sgoifo Andrea , De Boer Sietse F. , Buwalda Bauke , Korte-Bouws Gerdien , Tuma Jolanda , Bohus Bela , Zaagsma Johan , Koolhaas Jaap M.
Published: December 2017

An increased activity of the sympathetic nervous system is an important factor in the genesis of ventricular arrhythmias. Changes in average R-R interval, R-R interval variability (indirect measure of sympathovagal balance), occurrence of arrhythmias, and plasma norepinephrine concentrations were measured during a social stress episode (defeat) in two strains of rats, Wistar and wild type, which were supposed to differ in their autonomic stress responsiveness. Electrocardiograms were telemetrically recorded, and blood samples were withdrawn through jugular vein catheters from healthy, freely moving animals. R-R interval variability was estimated by the following time-domain parameters: the standard deviation of the mean R-R interval, the coefficient of variance, and the root mean square of successive differences in R-R interval. Average R-R interval and R-R interval variability measures, as well as plasma norepinephrine concentrations, indicated a higher sympathetic tone, a larger sympathetic responsiveness, and a lower parasympathetic antagonism after sympathetic activation in wild-type animals, which also showed a much higher incidence of arrhythmias (ventricular premature beats), compared with Wistar rats. These two strains might represent a valuable experimental model for studying the mechanisms (cellular/electrophysiological) responsible for the susceptibility to arrhythmias in healthy individuals exposed to stressful situations.
Effects of recirculating flow on U-937 cell adhesion to human umbilical vein endothelial cells
Authors: Barber Kevin M. , Pinero Aaron , Truskey George A.
Published: December 2017

We used a sudden-expansion flow chamber to examine U-937 cell adhesion to unactivated and tumor necrosis factor (TNF)-α-activated human umbilical vein endothelial cells (HUVEC) in recirculating flow. For both unactivated and TNF-α-activated HUVEC, U-937 cells exhibited transient arrests within ∼150 μm of flow reattachment. Few arrests occurred directly at the reattachment site. U-937 cell rolling was not observed. At all other locations within the recirculation zone, U-937 cells did not exhibit transient arrests or rolling. TNF-α activation increased the frequency of U-937 cell arrests near reattachment but did not change the median arrest duration. Numerically simulated cell trajectories failed to predict attachment near the reattachment point. Deviations between experiment and theory may result from the nonspherical shape and deformability of U-937 cells. These results demonstrate that U-937 cell transient arrests occur preferentially in the vicinity of the reattachment point in recirculating flow. Possible mechanisms for adhesion include low shear stress, curved streamlines, fluid velocity components normal to the endothelium, and formation of larger contact areas.
Inhibition of ATP-induced increase in muscarinic K+current by trypsin, alkaline pH, and anions
Authors: Pleumsamran Apisate , Wolak Michael L. , Kim Donghee
Published: December 2017

In atrial cells, the open probability of G protein-activated ACh-sensitive K+(KACh) channels can be increased approximately fivefold by intracellular ATP (ATPi). Using inside-out patches, we examined how proteases, changes in intracellular pH, and different anions affect G protein-mediated activation and ATP-induced stimulation of the KAChchannel. Treatment with trypsin (0.5 mg/ml) removed the GTP dependence of the KAChchannel and abolished the ATP-induced stimulation. Intracellular GTP activated KAChchannels at all intracellular pH values tested (6.0–8.0), with the concentration at which half-maximal activation ( K½) occurred ranging from 0.3 (pH 8.0) to 6.7 (pH 6.0) μM. However, the ATPi-induced increase in KAChchannel activity was inhibited at pH 8.0 ( K½= pH 7.4). All anions tested except sulfate, phosphate, fluoride, and iodide supported GTP-induced activation. Of the anions that supported GTP-induced activation, only citrate blocked the ATP-induced stimulation of the KAChchannel. These results indicate that the GTP- and ATP-mediated effects on the KAChchannel use separate signaling pathways. The ATP-mediated effect involves a trypsin- and pH-sensitive mechanism.
Effects of systemic hypoxia on R-R interval and blood pressure variabilities in conscious rats
Authors: Murasato Yoshinobu , Hirakawa Haruhisa , Harada Yuji , Nakamura Tadashi , Hayashida Yoshiaki
Published: December 2017

The effects of systemic hypoxia with different levels of CO2 on R-R interval (RRI) and systolic blood pressure (SBP) variabilities were investigated in conscious rats. Wistar rats chronically instrumented for the measurement of blood pressure, electrocardiogram, and renal sympathetic nerve activity (RSNA) were exposed to hypocapnic (Hypo), isocapnic (Iso), and hypercapnic (Hyper) hypoxia. On another day, the rats were treated with atropine and exposed to the same type of hypoxia. Sinoaortic denervation (SAD)-treated rats were exposed to Iso and Hyper, and RRI and SBP variabilities before and during hypoxia were analyzed using the maximum-entropy method with high resolution. With regard to RRI variability, very low frequency (VLF), low frequency (LF), and high frequency (HF) powers all decreased during Hypo, increased during Hyper, and did not change during Iso in intact rats. Changes during Hypo were attenuated by atropine, and those during Hyper were abolished by either atropine or SAD. The ratio of LF power to HF power decreased independently of increases in RSNA during each type of hypoxia. On the other hand, there were no changes in VLF, LF, or HF power in SBP variability during each type of hypoxia in intact rats. In atropine-treated rats, LF power increased during Iso and Hyper and HF power increased during each type of hypoxia. There was no difference in respiratory frequency among the three kinds of hypoxia in both intact and atropine-treated rats. The results suggest that arterial[Formula: see text] level rather than respiration frequency produces changes in powers of RRI variability through changes in parasympathetic nerve activity and that with regard to SBP variability, parasympathetic nerve activity masks changes in LF power that reflect an increase in RSNA and those in HF power that reflect a mechanical consequence of respiration.
Resting potentials and potassium currents during development of pulmonary artery smooth muscle cells
Authors: Evans A. M. , Osipenko O. N. , Haworth S. G. , Gurney A. M.
Published: December 2017

The pulmonary circulation changes rapidly at birth to adapt to extrauterine life. The neonate is at high risk of developing pulmonary hypertension, a common cause being perinatal hypoxia. Smooth muscle K+channels have been implicated in hypoxic pulmonary vasoconstriction in adults and O2-induced vasodilation in the fetus, channel inhibition being thought to promote Ca2+influx and contraction. We investigated the K+currents and membrane potentials of pulmonary artery myocytes during development, in normal pigs and pigs exposed for 3 days to hypoxia, either from birth or from 3 days after birth. The main finding is that cells were depolarized at birth and hyperpolarized to the adult level of −40 mV within 3 days. Hypoxia prevented the hyperpolarization when present from birth and reversed it when present from the third postnatal day. The mechanism of hyperpolarization is unclear but may involve a noninactivating, voltage-gated K+channel. It is not caused by increased Ca2+-activated or delayed rectifier current. These currents were small at birth compared with adults, declined further over the next 2 wk, and were suppressed by exposure to hypoxia from birth. Hyperpolarization could contribute to the fall in pulmonary vascular resistance at birth, whereas the low K+-current density, by enhancing membrane excitability, would contribute to the hyperreactivity of neonatal vessels. Hypoxia may hinder pulmonary artery adaptation by preventing hyperpolarization and suppressing K+current.
ATP-stimulated smooth muscle cell proliferation requires independent ERK and PI3K signaling pathways
Authors: Wilden Peter A. , Agazie Yehenew M. , Kaufman Rebecca , Halenda Stephen P.
Published: December 2017

Vascular smooth muscle cells respond to the purinergic agonist ATP by increasing intracellular calcium concentration and increasing the rate of cell proliferation. In many cells the extracellular signal-regulated kinase (ERK) cascade plays an important role in cellular proliferation. We have studied the effect of extracellular ATP on ERK activation and cell proliferation. ATP binding to a UTP-sensitive P2Y nucleotide receptor activates ERK1/ERK2 in a time- and dose-dependent manner in coronary artery smooth muscle cells (CASMC). ATP-induced activation of ERK1/ERK2 is dependent on the dual-specificity kinase mitogen-activated protein kinase/ERK kinase (i.e., MEK) but independent of phosphatidylinositol 3-kinase (PI3K) activity. We provide evidence that both ERK1/ERK2 and PI3K activities are required for CASMC proliferation. Thus ATP-stimulation of CASMC proliferation requires independent activation of both the ERK and PI3K signaling pathways.
BDM drives protein dephosphorylation and inhibits adenine nucleotide exchange in cardiomyocytes
Authors: Stapleton Mary T. , Fuchsbauer Claudia M. , Allshire Ashley P.
Published: December 2017

Contractile dysfunction plays a key role in injury sustained by ischemic myocardium at reperfusion, whereas interventions that impede hypercontracture enhance recovery. In permeabilized adult rat cardiomyocytes, the negative inotrope 2,3-butanedione monoxime (BDM; 10–50 mM) inhibited rigor at low MgATP concentration but stimulated net ATP hydrolysis. Hydrolysis was attenuated by H-7, kaempferol, chelerythrine, and genistein. Evidently BDM opposed phosphorylation of both serine/threonine and tyrosine kinase target proteins, either directly or by enhancing protein phosphatase activity, in a futile cycle of ATP hydrolysis independent of cross-bridge cycling. Although 20 mM BDM did not affect the onset of rigor contracture in permeabilized cells at low MgATP, in intact cells exposed to the metabolic inhibitors cyanide and 2-deoxyglucose rigor onset was accelerated, indicating that BDM increases ATP depletion in quiescent cardiomyocytes. Conversely, in cells exposed to the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone, BDM delayed the onset of contracture and hence ATP depletion, consistent with an inhibition of adenine nucleotide movement across the mitochondrial inner membrane. Such effects will limit the value of BDM as a cardioprotective agent at physiological temperature.
Rabbit polymorphonuclear leukocytes release a factor that causes constriction of the coronary vasculature
Authors: Hart-Favaloro Joanne L. , Woodman Owen L.
Published: December 2017

Polymorphonuclear leukocytes (PMN) have been shown to have numerous vasoactive effects, particularly in large artery bioassays. This study shows that rabbit PMN passively release a contractile factor that constricts the coronary vasculature of isolated, Langendorff-perfused rabbit hearts. The mechanism of action of this factor does not involve inhibition of nitric oxide (NO), production of cyclooxygenase metabolites, 5-hydroxytryptamine, or endothelin, or the activation of α-adrenoceptors but is a Ca2+-dependent process, because the constriction is inhibited by the Ca2+-channel blocker amlodipine. The activity of this factor is significantly inhibited if it is pretreated with trypsin or heated to 90°C for 10 min, and the active factor is concentrated in the retentate of 100-kDa cutoff centrifuge filters, indicating that the factor is a protein >100 kDa in size. This study shows that rabbit PMN spontaneously release a protein factor that causes constriction of isolated, perfused rabbit hearts by a NO-independent but Ca2+-dependent mechanism.
Localization of the ANG II type 2 receptor in the microcirculation of skeletal muscle
Authors: Nora Elizabeth H. , Munzenmaier Diane H. , Hansen-Smith Feona M. , Lombard Julian H. , Greene Andrew S.
Published: December 2017

Only functional studies have suggested the presence of the ANG II type 2 (AT2) receptor in the microcirculation. To determine the distribution of this receptor in the rat skeletal muscle microcirculation, a polyclonal rabbit anti-rat antiserum was developed and used for immunohistochemistry and Western blot analysis. The antiserum was prepared against a highly specific and antigenic AT2-receptor synthetic peptide and was validated by competition and sensitivity assays. Western blot analysis demonstrated a prominent, single band at ∼40 kDa in cremaster and soleus muscle. Immunohistochemical analysis revealed a wide distribution of AT2 receptors throughout the skeletal muscle microcirculation in large and small microvessels. Microanatomic studies displayed an endothelial localization of the AT2 receptor, whereas dual labeling with smooth muscle α-actin also showed colocalization of the AT2 receptor with vascular smooth muscle cells. Other cells associated with the microvessels also stained positive for AT2 receptors. Briefly, this study confirms previous functional data and localizes the AT2 receptor to the microcirculation. These studies demonstrate that the AT2 receptor is present on a variety of vascular cell types and that it is situated in a fashion that would allow it to directly oppose ANG II type 1 receptor actions.
Mutual information discloses relationship between hemodynamic variables in artificial heart-implanted dogs
Authors: Osaka Motohisa , Yambe Tomoyuki , Saitoh Hirokazu , Yoshizawa Makoto , Itoh Takashi , Nitta Shin-Ichi , Kishida Hiroshi , Hayakawa Hirokazu
Published: December 2017

A mutual information (MI) method for assessment of the relationship between hemodynamic variables was proposed and applied to the analysis of heart rate (HR), arterial blood pressure (BP), and renal sympathetic nerve activity (RSNA) in artificial heart-implanted dogs to quantify correlation between these parameters. MI measures the nonlinear as well as linear dependence of two variables. Simulation studies revealed that this MI technique furnishes mathematical features well suited to the investigation of nonlinear dynamics such as the cardiovascular system and can quantify a relationship between two parameters. To constitute a model free of the natural heart, two pneumatically actuated ventricular assist devices were implanted as biventricular bypasses in acute canine experiments. RSNA was detected with the use of bipolar electrodes attached to the renal sympathetic nerve. Analysis of data during control revealed that correlation between HR and RSNA was higher than that between HR and BP and that between RSNA and BP ( P < 0.05). Although RSNA seemed to fluctuate noncorrelatedly with BP in higher pacing rates, the MI values between them disclosed their strong correlation. Surprisingly, correlation between RSNA and BP was stronger during a pacing rate of 60 beats/min than during higher pacing rates and control ( P < 0.05). It is suggested that the baroreflex system may be susceptible to pacing rates during the total artificial heart state. We calculated the time delay between HR and RSNA, between RSNA and BP, and between HR and BP by regarding a time delay at which the maximum MI value between each pair of parameters was given as a physiological delay. Our results indicate that RSNA leads BP, BP leads HR, and RSNA leads HR during control ( P < 0.05). We conclude that this method could provide a powerful means for measuring correlation of physiological variables.
Abnormal myocyte Ca2+homeostasis in rabbits with pacing-induced heart failure
Authors: Yao Atsushi , Su Zhi , Nonaka Akihiko , Zubair Iram , Spitzer Kenneth W. , Bridge John H. B. , Muelheims Gerhard , Ross John , Barry William H.
Published: December 2017

To determine whether there are abnormalities in myocyte excitation-contraction coupling and intracellular Ca2+concentration ([Ca2+]i) homeostasis in pacing-induced heart failure (PF), we measured L-type Ca2+ current ( I Ca,L) and Na+/Ca2+exchanger current ( I Na/Ca) with voltage clamp and measured intracellular Na+ concentration ([Na+]i) and [Ca2+]iwith the use of sodium-binding benzofuran isophthalate (SBFI) and fluo 3 in ventricular myocytes isolated from control and paced rabbits. The peak systolic and diastolic levels and the amplitude of electrically stimulated [Ca2+]itransients (0.25 Hz, extracellular Ca2+ concentration = 1.08 mM) were significantly less in PF myocytes. Also, there was prolongation of the times to peak and decline of [Ca2+]itransients. I Ca,Ldensity was markedly decreased in PF myocytes. I Na/Ca at −40 mV elicited by rapid exposure to 0 Na+ solution with a rapid solution switcher was significantly reduced in PF myocytes, suggesting that the function of the Na+/Ca2+exchanger is impaired in these myocytes. In PF myocytes the decline of the [Ca2+]itransient when the Na+/Ca2+exchanger was abruptly disabled was markedly prolonged compared with the decline in control myocytes, consistent with depressed sarcoplasmic reticulum (SR) Ca2+-ATPase function. RNase protection assay showed decreased levels of Na+/Ca2+exchanger and SR Ca2+-ATPase mRNA in PF hearts, consistent with the function studies. We conclude that the functions of L-type Ca2+channels, Na+/Ca2+exchanger, and SR Ca2+-ATPase are impaired in myocytes from rabbit hearts with failure induced by rapid pacing. These abnormalities result in reduced [Ca2+]itransients and systolic and diastolic dysfunction and appear to account for the abnormal ventricular function observed.
Arterial baroreflex resetting mediates postexercise reductions in arterial pressure and heart rate
Authors: Chandler Margaret P. , Rodenbaugh David W. , DiCarlo Stephen E.
Published: December 2017

We tested the hypothesis that postexercise reductions in arterial pressure and heart rate (HR) are mediated by a lowering of the operating point and a reduction in the gain of the arterial baroreflex. To test this hypothesis, spontaneous changes in arterial pressure and the reflex responses of HR were examined before and after a single bout of mild to moderate dynamic exercise in 19 spontaneously hypertensive rats (SHR, 10 male and 9 female). Eleven SHR subjected to sinoaortic denervation (SAD) (6 male, 5 female) were also studied. All rats were instrumented with an arterial catheter for the measurement of arterial pressure and HR. After exercise, arterial pressure and HR were reduced below preexercise levels. Furthermore, the operating point and spontaneous gain (G) of the arterial baroreflex were reduced. Specifically, after exercise, the spontaneous range of HR (P1, 50%), the pressure at the midpoint of the pressure range (P3, 13%) and the HR at the midpoint of the HR range (H3, 10%), the spontaneous minimum HR (P4, 8%) and maximum HR (10%), and G (76%) were significantly attenuated. SAD significantly attenuated the relationship between arterial pressure and HR by reducing G (males 94%, females 95%). These results demonstrate that acute exercise resulted in a postexercise resetting of the operating point and a reduction in the gain of the arterial baroreflex. Furthermore, these data suggest that postexercise reductions in arterial pressure and HR are mediated by a lowering of the operating point of the arterial baroreflex.
Cardiovascular physiology in the twentieth century: great strides and missed opportunities
Authors: Granger Harris J.
Published: December 2017

In a broad sense, physiology is the study of the chemical and physical bases of life processes. Consequently, the evolution of our knowledge of cardiovascular functions is closely linked to the developments in many fields of science, including chemistry, physics, engineering, and biology. A cursory examination reveals that different “foundation” sciences predominated in different stages of the history of cardiovascular physiology. Today, cardiovascular physiology is poised to exploit new developments in all areas of scientific inquiry. However, cardiovascular physiologists have not always embraced the power of the multidisciplinary approach. In this brief overview of the history of cardiovascular physiology in the 20th century, the major focus is on some of the major advances in the field and the contributions of other disciplines to these developments. In addition, the forces that influenced cardiovascular science in this century and their impact on the evolution of the field in the new millennium are discussed.
Dynamic relations among length, tension, and intracellular Ca2+ in activated ferret papillary muscles
Authors: Saeki Yasutake , Kurihara Satoshi , Komukai Kimiaki , Ishikawa Tetsuya , Takigiku Kiyohiro
Published: December 2017

To study the effects of mechanical constraints on the Ca2+ affinity of cardiac troponin C, we analyzed the tension and aequorin light (AL) responses to sinusoidal length changes (5–10% of the initial muscle length) in aequorin-injected, tetanized cardiac muscles. The amplitude of the quasi-sinusoidal tension and AL responses decreased with increasing length-perturbation frequency from 0.5 to 1 Hz at 24°C and from 1 to 3 Hz at 30°C. The increase in AL corresponded well to the decrease in tension; likewise, the decrease in AL to the increase in tension and the tension response lagged behind the length change. A further increase in frequency (>1 Hz at 24°C and >3 Hz at 30°C) markedly increased the amplitude of the tension responses but decreased the amplitude of the AL responses. The increase in AL lagged behind the decrease in tension; likewise, the decrease in AL lagged behind the increase in tension, and the tension response led the length change. From previous mechanistic interpretations of the frequency dependence of the amplitude of tension response, we argue that the Ca2+affinity of cardiac troponin C changes in parallel with the active tension (i.e., the number of active cross bridges) but not with the passive tension produced by the length perturbation-induced cross-bridge strain.
Time course of endothelial-neutrophil interaction in splanchnic artery ischemia-reperfusion
Authors: Hayward Reid , Lefer Allan M.
Published: December 2017

Splanchnic artery occlusion and reperfusion (SAO/R) results in a severe form of circulatory shock that has a high mortality rate. To examine the time course of the early events involved in SAO/R, occlusion of the superior mesenteric artery (SMA) and the celiac artery (120 min) were followed by reperfusion periods of 0, 2.5, 5, 20, 30, 60, or 120 min. Relaxation of isolated SMA vascular rings to the endothelium-dependent vasodilator ACh was unimpaired following 120 min of ischemia (86 ± 5%); however, significant ( P < 0.01) reductions in endothelium-dependent vasorelaxation were observed following 2.5 min (53 ± 6%) of reperfusion with severe dysfunction ( P < 0.001) observed at 20 min (29 ± 4%). Neutrophil adherence to the endothelium increased as a function of reperfusion time with a 2.3-fold increase observed at 20 min ( P < 0.01) and a 3.4-fold increase observed at 120 min ( P < 0.001). Intestinal myeloperoxidase activity was significantly increased 30 min after reperfusion ( P < 0.05), whereas surface expression of P-selectin progressively increased at 5 ( P < 0.05) and 30 min ( P < 0.001) postreperfusion. These findings demonstrate that endothelial dysfunction is a very early event in the pathophysiology of SAO/R, subsequently resulting in increased surface expression of P-selectin and the adherence of neutrophils to the endothelium that leads to neutrophil accumulation in the splanchnic viscera.