bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute cardiovascular response to isocapnic hypoxia. II. Model validation
Authors: Ursino Mauro , Magosso Elisa
Published: December 2017

The role of the different mechanisms involved in the cardiovascular response to hypoxia [chemoreceptors, baroreceptors, lung stretch receptors, and central nervous system (CNS) hypoxic response] is analyzed in different physiological conditions by means of a mathematical model. The results reveal the following: 1) The model is able to reproduce the cardiovascular response to hypoxia very well between 100 and 28 mmHg Po 2. 2) Sensitivity analysis of the impact of each individual mechanism underlines the role of the baroreflex in avoiding excessive derangement of systemic arterial pressure and cardiac output during severe hypoxia and suggests the existence of significant redundancy among the other regulatory factors. 3) Simulation of chronic sinoaortic denervation (i.e., simultaneous exclusion of baroreceptors, chemoreceptors, and lung stretch receptors) shows that the CNS hypoxic response alone is able to maintain quite normal cardiovascular adjustments to hypoxia; however, suppression of the CNS hypoxic response, as might occur during anesthesia, led to a significant arterial hypotension. 4) Simulations of experiments with controlled ventilation show a significant decrease in heart rate that can only partly be ascribed to inactivation of lung stretch receptors. 5) Simulations performed by maintaining constant cardiac output suggest that during severe hypoxia the chemoreflex can produce a significant decrease in systemic blood volume. In all the previous cases, model predictions exhibit a satisfactory agreement with physiological data.
Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea
Authors: Phillips Bradley G. , Kato Masahiko , Narkiewicz Krzysztof , Choe Ian , Somers Virend K.
Published: December 2017

Patients with obstructive sleep apnea (OSA) are frequently obese and are predisposed to weight gain. They also have heightened sympathetic drive. We reasoned that noradrenergic activation of β3-receptors on adipocytes would inhibit leptin production, predisposing to obesity in sleep apnea. We therefore tested the hypothesis that obesity and predisposition to weight gain in OSA are associated with low levels of plasma leptin. We prospectively studied 32 male patients (43 ± 2 yr) with OSA who were newly diagnosed and never treated and who were free of any other diseases. Control measurements were obtained from 32 similarly obese closely matched male subjects (38 ± 2 yr). Leptin levels were 13.7 ± 1.3 and 9.2 ± 1.2 ng/ml in patients with OSA and controls, respectively ( P = 0.02). Weight gain over the year before diagnosis was 5.2 ± 1.7 and 0.5 ± 0.9 kg in sleep apnea patients and similarly obese control subjects, respectively ( P = 0.04). Muscle sympathetic activity was 46 ± 4 and 30 ± 4 bursts/min in patients with OSA ( n = 16) and control subjects ( n = 18), respectively ( P = 0.01). Plasma leptin levels are elevated in newly diagnosed otherwise healthy patients with untreated sleep apnea beyond the levels seen in similarly obese control subjects without sleep apnea. Higher leptin levels in OSA, independent of body fat content, suggest that OSA is associated with resistance to the weight-reducing effects of leptin.
Altered cardiac excitation-contraction coupling in ventricular myocytes from spontaneously diabetic BB rats
Authors: Ren Jun , Bode Ann M.
Published: December 2017

Cardiac excitation-contraction (E-C) coupling abnormalities in chemically induced diabetes have been well defined. Heart dysfunction has also been reported in diabetes of genetic origin. The purpose of this study was to determine whether heart dysfunction in genetically predisposed diabetes is attributable to impaired E-C coupling at the cellular level. Myocytes were isolated from 1-yr-old BioBreed (BB) spontaneously diabetic-prone (BB/DP) rats and their diabetic-resistant littermates (BB/DR). Mechanical properties were evaluated by use of a video edge-detection system. Myocytes were electrically stimulated at 0.5 Hz. The contractile properties analyzed included peak shortening (PS), time-to-peak shortening (TPS), time-to-90% relengthening (TR90), and maximal velocities of shortening and relengthening (±d L/d t). Intracellular Ca2+ handling was evaluated with fura 2 fluorescent dye. Myocytes from spontaneously diabetic hearts exhibited a depressed PS, prolonged TPS and TR90, and reduced ±d L/d t. Consistent with the mechanical response, myocytes from the BB/DP group displayed reduced resting and peak intracellular Ca2+ concentration associated with a slowed Ca2+-transient decay. Furthermore, myocytes from BB/DP hearts were less responsive to increases in extracellular Ca2+ and norepinephrine and equally responsive to increases in stimulation frequency and KCl compared with those from the BB/DR group. These results suggest that the genetic diabetic state produces altered cardiac E-C coupling, in part, because of abnormalities of the myocyte, similar to that demonstrable after chemically induced diabetes or during human diabetes.
Regulation of myocardial [13C]glucose metabolism in conscious rats
Authors: McNulty Patrick H. , Cline Gary W. , Whiting Jennifer M. , Shulman Gerald I.
Published: December 2017

Administration of supplemental glucose and/or insulin is postulated to improve the outcome from myocardial ischemia by increasing the heart's relative utilization of glucose as an energy substrate. To examine the degree to which circulating glucose and insulin levels actually influence myocardial substrate preference in vivo, we infused conscious, chronically catheterized rats withd-[1-13C]glucose and compared steady-state13C enrichment of plasma glucose with that of myocardial glycolytic ([3-13C]alanine) and oxidative ([4-13C]glutamate) intermediary metabolites. In fasting rats, [3-13C]alanine-to-[1-13C]glucose and [4-13C]glutamate-to-[3-13C]alanine ratios averaged 0.16 ± 0.12 and 0.14 ± 0.03, respectively, indicating that circulating glucose contributed 32% of myocardial glycolytic flux, whereas subsequent flux through pyruvate dehydrogenase contributed 14% of total tricarboxylic acid (TCA) cycle activity. Raising plasma glucose to 11 mmol/l, or insulin to 500 pmol/l, increased these contributions equivalently. At supraphysiological (>6,500 pmol/l) insulin levels, the plasma glucose contribution to glycolysis increased further, and addition of hyperglycemia made it the sole glycolytic substrate, yet [4-13C]glutamate-to-[3-13C]alanine ratios remained ≤0.60. Thus plasma levels of glucose and insulin independently regulate the proportional contribution of exogenous glucose to myocardial glycolytic and TCA cycle flux in vivo in a dose-dependent manner. However, even at supraphysiological levels, nonglucose substrates continue to supply ≥40% of myocardial TCA cycle flux.
Estimation of parallel conductance by dual-frequency conductance catheter in mice
Authors: Georgakopoulos Dimitrios , Kass David A.
Published: December 2017

The conductance catheter method has substantially enhanced the characterization of in vivo cardiovascular function in mice. Absolute volume determination requires assessment of parallel conductance ( V p) offset because of conductivity of structures external to the blood pool. Although such a determination is achievable by hypertonic saline bolus injection, this method poses potential risks to mice because of volume loading and/or contractility changes. We tested another method based on differences between blood and muscle conductances at various catheter excitation frequencies (20 vs. 2 kHz) in 33 open-chest mice. The ratio of mean frequency-dependent signal difference to V pderived by hypertonic saline injection was consistent [0.095 ± 0.01 (SD), n = 11], and both methods were strongly correlated ( r 2 = 0.97, P < 0.0001). This correlation persisted when the ratio was prospectively applied to a separate group of animals ( n = 12), with a combined regression relation of V p(DF) = 1.1 ∗ V p(Sal) − 2.5 [where V p(DF) is V p derived by the dual-frequency method and V p(Sal) is V p derived by hypertonic saline bolus injection], r 2 = 0.95, standard error of the estimate = 1.1 μl, and mean difference = 0.6 ± 1.4 μl. Varying V p(Sal) in a given animal resulted in parallel changes in V p(DF) (multiple regression r 2 = 0.92, P < 0.00001). The dominant source of V p in mice was found to be the left ventricular wall itself, since surrounding the heart in the chest with physiological saline or markedly varying right ventricular volumes had a minimal effect on the left ventricular volume signal. On the basis of V p and flow probe-derived cardiac output, end-diastolic volume and ejection fraction in normal mice were 28 ± 3 μl and 81 ± 6%, respectively, at a heart rate of 622 ± 28 min−1. Thus the dual-frequency method and independent flow signal can be used to provide absolute volumes in mice.
Diameter changes in skeletal muscle venules during arterial pressure reduction
Authors: Bishop Jeffrey J. , Nance Patricia R. , Popel Aleksander S. , Intaglietta Marcos , Johnson Paul C.
Published: December 2017

Previous studies in skeletal muscle have shown a substantial (>100%) increase in venous vascular resistance with arterial pressure reduction to 40 mmHg, but a microcirculatory study showed no significant venular diameter changes in the horizontal direction during this procedure. To examine the possibility of venular collapse in the vertical direction, a microscope was placed horizontally to view a vertically mounted rat spinotrapezius muscle preparation. We monitored the diameters of venules (mean diameter 73.8 ± 37.0 μm, range 13–185 μm) oriented horizontally and vertically with a video system during acute arterial pressure reduction by hemorrhage. Our analysis showed small but significant ( P < 0.0001) diameter reductions of 1.0 ± 2.5 μm and 1.8 ± 3.1 μm in horizontally and vertically oriented venules, respectively, upon reduction of arterial pressure from 115.0 ± 26.3 to 39.8 ± 12.3 mmHg. The venular responses were not different after red blood cell aggregation was induced by Dextran 500 infusion. We conclude that diameter changes in venules over this range of arterial pressure reduction are isotropic and would likely increase venous resistance by <10%.
Individualizing the aorto-radial pressure transfer function: feasibility of a model-based approach
Authors: Segers P. , Carlier S. , Pasquet A. , Rabben S. I. , Hellevik L. R. , Remme E. , De Backer T. , De Sutter J. , Thomas J. D. , Verdonck P.
Published: December 2017

We fitted a three-segment transmission line model for the radial-carotid/aorta pressure transfer function (TFF) in 31 controls and 30 patients with coronary artery disease using noninvasively measured (tonometry) radial and carotid artery pressures (Pcar). Except for the distal reflection coefficient (0.85 ± 0.21 in patients vs. 0.71 ± 0.25 in controls; P < 0.05), model parameters were not different between patients or controls. Parameters were not related to blood pressure, age, or heart rate. We further assessed a point-to-point averaged TFF (TFFavg) as well as upper (TFFmax) and lower (TFFmin) enveloping TFF. Pulse pressure (PP) and augmentation index (AIx) were derived on original and reconstructed Pcar (Pcar,r). TFFavg yielded closest morphological agreement between Pcar and Pcar,r (root mean square = 4.3 ± 2.3 mmHg), and TTFavg best predicted PP (41.5 ± 11.8 vs. 41.1 ± 10.0 mmHg measured) and AIx (−0.02 ± 0.19 vs. 0.01 ± 0.19). PP and AIx, calculated from Pcar or Pcar,r, were higher in patients than in controls, irrespectively of the TFF used. We conclude that 1) averaged TFF yield significant discrepancies between reconstructed and measured pressure waveforms and subsequent derived AIx; and 2) different TFFs seem to preserve the information in the pressure wave that discriminates between controls and patients.
Doppler echo evaluation of pulmonary venous-left atrial pressure gradients: human and numerical model studies
Authors: Firstenberg Michael S. , Greenberg Neil L. , Smedira Nicholas G. , Prior David L. , Scalia Gregory M. , Thomas James D. , Garcia Mario J.
Published: December 2017

The simplified Bernoulli equation relates fluid convective energy derived from flow velocities to a pressure gradient and is commonly used in clinical echocardiography to determine pressure differences across stenotic orifices. Its application to pulmonary venous flow has not been described in humans. Twelve patients undergoing cardiac surgery had simultaneous high-fidelity pulmonary venous and left atrial pressure measurements and pulmonary venous pulsed Doppler echocardiography performed. Convective gradients for the systolic (S), diastolic (D), and atrial reversal (AR) phases of pulmonary venous flow were determined using the simplified Bernoulli equation and correlated with measured actual pressure differences. A linear relationship was observed between the convective ( y) and actual ( x) pressure differences for the S ( y = 0.23 x + 0.0074, r = 0.82) and D ( y = 0.22 x + 0.092, r = 0.81) waves, but not for the AR wave ( y = 0.030 x + 0.13, r = 0.10). Numerical modeling resulted in similar slopes for the S ( y = 0.200 x − 0.127, r = 0.97), D ( y = 0.247 x − 0.354, r= 0.99), and AR ( y = 0.087 x − 0.083, r = 0.96) waves. Consistent with numerical modeling, the convective term strongly correlates with but significantly underestimates actual gradient because of large inertial forces.
Cross-bridge kinetics in rat myocardium: effect of sarcomere length and calcium activation
Authors: Wannenburg Thomas , Heijne Gerardus H. , Geerdink Jeroen H. , Van den Dool Hendrik W. , Janssen Paul M. L. , De Tombe Pieter P.
Published: December 2017

We tested the hypotheses that Ca2+ concentration ([Ca2+]) and sarcomere length (SL) modulate force development via graded effects on cross-bridge kinetics in chemically permeabilized rat cardiac trabeculae. Using sinusoidal length perturbations, we derived the transfer functions of stiffness over a range of [Ca2+] at a constant SL of 2.1 μm ( n = 8) and at SL of 2.0, 2.1, and 2.2 μm ( n = 4). We found that changes in SL affected only the magnitude of stiffness, whereas [Ca2+] affected the magnitude and phase-frequency relations. The data were fit to complex functions of two exponential processes. The characteristic frequencies ( b and c) of these processes are indexes of cross-bridge kinetics, with b relating to cross-bridge attachment to and c to detachment from certain non-force-generating states. Both were significantly affected by [Ca2+], with an increase in b and cof 140 and 44%, respectively, over the range of [Ca2+] studied ( P < 0.01). In contrast, SL had no effect on the characteristic frequencies ( P > 0.6). We conclude that Ca2+ activation modulates force development in rat myocardium, at least in part, via a graded effect on cross-bridge kinetics, whereas SL effects are mediated mainly by recruitment of cross bridges.
Altered E-C coupling in rat ventricular myocytes from failing hearts 6 wk after MI
Authors: Wasserstrom J. Andrew , Holt Even , Sjaastad Ivar , Lunde Per Kristian , Ødegaard Annlaug , Sejersted Ole M.
Published: December 2017

Excitation-contraction (E-C) coupling was investigated in rat hearts 6 wk after induction of myocardial infarction (MI) by ligation of the left coronary artery. Heart weight was increased by 74% and left ventricular end-diastolic pressure was 23 ± 2 mmHg in MI compared with 8 ± 2 mmHg in sham-operated controls (Sham, P < 0.001). Cell shortening was measured in voltage-clamped myocytes at 36°C. In solutions where Cs+ had been replaced by K+, the voltage dependence of contraction was sigmoidal between −20 and +100 mV in Sham and MI cells. Verapamil (20 μM) blocked L-type Ca2+current and reduced contraction in Sham cells by ∼50% ( P < 0.01) but did not decrease contraction significantly in MI cells at test potentials above +10 mV. Verapamil-insensitive contractions were blocked by Ni2+ (5 mM). Na+/Ca2+ exchange current was doubled in MI compared with Sham cells at test potentials between −20 and +80 mV ( P < 0.05), whereas mRNA and protein expression increased by 30–40%. Finally, voltage dependence of contraction was bell shaped in Na+-free solutions, but contraction was significantly increased in MI cells over a wider voltage range ( P < 0.05). The insensitivity to Ca2+channel block in MI cells may result from an increased contribution of the Na+/Ca+ exchanger to triggering of E-C coupling. These results suggest significant changes in E-C coupling in the hypertrophy and failure that develop in response to extensive MI.
Transgenic overexpression of cardiac A1adenosine receptors mimics ischemic preconditioning
Authors: Morrison R. Ray , Jones Rachael , Byford Anne M. , Stell Alyssa R. , Peart Jason , Headrick John P. , Matherne G. Paul
Published: December 2017

The role of A1adenosine receptors (A1AR) in ischemic preconditioning was investigated in isolated crystalloid-perfused wild-type and transgenic mouse hearts with increased A1AR. The effect of preconditioning on postischemic myocardial function, lactate dehydrogenase (LDH) release, and infarct size was examined. Functional recovery was greater in transgenic versus wild-type hearts (44.8 ± 3.4% baseline vs. 25.6 ± 1.7%). Preconditioning improved functional recovery in wild-type hearts from 25.6 ± 1.7% to 37.4 ± 2.2% but did not change recovery in transgenic hearts (44.8 ± 3.4% vs. 44.5 ± 3.9%). In isovolumically contracting hearts, pretreatment with selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine attenuated the improved functional recovery in both wild-type preconditioned (74.2 ± 7.3% baseline rate of pressure development over time untreated vs. 29.7 ± 7.3% treated) and transgenic hearts (84.1 ± 12.8% untreated vs. 42.1 ± 6.8% treated). Preconditioning wild-type hearts reduced LDH release (from 7,012 ± 1,451 to 1,691 ± 1,256 U · l−1 · g−1 · min−1) and infarct size (from 62.6 ± 5.1% to 32.3 ± 11.5%). Preconditioning did not affect LDH release or infarct size in hearts overexpressing A1AR. Compared with wild-type hearts, A1AR overexpression markedly reduced LDH release (from 7,012 ± 1,451 to 917 ± 1,123 U · l−1 · g−1 · min−1) and infarct size (from 62.6 ± 5.1% to 6.5 ± 2.1%). These data demonstrate that murine preconditioning involves endogenous activation of A1AR. The beneficial effects of preconditioning and A1AR overexpression are not additive. Taken with the observation that A1AR blockade equally eliminates the functional protection resulting from both preconditioning and transgenic A1AR overexpression, we conclude that the two interventions affect cardioprotection via common mechanisms or pathways.
Preconditioning reduces myocardial complement gene expression in vivo
Authors: Tanhehco Elaine J. , Yasojima Koji , McGeer Patrick L. , McGeer Edith G. , Lucchesi Benedict R.
Published: December 2017

This investigation examined the effect of preconditioning in an in vivo model of ischemia-reperfusion injury. Anesthetized New Zealand White rabbits underwent 30 min of regional myocardial ischemia followed by 2 h of reperfusion. Hearts preconditioned with two cycles of 5 min ischemia-10 min reperfusion (IPC) or with the ATP-sensitive K (KATP) channel opener, diazoxide (10 mg/kg), exhibited significantly ( P < 0.05) smaller infarcts compared with control. These treatments also significantly ( P < 0.001 to P < 0.05) reduced C1q, C1r, C3, C8, and C9 mRNA in the areas at risk (AAR). The KATPchannel blocker 5-hydroxydecanoate (5-HD; 10 mg/kg) attenuated infarct size reduction elicited by IPC and diazoxide treatment. 5-HD partially reversed the decrease in complement expression caused by IPC but not diazoxide. There were no significant differences in complement gene expression in the nonrisk regions and livers of all groups. Western blot analysis revealed that IPC also reduced membrane attack complex expression in the AAR. The data demonstrate that preconditioning significantly decreases reperfusion-induced myocardial complement expression in vivo.
Insulin resistance and endothelial dysfunction in smokers: effects of vitamin C
Authors: Hirai Nobutaka , Kawano Hiroaki , Hirashima Osamu , Motoyama Takeshi , Moriyama Yasushi , Sakamoto Tomohiro , Kugiyama Kiyotaka , Ogawa Hisao , Nakao Kazuwa , Yasue Hirofumi
Published: December 2017

Cigarette smoking impairs endothelial function and is one of the major risk factors for atherosclerosis and coronary heart disease. Insulin resistance is associated with major risk factors for atherosclerosis. We examined the effects of vitamin C on insulin sensitivity and endothelial function by measuring steady-state plasma glucose (SSPG) and flow-mediated dilation (FMD) of the brachial artery. We studied 16 current smokers with normal glucose tolerance, 15 nonsmokers with impaired glucose tolerance (IGT), and 17 nonsmokers with normal glucose tolerance as controls. Both SSPG and FMD were blunted in smokers and nonsmokers with IGT compared with controls. In smokers, vitamin C decreased SSPG ( P < 0.01 by ANOVA) with decreasing plasma thiobarbituric acid-reactive substances (TBARS) ( P < 0.05 by ANOVA) and improved FMD ( P < 0.05 by ANOVA). Furthermore, vitamin C improved both SSPG ( P < 0.005 by ANOVA) and FMD ( P < 0.05 by ANOVA) in nonsmokers with IGT. SSPG, FMD, or TBARS in controls did not change after vitamin C infusion. There was a significant correlation between SSPG and FMD both in smokers and nonsmokers with IGT, whereas no correlation was observed in controls. In conclusion, both insulin sensitivity and endothelial function were impaired in smokers and nonsmokers with IGT and were improved by vitamin C. Thus increased reactive oxygen species play an important role in the pathogenesis of insulin resistance as well as endothelial dysfunction in smokers and nonsmokers with IGT.
Inhibition of baroreflex vagal bradycardia by activation of the rostral ventrolateral medulla in rats
Authors: Nosaka Shoichiro , Murata Keiko , Kobayashi Masayoshi , Cheng Zhi Bin , Maruyama Junko
Published: December 2017

In stressful conditions, baroreflex vagal bradycardia (BVB) is often suppressed while blood pressure is increased. To address the role of the rostral ventrolateral medulla (RVL), a principal source of sympathetic tone, in inhibition of BVB, we microinjected dl-homocysteic acid (DLH, 6 nmol) into the RVL of chloralose-urethan-anesthetized, sinoaortic-denervated rats to examine the effect on BVB. The BVB was provoked by electrical stimulation of the aortic depressor nerve ipsilateral to the injection sites. DLH microinjection was found to suppress BVB while increasing blood pressure. The inhibition of BVB was observed even during the early phase in which DLH transiently suppressed central inspiratory activity. The inhibition was not affected either by upper spinal cord transection or suprapontine decerebration. Similar results were obtained by microinjection of bicuculline methiodide (160 pmol), a GABA antagonist, into the RVL of carotid sinus nerve-preserved rats due to withdrawal of a tonic GABA-mediated, inhibitory influence including the input from arterial baroreceptors. In conclusion, activation of the RVL inhibits BVB at brain stem level independently of central inspiratory drive.
Selegiline improves cardiac sympathetic terminal function and β-adrenergic responsiveness in heart failure
Authors: Shite Junya , Dong Erdon , Kawai Hiroya , Stevens Suzanne Y. , Liang Chang-Seng
Published: December 2017

Selegiline is a centrally acting sympatholytic agent with neuroprotective properties. It also has been shown to promote sympathetic reinnervation after sympathectomy. These actions of selegiline may be beneficial in heart failure that is characterized by increased sympathetic nervous activity and functional sympathetic denervation. Twenty-seven rabbits with rapid cardiac pacing (360 beats/min, 8 wk) and twenty-three rabbits without pacing were randomly assigned to receive selegiline (1 mg/day, 8 wk) or placebo. Rapid pacing increased plasma norepinephrine (NE) and decreased left ventricular fractional shortening, baroreflex sensitivity, cardiac sympathetic nerve terminal profiles, cardiac NE uptake activity, and myocardial β-adrenoceptor density. Selegiline administration to animals with rapid ventricular pacing attenuated the increase in plasma NE and decreases in fractional shortening, baroreflex sensitivity, sympathetic nerve profiles, NE uptake activity and β-adrenoceptor density. Thus selegiline appears to exert a sympatholytic and cardiac neuroprotective effect in pacing-induced cardiomyopathy. The effects are potentially beneficial because selegiline not only improves cardiac function but also increases baroreflex sensitivity in heart failure.
Acute upregulation of blood-brain barrier glucose transporter activity in seizures
Authors: Cornford Eain M. , Nguyen Eddy V. , Landaw Elliot M.
Published: December 2017

Brain extraction of18F-labeled 2-fluoro-2-deoxy-d-glucose (FDG) was significantly higher in pentylene tetrazole (PTZ)-treated rats (32 ± 4%) than controls (25 ± 4%). The FDG permeability-surface area product ( PS) was also significantly higher with PTZ treatment (0.36 ± 0.05 ml · min−1· g−1) than in controls (0.20 ± 0.06 ml · min−1· g−1). Cerebral blood flow rates were also elevated by 50% in seizures. The internal carotid artery perfusion technique indicated mean [14C]glucose clearance (and extraction) was increased with PTZ treatment, and seizures increased the PS by 37 ± 16% ( P < 0.05) in cortical regions. Because kinetic analyses suggested the glucose transporter half-saturation constant ( Km) was unchanged by PTZ, we derived estimates of 1) treated and 2) control maximal transporter velocities ( Vmax) and 3) a single Km. In cortex, the glucose transporter Vmaxwas 42 ± 11% higher ( P < 0.05) in PTZ-treated animals (2.46 ± 0.34 μmol · min−1· g−1) than in control animals (1.74 ± 0.26 μmol · min−1· g−1), and the Km= 9.5 ± 1.6 mM. Blood-brain barrier (BBB) Vmaxwas 31 ± 10% greater ( P < 0.05) in PTZ-treated (2.36 ± 0.30 μmol · min−1· g−1) than control subcortex (1.80 ± 0.25 μmol · min−1· g−1). We conclude acute upregulation of BBB glucose transport occurs within 3 min of an initial seizure. Transporter Vmaxand BBB glucose permeability increase by 30–40%.
Aging-associated changes in whole cell K+ and L-type Ca2+ currents in rat ventricular myocytes
Authors: Liu Shi J. , Wyeth Richard P. , Melchert Russell B. , Kennedy Richard H.
Published: December 2017

The effect of aging on cardiac membrane currents remains unclear. This study examined the inward rectifier K+ current ( I K1), the transient outward K+current ( I to), and the L-type Ca2+ channel current ( I Ca,L) in ventricular myocytes isolated from young adult (6 mo) and aged (>27 mo) Fischer 344 rats using whole cell patch-clamp techniques. Along with an increase in the cell size and membrane capacitance, aged myocytes had the same magnitude of peak I K1 with a greater slope conductance but displayed smaller steady-state I K1. Aged myocytes also had a greater I to with an increased rate of activation, but the I to inactivation kinetics, steady-state inactivation, and responsiveness to l-phenylephrine, an α1-adrenergic agonist, were unaltered. The magnitude of peak I Ca,L in aged myocytes was decreased and accompanied by a slower inactivation, but the I Ca,L steady-state inactivation was unaltered. Action potential duration in aged myocytes was prolonged only at 90% of full repolarization (APD90) when compared with the action potential duration of young adult myocytes. Aged myocytes from Long-Evans rats showed similar changes in I toand I Ca,L but an increased I K1. These results demonstrate aging-associated changes in action potential, in morphology, and in I K1, I to, and I Ca,L of rat ventricular myocytes that possibly contribute to the decreased cardiac function of aged hearts.
Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine β-synthase-deficient mice
Authors: Lentz Steven R. , Erger Rochelle A. , Dayal Sanjana , Maeda Nobuyo , Malinow M. René , Heistad Donald D. , Faraci Frank M.
Published: December 2017

Hyperhomocysteinemia is a risk factor for stroke, myocardial infarction, and venous thrombosis. Moderate hyperhomocysteinemia is associated with impaired endothelial function, but the mechanisms responsible for endothelial dysfunction in hyperhomocysteinemia are poorly understood. We have used genetic and dietary approaches to produce hyperhomocysteinemia in mice. Heterozygous cystathionine β-synthase-deficient mice (CBS +/−), which have a selective defect in homocysteine transsulfuration, and wild-type (CBS +/+) littermates were fed either a control diet or a diet that is relatively deficient in folic acid for 6 wk. Plasma total homocysteine was 5.3 ± 0.7 μM in CBS +/+ mice and 6.4 ± 0.6 μM in CBS +/− mice ( P = 0.3) given the control diet. Plasma total homocysteine was 11.6 ± 4.5 μM in CBS +/+ mice and 25.1 ± 3.2 μM in CBS +/− mice ( P = 0.004) given a low-folate diet. In mice fed the control diet, relaxation of aortic rings in response to the endothelium-dependent vasodilator acetylcholine did not differ significantly between CBS +/+ mice and CBS +/− mice. In contrast, in mice fed a low-folate diet, maximal relaxation to acetylcholine was markedly impaired in CBS +/− mice (58 ± 9%) compared with CBS +/+ mice (84 ± 4%) ( P = 0.01). No differences in relaxation to the endothelium-independent vasodilator sodium nitroprusside were observed among the four groups of mice. These data indicate that CBS-deficient mice are predisposed to hyperhomocysteinemia during dietary folate deficiency, and moderate hyperhomocysteinemia is associated with marked impairment of endothelial function in mice.
Improved energy homeostasis of the heart in the metabolic state of exercise
Authors: Goodwin Gary W. , Taegtmeyer Heinrich ,   (With the Technical Assistance of Patrick H. Guthrie)
Published: December 2017

We postulate that metabolic conditions that develop systemically during exercise (high blood lactate and high nonesterified fatty acids) are favorable for energy homeostasis of the heart during contractile stimulation. We used working rat hearts perfused at physiological workload and levels of the major energy substrates and compared the metabolic and contractile responses to an acute low-to-high work transition under resting versus exercising systemic metabolic conditions (low vs. high lactate and nonesterified fatty acids in the perfusate). Glycogen preservation, resulting from better maintenance of high-energy phosphates, was a consequence of improved energy homeostasis with high fat and lactate. We explained the result by tighter coupling between workload and total β-oxidation. Total fatty acid oxidation with high fat and lactate reflected increased availability of exogenous and endogenous fats for respiration, as evidenced by increased long-chain fatty acyl-CoA esters (LCFA-CoAs) and by an increased contribution of triglycerides to total β-oxidation. Triglyceride turnover (synthesis and degradation) also appeared to increase. Elevated LCFA-CoAs caused high total β-oxidation despite increased malonyl-CoA. The resulting bottleneck at mitochondrial uptake of LCFA-CoAs stimulated triglyceride synthesis. Our results suggest the following. First, both malonyl-CoA and LCFA-CoAs determine total fatty acid oxidation in heart. Second, concomitant stimulation of peripheral glycolysis and lipolysis should improve cardiac energy homeostasis during exercise. We speculate that high lactate contributes to the salutary effect by bypassing the glycolytic block imposed by fatty acids, acting as an anaplerotic substrate necessary for high tricarbocylic acid cycle flux from fatty acid-derived acetyl-CoA.
Alterations in myocardial collagen content affect rat papillary muscle function
Authors: Matsubara Luiz S. , Matsubara Beatriz B. , Okoshi Marina P. , Cicogna Antonio C. , Janicki Joseph S.
Published: December 2017

We investigated the influence of myocardial collagen volume fraction (CVF, %) and hydroxyproline concentration (μg/mg) on rat papillary muscle function. Collagen excess was obtained in 10 rats with unilateral renal ischemia for 5 wk followed by 3-wk treatment with ramipril (20 mg · kg−1· day−1) (RHTR rats; CVF = 3.83 ± 0.80, hydroxyproline = 3.79 ± 0.50). Collagen degradation was induced by double infusion of oxidized glutathione (GSSG rats; CVF = 2.45 ± 0.52, hydroxyproline = 2.85 ± 0.18). Nine untreated rats were used as controls (CFV = 3.04 ± 0.58, hydroxyproline = 3.21 ± 0.30). Active stiffness (AS; g · cm−2· % Lmax−1) and myocyte cross-sectional area (MA; μm2) were increased in the GSSG rats compared with controls [AS 5.86 vs. 3.96 ( P < 0.05); MA 363 ± 59 vs. 305 ± 28 ( P < 0.05)]. In GSSG and RHTR groups the passive tension-length curves were shifted downwards, indicating decreased passive stiffness, and upwards, indicating increased passive stiffness, respectively. Decreased collagen content induced by GSSG is related to myocyte hypertrophy, decreased passive stiffness, and increased AS, and increased collagen concentration causes myocardial diastolic dysfunction with no effect on systolic function.
Validation of a mouse conductance system to determine LV volume: comparison to echocardiography and crystals
Authors: Feldman Marc D. , Erikson John M. , Mao Yi , Korcarz Claudia E. , Lang Roberto M. , Freeman Gregory L.
Published: December 2017

The application of left ventricular pressure-volume analysis to transgenic mice to characterize the cardiac phenotype has been problematic due to the small size of the mouse heart and the rapid heartbeat. Conductance technology has been miniaturized for the mouse and can solve this problem. However, there has been no validation of this technique. Accordingly, we performed echocardiography followed by simultaneous ultrasonic crystals, flow probe, and conductance studies in 18 CD-1 mice. Raw conductance volumes were corrected for an inhomogenous electrical field (α) and parallel conductance ( G pi) yielding a stroke volume of 14.1 ± 3.7 μl/beat, end-diastolic volume of 20.8 ± 6.5 μl, and end-systolic volume of 9.0 ± 5.8 μl. The mean conductance volumes were no different from those derived by flow probe and echocardiography but did differ from ultrasonic crystals. G pi was determined to be 14.9 ± 8.7 μl. However, hypertonic saline altered dimension and pressure in the mouse left ventricle. Although G pi can be determined by the hypertonic saline method, saline altered hemodynamics, questioning its validity in the mouse. Although mean measures of absolute volume may be similar among different techniques, individual values did not correlate.
Endocardial activation during ventricular fibrillation in normal and failing canine hearts
Authors: Pierpont Gordon L. , Chugh Sumeet S. , Hauck John A. , Gornick Charles C.
Published: December 2017

Because congestive heart failure (CHF) promotes ventricular fibrillation (VF), we compared VF in seven dogs with CHF induced by combined myocardial infarction and rapid ventricular pacing to VF in six normal dogs. A noncontact, multielectrode array balloon catheter provided full-surface real-time left ventricular (LV) endocardial electrograms and a dynamic color-coded display of endocardial activation projected onto a three-dimensional model of the LV. Fast Fourier transform (FFT) analysis of virtual electrograms showed no difference in peak or centroid frequency in CHF dogs compared with normals. The average number of simultaneous noncontiguous wavefronts present during VF was higher in normals (2.4 ± 1.0 at 10 s of VF) than in CHF dogs (1.3 ± 1.0, P < 0.005) and decreased in both over time. The wavefront “turnover” rate, estimated using FFT of the noncontiguous wavefront data, did not differ between normals and CHF and did not change over 5 min of VF. Thus the fundamental frequency characteristics of VF are unaltered by CHF, but dilated abnormal ventricles sustain fewer active wavefronts than do normal ventricles.
Methods for assessing hepatic distending pressure and changes in hepatic capacitance in pigs
Authors: Kjekshus Harald , Risoe Cecilie , Scholz Tim , Smiseth Otto A.
Published: December 2017

The equilibrium pressure obtained during simultaneous occlusion of hepatic vascular inflow and outflow was taken as the reference estimate of hepatic vascular distending pressure (Phd). Phdat baseline was 1.1 ± 0.2 (mean ± SE) mmHg higher than hepatic vein pressure (Phv) and 0.7 ± 0.3 mmHg lower than portal vein pressure (Ppv). Norepinephrine (NE) infusion increased Phdby 1.5 ± 0.5 mmHg and Ppvby 3.7 ± 0.6 mmHg but did not significantly increase Phv. Hepatic lobar vein pressure (Phlv) measured by a micromanometer tipped 2-Fr catheter closely resembled Phdboth at baseline and during NE-infusion. Dynamic pressure-volume (PV) curves were constructed from continuous measurements of Phvand hepatic blood volume increases (estimated by sonomicrometry) during brief occlusions of hepatic vascular outflow and compared with static PV curves constructed from Phddeterminations at five different hepatic volumes. Estimates of hepatic vascular compliance and changes in unstressed blood volume from the two methods were in close agreement with hepatic compliance averaging 32 ± 2 ml · mmHg−1· kg liver−1. NE infusion reduced unstressed blood volume by 110 ± 38 ml/kg liver but did not alter compliance. In conclusion, Phlvreflects hepatic distending pressure, and the construction of dynamic PV curves is a fast and valid method for assessing hepatic compliance and changes in unstressed blood volume.
Plasma viscosity and cerebral blood flow
Authors: Tomiyama Yoshinobu , Brian Johnny E. , Todd Michael M.
Published: December 2017

We hypothesized that the response of cerebral blood flow (CBF) to changing viscosity would be dependent on “baseline” CBF, with a greater influence of viscosity during high-flow conditions. Plasma viscosity was adjusted to 1.0 or 3.0 cP in rats by exchange transfusion with red blood cells diluted in lactated Ringer solution or with dextran. Cortical CBF was measured by H2 clearance. Two groups of animals remained normoxic and normocarbic and served as controls. Other groups were made anemic, hypercapnic, or hypoxic to increase CBF. Under baseline conditions before intervention, CBF did not differ between groups and averaged 49.4 ± 10.2 ml · 100 g−1 · min−1 (±SD). In control animals, changing plasma viscosity to 1.0 or 3.0 cP resulted in CBF of 55.9 ± 8.6 and 42.5 ± 12.7 ml · 100 g−1 · min−1, respectively (not significant). During hemodilution, hypercapnia, and hypoxia with a plasma viscosity of 1.0 cP, CBF varied from 98 to 115 ml · 100 g−1 · min−1. When plasma viscosity was 3.0 cP during hemodilution, hypercapnia, and hypoxia, CBF ranged from 56 to 58 ml · 100 g−1 · min−1 and was significantly reduced in each case ( P < 0.05). These results support the hypothesis that viscosity has a greater role in regulation of CBF when CBF is increased. In addition, because CBF more closely followed changes in plasma viscosity (rather than whole blood viscosity), we believe that plasma viscosity may be the more important factor in controlling CBF.
Na+-K+-ATPase α2-isoform expression in guinea pig hearts during transition from compensation to decompensation
Authors: Trouve Pascal , Carre François , Belikova Ioulia , Leclercq Christophe , Dakhli Thierry , Soufir Lilia , Coquard Isabelle , Ramirez-Gil Juan , Charlemagne Danièle
Published: December 2017

Disturbance in ionic gradient across sarcolemma may lead to arrhythmias. Because Na+-K+-ATPase regulates intracellular Na+and K+concentrations, and therefore intracellular Ca2+concentration homeostasis, our aim was to determine whether changes in the Na+-K+-ATPase α-isoforms in guinea pigs during transition from compensated (CLVH) to decompensated left ventricular hypertrophy (DLVH) were concomitant with arrhythmias. After 12- and 20-mo aortic stenosis, CLVH and DLVH were characterized by increased mean arterial pressure (30% and 52.7%, respectively). DLVH differed from CLVH by significantly increased end-diastolic pressure (34%), decreased sarco(endo)plasmic reticulum Ca2+-ATPase (−75%), and increased Na+/Ca2+exchanger (25%) mRNA levels and by the occurrence of ventricular arrhythmias. The α-isoform (mRNA and protein levels) was significantly lower in DLVH (2.2 ± 0.2- and 1.4 ± 0.15-fold, respectively, vs. control) than in CLVH (3.5 ± 0.4- and 2.2 ± 0.13-fold, respectively) and was present in sarcolemma and T tubules. Changes in the levels of α1- and α3-isoform in CLVH and DLVH appear physiologically irrelevant. We suggest that the increased level of α2-isoform in CLVH may participate in compensation, whereas its relative decrease in DLVH may enhance decompensation and arrhythmias.
Effect of aerobic and resistance exercise training on vascular function in heart failure
Authors: Maiorana Andrew , O'Driscoll Gerard , Dembo Lawrence , Cheetham Craig , Goodman Carmel , Taylor Roger , Green Daniel
Published: December 2017

Exercise training of a muscle group improves local vascular function in subjects with chronic heart failure (CHF). We studied forearm resistance vessel function in 12 patients with CHF in response to an 8-wk exercise program, which specifically excluded forearm exercise, using a crossover design. Forearm blood flow (FBF) was measured using strain-gauge plethysmography. Responses to three dose levels of intra-arterial acetylcholine were significantly augmented after exercise training when analyzed in terms of absolute flows (7.0 ± 1.8 to 10.9 ± 2.1 ml · 100 ml−1 · min−1 for the highest dose, P < 0.05 by ANOVA), forearm vascular resistance (21.5 ± 5.0 to 15.3 ± 3.9 ml · 100 ml forearm−1 · min−1, P< 0.01), or FBF ratios ( P < 0.01, ANOVA). FBF ratio responses to sodium nitroprusside were also significantly increased after training ( P < 0.05, ANOVA). Reactive hyperemic flow significantly increased in both upper limbs after training (27.9 ± 2.7 to 33.5 ± 3.1 ml · 100 ml−1 · min−1, infused limb; P < 0.05 by paired t-test). Exercise training improves endothelium-dependent and -independent vascular function and peak vasodilator capacity in patients with CHF. These effects on the vasculature are generalized, as they were evident in a vascular bed not directly involved in the exercise stimulus.
SOD-1 expression in pig coronary arterioles is increased by exercise training
Authors: Rush James W. E. , Laughlin M. Harold , Woodman Christopher R. , Price Elmer M.
Published: December 2017

Coronary arterioles of exercise-trained (EX) pigs have enhanced nitric oxide (NO·)-dependent dilation. Evidence suggests that the biological half-life of NO· depends in part on the management of the superoxide anion. The purpose of this study was to test the hypothesis that expression of cytosolic copper/zinc-dependent superoxide dismutase (SOD)-1 is increased in coronary arterioles as a result of exercise training. Male Yucatan pigs either remained sedentary (SED, n = 4) or were EX ( n = 4) on a motorized treadmill for 16–20 wk. Individual coronary arterioles (∼100-μm unpressurized internal diameter) were dissected and frozen. Coronary arteriole SOD-1 protein (via immunoblots) increased as a result of exercise training (2.16 ± 0.35 times SED levels) as did SOD-1 enzyme activity (measured via inhibition of pyrogallol autooxidation; ∼75% increase vs. SED). In addition, SOD-1 mRNA levels (measured via RT-PCR) were higher in EX arterioles (1.68 ± 0.16 times the SED levels). There were no effects of exercise training on the levels of SOD-2 (mitochondrial), catalase, or p67phox proteins. Thus chronic aerobic exercise training selectively increases the levels of SOD-1 mRNA, protein, and enzymatic activity in porcine coronary arterioles. Increased SOD-1 could contribute to the enhanced NO·-dependent dilation previously observed in EX porcine coronary arterioles by improving management of superoxide in the vascular cell environment, thus prolonging the biological half-life of NO·.
Effect of time and vascular pressure on permeability and cyclic nucleotides in ischemic lungs
Authors: Pearse David B. , Becker Patrice M.
Published: December 2017

We previously found that increased intravascular pressure decreased ischemic lung injury by a nitric oxide (NO)-dependent mechanism (Becker PM, Buchanan W, and Sylvester JT. J Appl Physiol 84: 803–808, 1998). To determine the role of cyclic nucleotides in this response, we measured the reflection coefficient for albumin (ςalb), fluid flux ( J˙), cGMP, and cAMP in ferret lungs subjected to either 45 min (“short”; n = 7) or 180 min (“long”) of ventilated ischemia. Long ischemic lungs had “low” (1–2 mmHg, n = 8) or “high” (7–8 mmHg, n = 6) vascular pressure. Other long low lungs were treated with the NO donor ( Z)-1-[ N-(3-ammoniopropyl)- N-( n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA-NONOate; 5 × 10−4 M, n = 6) or 8-bromo-cGMP (5 × 10−4 M, n = 6). Compared with short ischemia, long low ischemia decreased ςalb (0.23 ± 0.04 vs. 0.73 ± 0.08; P < 0.05) and increased J˙ (1.93 ± 0.26 vs. 0.58 ± 0.22 ml · min−1 · 100 g−1; P < 0.05). High pressure prevented these changes. Lung cGMP decreased by 66% in long compared with short ischemia. Lung cAMP did not change. PAPA-NONOate and 8-bromo-cGMP increased lung cGMP, but only 8-bromo-cGMP decreased permeability. These results suggest that ischemic vascular injury was, in part, mediated by a decrease in cGMP. Increased vascular pressure prevented injury by a cGMP-independent mechanism that could not be mimicked by administration of exogenous NO.
NOC/oFQ contributes to age-dependent impairment of NMDA-induced cerebrovasodilation after brain injury
Authors: Armstead William M.
Published: December 2017

This study characterized the effects of fluid percussion brain injury (FPI) on N-methyl-d-aspartate (NMDA)-induced vasodilation and determined the role of nociceptin/orphanin FQ (NOC/oFQ) in such changes as a function of age and time postinsult. FPI elevated cerebrospinal fluid (CSF) NOC/oFQ from 70 ± 3 to 444 ± 56 pg/ml (≈10−10 M) within 1 h and to 1,931 ± 112 pg/ml within 8 h, whereas values returned to control levels within 168 h in the newborn pig. In contrast, FPI elevated CSF NOC/oFQ from 77 ± 4 to 202 ± 16 pg/ml within 1 h and values returned to control levels within 8 h in the juvenile pig. Topical NOC/oFQ (10−10 M) had no effect on pial artery diameter but attenuated NMDA (10−8, 10−6M)-induced dilation (9 ± 1 and 16 ± 1 vs. 5 ± 1 and 10 ± 1%) in both age groups. In the newborn, NMDA-induced pial artery dilation was reversed to vasoconstriction within 1 h post-FPI and responses remained impaired for 72 h, but such vasoconstriction was attenuated by pretreatment with [F/G]NOC/oFQ(1–13)-NH2 (10−6 M, 1 mg/kg iv), an NOC/oFQ antagonist (9 ± 1 and 16 ± 1 vs. −7 ± 1 and −12 ± 1 vs −2 ± 1 and −3 ± 1% for control, FPI, and FPI pretreated with the NOC/oFQ antagonist). In contrast, in the juvenile, NMDA-induced vasodilation was only attenuated within 1 h post-FPI and returned to control within 8 h. Such dilation was also partially restored by the NOC/oFQ antagonist. These data indicate that NOC/oFQ contributes to impaired NMDA pial artery dilation after FPI. These data suggest that the greater NOC/oFQ release in the newborn versus the juvenile may contribute to age-related differences in FPI effects on excitatory amino acid-induced pial dilation.