bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactions between CO2chemoreflexes and arterial baroreflexes
Authors: Henry Rebecca A. , Lu I-Li , Beightol Larry A. , Eckberg Dwain L.
Published: December 2017

We studied interactions between CO2 chemoreflexes and arterial baroreflexes in 10 supine healthy young men and women. We measured vagal carotid baroreceptor-cardiac reflexes and steady-state fast Fourier transform R-R interval and photoplethysmographic arterial pressure power spectra at three arterial pressure levels (nitroprusside, saline, and phenylephrine infusions) and three end-tidal CO2 levels (3, 4, and 5%, fixed-frequency, large-tidal-volume breathing, CO2 plus O2). Our study supports three principal conclusions. First, although low levels of CO2 chemoreceptor stimulation reduce R-R intervals and R-R interval variability, statistical modeling suggests that this effect is indirect rather than direct and is mediated by reductions of arterial pressure. Second, reductions of R-R intervals during hypocapnia reflect simple shifting of vagally mediated carotid baroreflex responses on the R-R interval axis rather than changes of baroreflex gain, range, or operational point. Third, the influence of CO2 chemoreceptor stimulation on arterial pressure (and, derivatively, on R-R intervals and R-R interval variability) depends critically on baseline arterial pressure levels: chemoreceptor effects are smaller when pressure is low and larger when arterial pressure is high.
Gel stretch method: a new method to measure constitutive properties of cardiac muscle cells
Authors: Zile Michael R. , Cowles Monica Kelly , Buckley J. Michael , Richardson Kendrick , Cowles Bradford A. , Baicu Catalin F. , Cooper George , Gharpuray Vasanti
Published: December 2017

Diastolic dysfunction is an important cause of congestive heart failure; however, the basic mechanisms causing diastolic congestive heart failure are not fully understood, especially the role of the cardiac muscle cell, or cardiocyte, in this process. Before the role of the cardiocyte in this pathophysiology can be defined, methods for measuring cardiocyte constitutive properties must be developed and validated. Thus this study was designed to evaluate a new method to characterize cardiocyte constitutive properties, the gel stretch method. Cardiocytes were isolated enzymatically from normal feline hearts and embedded in a 2% agarose gel containing HEPES-Krebs buffer and laminin. This gel was cast in a shape that allowed it to be placed in a stretching device. The ends of the gel were held between a movable roller and fixed plates that acted as mandibles. Distance between the right and left mandibles was increased using a stepper motor system. The force applied to the gel was measured by a force transducer. The resultant cardiocyte strain was determined by imaging the cells with a microscope, capturing the images with a CCD camera, and measuring cardiocyte and sarcomere length changes. Cardiocyte stress was characterized with a finite-element method. These measurements of cardiocyte stress and strain were used to determine cardiocyte stiffness. Two variables affecting cardiocyte stiffness were measured, the passive elastic spring and viscous damping. The passive spring was assessed by increasing the force on the gel at 1 g/min, modeling the resultant stress vs. strain relationship as an exponential [ς = A/ k( e kε− 1)]. In normal cardiocytes, A = 23.0 kN/m2 and k = 16. Viscous damping was assessed by examining the loop area between the stress vs. strain relationship during 1 g/min increases and decreases in force. Normal cardiocytes had a finite loop area = 1.39 kN/m2, indicating the presence of viscous damping. Thus the gel stretch method provided accurate measurements of cardiocyte constitutive properties. These measurements have allowed the first quantitative assessment of passive elastic spring properties and viscous damping in normal mammalian cardiocytes.
α1-Adrenergic activation of L-type Ca current in rat ventricular myocytes: perforated patch-clamp recordings
Authors: Liu Shi J. , Kennedy Richard H.
Published: December 2017

α1-Adrenergic stimulation has little effect on L-type Ca2+channel current ( I Ca,L) in adult cardiac myocytes measured using conventional whole cell voltage-clamp techniques. In this study using perforated-patch techniques, we reevaluated the effect of α1-adrenergic stimulation on I Ca,L in adult rat ventricular myocytes. Action potentials and I Ca,L were examined in the presence of 1 μM nadolol, a β-adrenergic antagonist, in myocytes internally dialyzed with Na+- and K+-free solutions (Cs+ and tetraethylammonium as substitutes). Phenylephrine (PE; 30 μM) increased the action potential duration measured at 25 and 70% of repolarization by 104 and 86%, respectively. In the perforated-patch configuration, PE elicited a transient decrease followed by a ∼60% increase in I Ca,L, whereas only the transient decrease in I Ca,L was observed in myocytes when the conventional whole cell configuration was used. The PE-induced increase in I Ca,L was reversibly blocked by 1 μM prazosin, an α1-adrenergic antagonist. These results suggest that α1-adrenergic stimulation enhances cardiac I Ca,L and that obligatory intracellular mediators for this action are lost during whole cell recordings.
5,6-Epoxyeicosatrienoic acid reduces increases in pulmonary vascular resistance in the dog
Authors: Stephenson Alan H. , Sprague Randy S. , Lonigro Andrew J.
Published: December 2017

We recently reported that canine pulmonary microsomes metabolize arachidonic acid to all four regioisomeric epoxyeicosatrienoic acids (EET). 5,6-EET dilates blood vessels in several nonpulmonary vascular beds, often in a cyclooxygenase-dependent manner. The present study was designed to determine whether 5,6-EET can decrease pulmonary vascular resistance (PVR) in the intact pulmonary circulation. In isolated canine lungs perfused with physiological salt solution, a constant infusion of U-46619 (3.28 ± 0.99 nmol/min) increased PVR 62.1 ± 4.5%. Administration of 5,6-EET (10−5M) into the perfusate reduced the U-46619-mediated increase in PVR by 23.6 ± 6.1%. These effects of U-46619 and 5,6-EET were limited to changes in resistance solely in the pulmonary venous segment. In contrast, venous as well as arterial segmental resistances were increased in 5-hydroxytryptamine (5-HT)-treated lungs. However, in the latter instance, 5,6-EET reduced arterial but not venous segmental resistance. 5,6-EET increased pulmonary PGI2synthesis from 70.5 ± 18.4 to 675.9 ± 125.4 ng/min. In the presence of indomethacin (10−4M), 5,6-EET did not increase PGI2synthesis nor did it decrease U-46619- or 5-HT-mediated increases in PVR. In canine intrapulmonary vessels, 5,6-EET decreased active tension in veins contracted with U-46619. 5,6-EET decreased active tension in arteries but not veins contracted with 5-HT, consistent with results in the perfused lungs. These results demonstrate that 5,6-EET is a vasodilator in the intact pulmonary circulation. Its dilator activity depends on the constrictor agent present, the segmental resistance, and cyclooxygenase activity.
Inhibition of p42 and p44 MAP kinase does not alter smooth muscle contraction in swine carotid artery
Authors: Gorenne Isabelle , Su Xiaoling , Moreland Robert S.
Published: December 2017

Caldesmon inhibits myosin ATPase activity; phosphorylation of caldesmon reverses the inhibition. The caldesmon kinase is believed to be mitogen-activated protein (MAP) kinase. MAP kinases are activated during vascular stimulation, but a cause-and-effect relationship between kinase activity and contraction has not been established. We examined the role of MAP kinase in contraction using PD-098059, an inhibitor of MAP kinase kinase (MEK). MAP kinase activity was assessed using an anti-active MAP kinase antibody and direct measurement of MAP kinase catalyzed phosphorylation of myelin basic protein, MBP-(95—98). MAP kinase phosphorylation, stimulated by histamine (50 μM) or phorbol 12,13-dibutyrate (PDBu, 0.1 μM), was inhibited by PD-098059 (100 μM). PD-098059 did not alter the sensitivity or the maximal level of force in smooth muscle stimulated by histamine or PDBu, nor did PD-098059 affect contraction of β-escin-permeabilized tissue. Our data suggest that p44 and p42 MAP kinases are not involved in regulation of vascular smooth muscle contraction. These results do not, however, preclude a role for other isoforms of the MAP kinase family.
The endothelium modulates the contribution of chloride currents to norepinephrine-induced vascular contraction
Authors: Lamb Fred S. , Barna Thomas J.
Published: December 2017

Activation of a Cl−current is critical to agonist-induced activation of rat aortic smooth muscle contraction. Substituting extracellular Cl−with 130 mM methanesulfonate (8 mM Cl−) increases the contractile response to norepinephrine (NE) but not to KCl. We hypothesized that endothelial factors modulate this effect. Removing the endothelium (rubbing) or treatment with N-nitrol-arginine (l-NNA) markedly increased the potentiation of NE-induced contraction by low-Cl−buffer. Indomethacin had no effect. The previously demonstrated ability of Cl−-channel blockers (DIDS, anthracene-9-carboxylic acid, niflumic acid) or Cl−transport inhibitors (bumetanide, bicarbonate-free buffer) to inhibit responses to NE was not altered by l-NNA. Low-Cl−buffer alone did not contract intact rings but produced nifedipine-sensitive contractile responses after rubbing or l-NNA treatment. These data suggest that the Cl−conductance of smooth muscle in intact blood vessels is low but increases with withdrawal of reduced nitric oxide (NO′) or agonist stimulation. Rubbing orl-NNA increased the sensitivity of rings to KCl but not to NE. Nifedipine reduced both sensitivity and maximum response to NE in intact vessels.l-NNA increased the maximum response to NE in nifedipine-treated rings without changing sensitivity. We conclude that although NO′ affects both the voltage-dependent and voltage-independent components of contraction, sensitivity to NE is determined by the voltage-dependent portion. The voltage change required for a full response to NE is dependent on activation of a Cl−current that may be under the tonic regulatory influence of NO′.
Dynamics of spectral components of heart rate variability during changes in autonomic balance
Authors: Højgaard Michael V. , Holstein-Rathlou Niels-Henrik , Agner Erik , Kanters Jørgen K.
Published: December 2017

Frequency domain analysis of heart rate variability (HRV) has been proposed as a semiquantitative method for assessing activities in the autonomic nervous system. We examined whether absolute powers, normalized powers, and the low frequency-to-high frequency ratio (LF/HF) derived from the HRV power spectrum could detect shifts in autonomic balance in a setting with low sympathetic nervous tone. Healthy subjects were examined for 3 h in the supine position during 1) control conditions ( n = 12), 2) acute β-blockade ( n = 11), and 3) chronic β-blockade ( n = 10). Heart rate fell during the first 40 min of the control session (72 ± 2 to 64 ± 2 beats/min; P < 0.005) and was even lower during acute and chronic β-blockade (56 ± 2 beats/min; P < 0.005). The powers of all spectral areas rose during the first 60 min in all three settings, more so with β-blockade ( P < 0.05). LF/HF was found to contain the same information as powers expressed in normalized units. LF/HF detected the shift in autonomic balance induced by β-blockade but not the change induced by supine position. In conclusion, none of the investigated measures derived from power spectral analysis comprehensively and consistently described the changes in autonomic balance.
Recovery of blood flow and oxygen transport after temporary ischemia of rat liver
Authors: Kazuo Hiromu , Nishida Toshirou , Seiyama Akitoshi , Ueshima Shigeyuki , Hamada Eisaku , Ito Toshinori , Matsuda Hikaru
Published: December 2017

Hepatic tissue perfusion and O2 supply after ischemia are indispensable for recovery of cellular functions, but few studies have been performed regarding the recovery of tissue blood flow and O2 transport. After 5, 15, and 30 min of ischemia of rat livers, hepatic tissue perfusion, hepatic arterial and portal blood flow, plasma[Formula: see text], and O2 transport parameters were measured. Hepatic tissue blood flow and erythrocyte velocity in the sinusoids showed biphasic recoveries after temporal ischemia for 5, 15, and 30 min. The first peak in the flow appeared at 3–4 min after the initiation of tissue perfusion, and the second peak appeared at ∼20 min, irrespective of the ischemic period. Hepatic blood flow during the initial increase contained relatively low O2-saturated blood compared with that in the second increase. Livers that had been subjected to a prior hepatic artery ligation only showed the first peak at ∼4 min. The first increase in hepatic blood flow corresponded to the peak in the portal venous flow, and the second increase corresponded to that of the hepatic artery. These results suggested that hepatic microcirculation after temporary hepatic ischemia showed biphasic recoveries because of different restoration patterns of the portal vein and hepatic artery.
Thyroid control of sarcolemmal Na+/Ca2+exchanger and SR Ca2+-ATPase in developing rat heart
Authors: Cernohorský Jan , Kolář František , Pelouch Václav , Korecky Borivoj , Vetter Roland
Published: December 2017

Thyroid hormone (TH) levels increase in the postnatal life and are essential for maturation of myocardial Ca2+handling. During this time, the sarcolemmal (SL) Na+/Ca2+exchanger (NCX) function decreases and the sarco endoplasmic reticulum (SR) Ca2+-ATPase (SERCA2) function increases. We examined the effects of postnatal hypo- or hyperthyroidism on NCX and SERCA2 in rat hearts. Animals were rendered hypothyroid by 0.05% 6- n-propyl-2-thiouracil in drinking water given to nursing mothers from days 2 to 21 postpartum. Hyperthyroidism was induced by daily injections of 10 μg/100 g body weight of 3,3′,5-triiodo-l-thyronine during this period. Ventricular steady-state mRNA and protein levels of NCX and SERCA2 were analyzed by Northern and Western blotting. These were compared with SL Na+gradient-induced and SR oxalate-supported Ca2+transports in isolated membranes. In hypothyroidism, NCX mRNA and protein were elevated by 66 and 80%, respectively, and SERCA2 mRNA and protein were reduced to 55 and 70%, respectively ( P < 0.05 vs. euthyroid). Corresponding differences were observed in the respective Ca2+transports. Conversely, reduced NCX (by 50%) and elevated SERCA2 (by 150%) activities were found in hyperthyroidism ( P < 0.05). The levels of NCX and SERCA2 mRNA and protein were, however, unchanged in hyperthyroidism, indicating that functional changes are not due to altered NCX and SERCA2 expression. In this case, a decline in noninhibitory phosphorylated phospholamban is a likely explanation for the elevated SR Ca2+transport. In conclusion, physiological TH levels appear to be essential for normal reciprocal changes in the expression and function of myocardial NCX and SERCA2 during postnatal development.
Anaphylaxis-induced mesenteric vascular permeability, granulocyte adhesion, and platelet aggregates in rat
Authors: Withers Geoffrey D. , Kubes Paul , Ibbotson Geoffrey , Scott R. Brent
Published: December 2017

This study investigates the response of small venules to IgE-dependent, antigen-mediated mast cell activation. Intravital microscopy was utilized to visualize 25- to 40-μm mesenteric venules, mast cell degranulation (on-line detection), vascular permeability changes (albumin leakage), leukocyte adhesion, and the formation of platelet aggregates in rats sensitized with 10 μg of intraperitoneal egg albumin (EA) in saline- or sham-sensitized (saline alone) rats. Sensitized rats challenged with EA (1 mg/ml superfusing mesentery), but not sensitized rats challenged with BSA or sham-sensitized rats challenged with EA, exhibited mast cell degranulation with significant time-dependent increases in vascular permeability (inhibited by diphenhydramine, salbutamol, and indomethacin), leukocyte adhesion (inhibited by Web-2086), and the formation of cellular aggregates (platelet), which were associated with intermittent obstruction of venular flow. Anti-platelet antibody, but not anti-neutrophil antibody or fucoidin (selectin antagonist), prevented platelet aggregate formation. Compound 48/80-induced mast cell degranulation caused similar changes in permeability (via different mediators) and leukocyte adhesion but did not induce platelet aggregation. EA-induced platelet aggregation was not inhibited by any of the mediators tested, and platelets isolated from sensitized rats failed to aggregate in response to direct EA challenge, suggesting release of an unidentified inflammatory mediator as the factor initiating platelet aggregation.
17β-Estradiol effect on critical cardiac output with reduction of cardiac output in oophorectomized sheep
Authors: Evans Wayne , Phernetton Terrance M. , Magness Ronald R.
Published: December 2017

Acute administration of 17β-estradiol (E2β) leads to increases in cardiac output, oxygen delivery, and oxygen consumption and increases the critical cardiac output in the nonpregnant sheep. We sought to determine whether the lack of a critical cardiac output or flow-dependent oxygen consumption during states of low cardiac output in late gestation can be reproduced in nonpregnant sheep treated with estrogen. We studied five nonpregnant oophorectomized sheep in a randomized crossover design by placing catheters in the pulmonary artery, the right atrium, and the descending aorta. Three experiments were randomly performed on each sheep 3 to 5 days apart: 1) without estrogen or vehicle, 2) 2–3 h after intravenous administration of vehicle, and 3) 2–3 h after intravenous E2β (3 μg/kg). Cardiac output was gradually reduced while hemodynamic, cardiorespiratory, acid-base, and metabolic variables were simultaneously evaluated. There was a 70% increase in cardiac output in animals given E2β compared with that in the same animals given either vehicle or nothing (194.0 ± 13.0, 120.0 ± 14.5, and 114.0 ± 16.2 ml ⋅ min−1 ⋅ kg−1, respectively; P < 0.05). Oxygen consumption was twofold higher in the E2β series compared with that in the no-treatment and vehicle series (10.01 ± 1.3, 6.04 ± 0.77, and 4.52 ± 0.42 ml O2 ⋅ min−1 ⋅ kg−1, respectively; P < 0.05). Tissue oxygen extraction was unaltered by estrogen. However, tissue oxygen extraction at the critical cardiac output was lower in the estradiol group. In relation to oxygen consumption, all three groups demonstrated a critical cardiac output when cardiac output was gradually reduced. However, the level of critical cardiac output was significantly higher in the E2β group (68.4 ± 2.4, 42.8 ± 2.6, and 46.2 ± 2.6 ml ⋅ min−1 ⋅ kg−1, respectively; P < 0.05). We conclude that E2β exhibits increases in systemic tissue blood flow and oxygen consumption. Animals given E2β show increases in critical cardiac output and impairment of tissue oxygen extraction at critical cardiac output, which leads to development of flow-dependent oxygen consumption at higher cardiac outputs than in the control animals.
The role of coronary flow and adenosine in postischemic recovery of septic rat hearts
Authors: Ismail Jitka A. , McDonough Kathleen H.
Published: December 2017

Sepsis depresses myocardial function but prevents subsequent ischemia-reperfusion injury. Elevated coronary flow (CF) and endogenous adenosine may be important factors in the complete recovery of postischemic myocardial function observed in septic rat hearts. The purpose of this study was to determine the effects of manipulating CF and of antagonizing adenosine receptors on the postischemic recovery of left ventricular developed pressure (LVDP) in septic and control rat hearts. The relationship between CF and LVDP in septic rat hearts before ischemia was depressed compared with control. However, this relationship was unaltered by ischemia in septic hearts, whereas in control hearts it was severely depressed. Preventing the elevation of CF during reperfusion did not significantly affect the recovery of LVDP in septic rat hearts. Adenosine antagonism by 8-phenyltheophylline (0.1 and 1 nM) prevented the elevated CF during reperfusion, and the higher dose significantly depressed postischemic function. We conclude that elevated CF did not contribute to the recovery of postischemic LVDP in septic rat hearts but that endogenous adenosine may provide protection from ischemia.
Development of heart rate irregularities in chick embryos
Authors: Höchel Joachim , Akiyama Ryuichi , Masuko Takuya , Pearson James T. , Nichelmann Martin , Tazawa Hiroshi
Published: December 2017

Heart rate (HR) irregularities in chick embryos were defined as large fluctuations (>10 beats/min) comprising irregular, brief deceleration and/or acceleration of instantaneous HR (IHR). IHR was determined directly from the arterial blood pressure while adequate gas exchange was maintained through an eggshell and chorioallantoic membrane. Five embryos were examined on each day from day 11 to day 19 of incubation. Baseline HR was stable until day 12–13, and on around day 13–14 transient, rapid deceleration of HR (termed V pattern) began to appear, with a subsequent increase in its frequency and magnitude. The acceleration patterns (lambda, avian omega, and periodic patterns) appeared later, and the IHR became increasingly irregular, with additional, spontaneous deceleration and acceleration patterns toward hatching. Additional experiments with intravenous administration of autonomic drugs clearly showed that rapid deceleration of HR was mediated by parasympathetic nervous function but did not always show clear relations of sympathomimetic and sympathetic blocking agents to the acceleration patterns.
ANG II-related myocardial damage: role of cardiac sympathetic catecholamines and β-receptor regulation
Authors: Henegar Jeffrey R. , Schwartz Dean D. , Janicki Joseph S.
Published: December 2017

The objectives of this study were 1) to determine whether ANG II-induced myocardial damage (ANG Dam) is mediated via the β1-adrenergic receptor, 2) to elucidate whether adrenal medulla or cardiac sympathetic neuron catecholamines are responsible for ANG Dam, and 3) to determine whether the lack of damage after 3 days of elevated ANG II levels is due to β1-receptor downregulation. To this end, ANG II was administered to rats 1) that were treated with a β-receptor blocker, 2) after adrenal medullectomy and/or cardiac sympathectomy, and 3) for 3 or 8 days. ANG II caused both myocyte necrosis and coronary vascular damage after adrenal medullectomy but not after cardiac sympathectomy. There was a 38 and 55% decrease in β-receptor density after 3 and 8 days, respectively, of ANG II infusion, and an upregulation to control levels 5 days after a 3-day ANG II infusion was stopped. We conclude that cardiac sympathetic neuron catecholamines are responsible for ANG Dam and that the acute nature of this damage is associated with a downregulation of β1-adrenergic receptors.
Changes in ventricular repolarization during acidosis and low-flow ischemia
Authors: Bethell Hugh W. L. , Vandenberg Jamie I. , Smith Gerry A. , Grace Andrew A.
Published: December 2017

Myocardial ischemia, primarily a metabolic insult, is also defined by altered cardiac mechanical and electrical activity. We have investigated the metabolic contributions to the electrophysiological changes during low-flow ischemia (7.5% of the control flow) using31P NMR spectroscopy to monitor metabolic parameters, suction electrodes to study epicardial monophasic action potentials, and86Rb as a tracer for K+-equivalent efflux during low-flow ischemia in the Langendorff-perfused ferret heart. Shortening of the action potential duration at 90% repolarization (APD90) was most marked between 1 and 5 min after induction of ischemia, at which time it shortened from 261 ± 4 to 213 ± 8 ms. The period of marked APD90shortening was accompanied by a fivefold increase in the rate of86Rb efflux, both of which were inhibited by the ATP-sensitive K+(KATP)-channel blockers glibenclamide and 5-hydroxydecanoate (5-HD), as well as by a significant fall in intracellular pH (pHi) from 7.14 ± 0.02 to 6.83 ± 0.03 but no change in intracellular ATP concentration ([ATP]i). We therefore investigated whether a fall in pHicould be the metabolic change responsible for modulating cardiac KATPchannel activity in the intact heart during ischemia. Both metabolic (30 mM lactate added to extracellular solution) and respiratory ([Formula: see text] increased to 15%) acidosis caused an initial lengthening of APD90to 112 ± 1.5 and 113 ± 0.9%, respectively, followed by shortening during continued acidosis to 106 ± 1.2 and 106 ± 1.4%, respectively. The shortening of APD90during continued acidosis was inhibited by glibenclamide, consistent with acidosis causing activation of KATPchannels at normal [ATP]i. The similar responses to metabolic (induced by adding either l- or d-lactate) and respiratory acidosis suggest that lactate has no independent metabolic effect on action potential repolarization.
Differential frequency-dependent reflex integration of myelinated and nonmyelinated rat aortic baroreceptors
Authors: Fan Wei , Andresen Michael C.
Published: December 2017

Electrical activation of myelinated (A type) and nonmyelinated (C type) baroreceptor axons (BR) in aortic depressor nerve (ADN) evoked baroreflex changes in mean arterial pressure (MAP) in chloralose-urethan-anesthetized rats. Low stimulation intensities (<3 V) activated only A-type BR electroneurograms (ENG). A-type selective stimulus trains required minimum frequencies >10 Hz to evoke reflex MAP decreases, and the largest MAP responses occurred at 50 Hz and higher. In contrast, high stimulation intensities (18–20 V) maximally activated two volleys in ADN ENG corresponding to A- and C-type BR volleys. High-intensity trains decreased MAP at low frequency (1 Hz) and largest reflex responses at ≥5 Hz. Capsaicin (Cap) applied periaxonally to ADN selectively blocked C-type ENG volleys but not A-type volleys. Reflex curves with supramaximal intensity during Cap were indistinguishable from the pre-Cap, low-intensity baroreflexes. In comparison, vagus ENG showed graded Cap block of the C-fiber volley (ED50 = 200 nM) without significant attenuation of the A-type volley below 1 μM. However, 100 μM Cap blocked conduction in all myelinated vagal axons as well as C-type axons. Thus Cap is selective for sensory C-type axons only at low micromolar concentrations. Myelinated and nonmyelinated arterial BR evoke characteristically different frequency-response reflex relations that suggest distinct differences in sensory information processing mechanisms.
Estimating glucose metabolism using glucose analogs and two tracer kinetic models in isolated rabbit heart
Authors: Marshall Robert C. , Powers-Risius Patricia , Huesman Ronald H. , Reutter Bryan W. , Taylor Scott E. , Maurer Heidi E. , Huesman Michelle K. , Budinger Thomas F.
Published: December 2017

The purpose of this investigation was to 1) evaluate the relative accuracy of the Sokoloff and Patlak tracer kinetic models in estimating glucose metabolic rate (GMR) in the presence and absence of insulin; 2) evaluate the effect of nutritional state on the lumped constant (LC); and 3) compare the kinetics of 2-fluoro-2-deoxy-d-[14C]glucose (FDG) and 2-deoxy-d-[3H]glucose (DG) membrane transport and phosphorylation. The experimental preparation was the isolated, red blood cell-albumin-perfused rabbit heart. Our results showed that both tracer kinetic models provided GMR estimates that correlated well with the Fick method (for FDG, R = 0.84 and 0.91 for the Sokoloff and Patlak models, respectively); nutritional state did not affect the LC; and FDG and DG have different transport and/or phosphorylation parameters. We also observed that 1) the addition of a fourth compartment to the Sokoloff model reduced the mean squared error between measured and modeled data by a factor of 7.4; 2) a longer time (21.8 min) was required to obtain a linear phase of the Patlak plot than is allowed in clinical studies; and 3) accurate GMR estimates were obtained only by using different LCs reflecting insulin’s presence or absence. Our results indicate potential sources of error in the use of FDG and positron emission tomography to quantify GMR in patients.
Human neuropeptide Y potentiates α1-adrenergic blood pressure responses in vivo
Authors: Schuerch Leander V. , Linder Lilly M. , Grouzmann Eric , Haefeli Walter E.
Published: December 2017

Human neuropeptide Y (hNPY) potentiates the postjunctional vasoconstrictor effects of α1-adrenoceptor agonists in animals and in human hand veins in vivo. We therefore hypothesized that such an interaction might also occur in the human arterial bed. With the present single-blind cross-over study in 12 healthy volunteers, the effect of subpressor doses of hNPY on the blood pressure response to α1-adrenoceptor stimulation was evaluated. Dose-response curves were constructed to intravenously infuse phenylephrine with and without coinfusion with two different doses of hNPY (1.4 and 14.3 pmol ⋅ kg−1 ⋅ min−1). Blood pressure, heart rate, and forearm blood flow were recorded, and plasma hNPY was determined. During infusion of the higher hNPY dose, which increased hNPY from 24.0 ± 12.0 to 495.1 ± 12.6 pmol/l, blood pressure curves were 2.4-fold shifted toward lower phenylephrine dose rates ( P < 0.001). Forearm vascular resistance showed a similar trend, whereas the counterregulatory decrease of heart rate was similar in both groups. In contrast, the lower hNPY dose rate producing a fourfold increase in hNPY concentrations did not modify the response to phenylephrine. This in vivo study in humans demonstrates that hNPY induced potentiating effects on α1-adrenergic constriction also in the systemic arterial circulation and suggests that circulating hNPY may participate in the control of vascular tone.
Flow-induced responses in skeletal muscle venules: modulation by nitric oxide and prostaglandins
Authors: Koller Akos , Dörnyei Gabriella , Kaley Gabor
Published: December 2017

Skeletal muscle arterioles dilate in response to increases in flow velocity/wall shear stress (WSS). The effect of flow/WSS on the diameter of skeletal muscle venules and the possible endothelial mediation of the response, however, have not yet been characterized. Thus changes in diameter of pressurized (10 mmHg) and norepinephrine-preconstricted venules (179 ± 8 μm in diameter) to increases in perfusate flow before and after endothelium removal or application of inhibitors of NO and prostaglandin (PG) synthesis, N ω-nitro-l-arginine (l-NNA, 104 M) and indomethacin (Indo, 2.8 × 105 M), respectively, were measured. Increases in perfusate flow [elicited by increases in the pressure difference (Pdiff) between proximal and distal cannulas] evoked with a delay of 17 ± 2 s dilations, up to 36 ± 9 μm at the highest flow, a response that was completely eliminated by removal/disruption of the venular endothelium. Calculation of WSS indicated that in endothelium-intact venules, the midpoint of the shear stress-diameter curve was at ∼8 dyn/cm2, whereas in endothelium-denuded vessels, shear stress increased in a linear fashion with increases in flow, up to 40 dyn/cm2.l-NNA significantly reduced flow-induced dilations (from 38 ± 11 to 17 ± 9 μm at 14 mmHg Pdiff), whereas in the additional presence of Indo, flow elicited constriction of venules decreasing basal diameter (by 21 ± 8 μm at Pdiff 12 mmHg). Thus in skeletal muscle venules an increase in shear stress due to increases in perfusate flow stimulates the release of endothelium-derived NO and PGs eliciting dilation, which in turn, regulates WSS, albeit at a lower value than what is observed in arterioles. In the absence of NO and PGs, flow-induced constriction is revealed, the cause of which remains obscure. From these data, we propose that shear stress-related responses of venules are involved in the regulation of venular resistance, especially during high flow conditions, such as reactive and exercise hyperemia.
Augmented renal sympathetic nerve activity by central command during overground locomotion in decerebrate cats
Authors: Matsukawa Kanji , Murata Jun , Wada Tetsuya
Published: December 2017

We examined whether the cerebrum is essential for producing the rapid autonomic adjustment at the onset of spontaneous overground locomotion. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), heart rate (HR), and electromyogram of the forelimb triceps brachialis were measured when freely moving, decerebrate cats spontaneously produced overground locomotion, supporting body weight. Decerebration was performed at the level of the precollicular-premammillary body. RSNA increased 95 ± 14 impulses/s (68 ± 10% of baseline value) at the onset of spontaneous locomotion, which was followed by rises in MAP and HR (7 ± 1 mmHg and 18 ± 2 beats/min, respectively). Concomitantly with the MAP rise, RSNA declined toward control values and then increased again during the subsequent period of locomotion. The same rapid increase in RSNA at the onset of locomotion was observed after sinoaortic denervation and vagotomy. It is concluded that some central site(s), other than the cerebrum and the rostral part of the diencephalon, can generate the centrally induced autonomic adjustment at the onset of spontaneous overground locomotion, which is independent of arterial baroreceptor and vagal afferents.
Regression of LV hypertrophy with captopril normalizes membrane currents in rabbits
Authors: Rials Seth J. , Xu Xiaoping , Wu Ying , Marinchak Roger A. , Kowey Peter R.
Published: December 2017

Recent studies indicate that regression of left ventricular hypertrophy (LVH) normalizes the in situ electrophysiological abnormalities of the left ventricle. This study was designed to determine whether regression of LVH also normalizes the abnormalities of individual membrane currents. LVH was induced in rabbits by renal artery banding. Single ventricular myocytes from rabbits with LVH at 3 mo after renal artery banding demonstrated increased cell membrane capacitance, prolonged action potential duration, decreased inward rectifier K+ current density, and increased transient outward K+ current density compared with myocytes from age-matched controls. Additional rabbits were randomized at 3 mo after banding to treatment with either vehicle or captopril for an additional 3 mo. Myocytes from LVH rabbits treated with vehicle showed persistent membrane current abnormalities. However, myocytes isolated from LVH rabbits treated with captopril had normal cell membrane capacitance, action potential duration, and membrane current densities. Captopril had no direct effect on membrane currents of either control or LVH myocytes. These data support the hypothesis that the action potential prolongation and membrane current abnormalities of LVH are reversed by regression. Normalization of membrane currents probably explains the reduced vulnerability to ventricular arrhythmia observed in this LVH model after treatment with captopril.
Quantification of sympathetic and parasympathetic tones by nonlinear indexes in normotensive rats
Authors: Dabiré Hubert , Mestivier Denis , Jarnet Jacqueline , Safar Michel E. , Chau Nguyen Phong
Published: December 2017

Because the use of spectral powers of blood pressure (BP) and R-R interval (RR) in the low (LF) and high frequencies (HF) to quantify sympathetic and parasympathetic activities is still under debate, we questioned whether nonlinear methods may give better results. The BP signal was recorded for 30 min before and after intravenous injection of hexamethonium (20 mg/kg), atropine (0.5 mg/kg), atenolol (1 mg/kg), and prazosin (1 mg/kg) in conscious, normotensive Wistar-Kyoto rats. Three nonlinear indexes [percentage of recurrence, percentage of determinism, and length index ( L max)] extracted from the recurrence plot method were used to analyze the BP signal. Sympathetic but not parasympathetic blockade reduced BP level and its LF component. RR increased and decreased after β- and α-blockades, respectively. Hexamethonium increased HF, and atropine reduced LF, of RR. Sympathetic blockade and, in particular, α-sympathetic blockade increased nonlinear indexes of BP. In contrast, parasympathetic blockade by atropine increased nonlinear indexes of RR. These results suggest that, compared with spectral indexes, nonlinear indexes may be more specific markers of sympathetic and parasympathetic tones.
Overexpression of α1B-adrenergic receptor induces left ventricular dysfunction in the absence of hypertrophy
Authors: Grupp Ingrid L. , Lorenz John N. , Walsh Richard A. , Boivin Gregory P. , Rindt Hansjörg
Published: December 2017

The stimulation of cardiac α1-adrenergic receptors (AR) modulates the heart’s inotropic response and plays a role in the induction of cardiomyocyte hypertrophy. We have analyzed transgenic mouse lines overexpressing a wild-type α1B-AR specifically in the heart. Basal level systolic and diastolic left ventricular (LV) contractile function was depressed both in the anesthetized closed-chest mouse and the perfused working-heart preparation. Intrinsic LV function was further characterized under controlled preload and afterload conditions using the perfusion model. Contractile parameters were restored by chronic treatment with the α-AR antagonist prazosin. In ventricular function curves, the load-dependent force increases (length-tension effects) remained intact, although the transgenic curve was shifted to lower levels. The basal level contractile deficits were paralleled by a decrease in calcium transients in isolated LV cardiomyocytes. LV function comparable to controls was restored by isoproterenol stimulation. The physiological changes occurred in the absence of cardiomyocyte hypertrophy. This transgenic model will be useful for studying the potential role of α1-AR in cardiac contractility and hypertrophy.
Hemodynamics of gastric microcirculation in rats
Authors: Peti-Peterdi János , Kovács Gergely , Hamar Péter , Rosivall László
Published: December 2017

Recently, we described a novel preparation of rat stomach for vascular micropuncture studies. The aim of the present study was to directly measure basic microvascular parameters along the length of the gastric vasculature. Blood vessels were identified, and intravascular pressure was measured with a servo-null transducer, vessel dimensions with videometry, blood flow with microspheres, and plasma colloid osmotic pressure with an osmometer. When systemic arterial pressure was 100–110 mmHg, intravascular pressures in small arteries, primary, secondary, and tertiary submucosal arterioles, mucosal terminal arterioles, and muscle arterioles were 77.8 ± 2.6, 74.6 ± 2.5, 54.1 ± 1.8, 34.4 ± 1.6, 32.4 ± 1.2, and 30.5 ± 1.4 (SE) mmHg, respectively. Intravascular pressures in collecting veins, secondary and primary submucosal venules, muscle venules, and small veins were 26.6 ± 1.1, 21.8 ± 1.6, 17.1 ± 0.8, 18.2 ± 0.9, and 14.4 ± 0.6 mmHg, respectively. Capillary pressure in the mucosa (28 mmHg), as estimated by interpolation between terminal arteriole and collecting venule pressures, was significantly higher than in the muscle layer (23.6 ± 1.4 mmHg). A total of 155 vessels from 25 animals were sampled. Relative blood flows were 16 ± 3% in the muscle and 84 ± 3% in the mucosa-submucosa. Analysis of filtration forces in these two different capillary beds suggests that gastric mucosal capillaries are primarily a filtering network, whereas muscle capillaries are in fluid balance. Calculated resistance ratios indicate low precapillary but relatively high postcapillary vascular resistance in the gastric mucosa.
Sensitivity of canine intrinsic cardiac neurons to H2O2and hydroxyl radical
Authors: Thompson Gregory W. , Horackova Magda , Armour J. Andrew
Published: December 2017

To determine whether intrinsic cardiac neurons are sensitive to oxygen-derived free radicals in situ, studies were performed in 44 open-chest anesthetized dogs. 1) When H2O2(600 μM) was administered to right atrial neurons of 36 dogs via their local arterial blood supply, neuronal activity either increased (+92% in 16 dogs) or decreased (−61% in 20 dogs), depending on the population of neurons studied. H2O2(600 μM) administered into the systemic circulation did not affect neuronal activity, measured cardiac indexes, or aortic pressure. 2) The iron-chelating agent deferoxamine (20 mg/kg iv), a chemical that prevents the formation of oxygen-derived free radicals, reduced the activity generated by neurons (−57%) in 8 of 10 dogs. 3) H2O2did not affect neuronal activity when administered in the presence of deferoxamine in these 10 dogs. 4) When the ATP-sensitive potassium (KATP) channel opener cromakalim (20 μM) was administered to intrinsic cardiac neurons in another 21 animals via their regional arterial blood supply, ongoing neuronal activity in 15 of these dogs decreased by 54%. 5) Neuronal activity was not affected by H2O2when administered in the presence of cromakalim in 16 dogs. These data indicate that 1) some intrinsic cardiac neurons are sensitive to exogenous H2O2, 2) such neurons are tonically influenced by locally produced oxygen-derived free radicals in situ, and 3) intrinsic cardiac neurons possess KATPchannels that are functionally important during oxidative challenge.
Leukocyte activation does not mediate myocardial leukocyte retention during endotoxemia in rabbits
Authors: Goddard Christopher M. , Poon Betty Y. , Klut M. Emilia , Wiggs Barry R. , vanEeden Stephan F. , Hogg James C. , Walley Keith R.
Published: December 2017

Our goal was to determine whether coronary leukocyte retention after endotoxin infusion was due primarily to leukocyte activation. Leukocytes were activated by infusion of endotoxin into 12 blood donor rabbits. Separately, 12 isolated rabbit hearts were perfused with blood from an endotoxemic support rabbit to expose coronary endothelium to an inflammatory stimulus. During an infusion of 20 ml of donor blood into the isolated heart, the coronary transit time of leukocytes was determined by deconvolution of multiple measurements of injectate and collected leukocyte concentrations. With no leukocyte activation or inflammatory stimulation of endothelium, leukocyte transit time was 9.2 ± 3.5 s, and 11.6 ± 4.1 × 106leukocytes were retained in the coronary circulation. Leukocyte activation alone did not alter transit time (9.8 ± 3.2 s) or retention (9.3 ± 4.6 × 106leukocytes). Inflammatory stimulation of endothelium with and without leukocyte activation increased transit time (18.0 ± 3.6 and 18.9 ± 3.8 s, respectively; P < 0.05) and retention (24.8 ± 8.4 and 25.3 ± 6.8 × 106leukocytes, respectively; P < 0.05) to the same extent. Differential counts showed that neutrophils (but not lymphocytes) were slowed and retained. Inflammatory stimulation of endothelium caused coronary capillary endothelial swelling and pseudopod formation. Thus increased coronary neutrophil transit time and retention are due to structural changes of coronary endothelial cells or other effects of the inflammatory response occurring within coronary capillaries, not only due to activation of leukocytes.
Mitochondrial ATP-sensitive K+channels modulate cardiac mitochondrial function
Authors: Holmuhamedov Ekshon L. , Jovanović Sofija , Dzeja Petras P. , Jovanović Aleksandar , Terzic Andre
Published: December 2017

Discovered in the cardiac sarcolemma, ATP-sensitive K+(KATP) channels have more recently also been identified within the inner mitochondrial membrane. Yet the consequences of mitochondrial KATPchannel activation on mitochondrial function remain partially documented. Therefore, we isolated mitochondria from rat hearts and used K+channel openers to examine the effect of mitochondrial KATPchannel opening on mitochondrial membrane potential, respiration, ATP generation, Ca2+transport, and matrix volume. From a mitochondrial membrane potential of −180 ± 15 mV, K+channel openers, pinacidil (100 μM), cromakalim (25 μM), and levcromakalim (20 μM), induced membrane depolarization by 10 ± 7, 25 ± 9, and 24 ± 10 mV, respectively. This effect was abolished by removal of extramitochondrial K+or application of a KATPchannel blocker. K+channel opener-induced membrane depolarization was associated with an increase in the rate of mitochondrial respiration and a decrease in the rate of mitochondrial ATP synthesis. Furthermore, treatment with a K+channel opener released Ca2+from mitochondria preloaded with Ca2+, an effect also dependent on extramitochondrial K+concentration and sensitive to KATPchannel blockade. In addition, K+channel openers, cromakalim and pinacidil, increased matrix volume and released mitochondrial proteins, cytochrome cand adenylate kinase. Thus, in isolated cardiac mitochondria, KATPchannel openers depolarized the membrane, accelerated respiration, slowed ATP production, released accumulated Ca2+, produced swelling, and stimulated efflux of intermembrane proteins. These observations provide direct evidence for a role of mitochondrial KATPchannels in regulating functions vital for the cardiac mitochondria.
Increased endothelial NOS in lambs with increased pulmonary blood flow and pulmonary hypertension
Authors: Black Stephen M. , Fineman Jeffrey R. , Steinhorn Robin H. , Bristow James , Soifer Scott J.
Published: December 2017

Altered pulmonary vascular reactivity is a source of morbidity and mortality for children with congenital heart defects and increased pulmonary blood flow. Nitric oxide (NO) is an important mediator of pulmonary vascular reactivity. The objective of this study was to characterize potential early alterations in expression, localization, and activity of endothelial NO synthase (eNOS) induced by increased pulmonary blood flow and pulmonary hypertension. Utilizing aortopulmonary vascular graft placement in the fetal lamb, we have established a unique animal model of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow. Ten fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). RNase protection assays and Western blotting were performed on lung tissue prepared from 4-wk-old shunt lambs and age-matched controls. eNOS mRNA (2.4:1, P < 0.05) and protein (2.08:1, P < 0.05) were increased in lungs of shunt lambs. In situ hybridization and immunohistochemistry revealed that the increase was confined to the endothelium of pulmonary arteries. eNOS protein (1.55:1, P < 0.05) and tissue cGMP concentrations (2.1:1, P < 0.05) were also increased in isolated fifth-generation pulmonary arteries of shunt lambs. In addition, total lung eNOS activity was increased (2.9:1, P < 0.05). Thus we report a previously undescribed, early upregulation of eNOS gene expression and activity in lambs with increased pulmonary blood flow and pulmonary hypertension.
Myocardial aerobic metabolism is impaired in a cell culture model of cyanotic heart disease
Authors: Merante Frank , Mickle Donald A. G. , Weisel Richard D. , Li Ren-Ke , Tumiati Laura C. , Rao Vivek , Williams William G. , Robinson Brian H.
Published: December 2017

A human pediatric cardiomyocyte cell culture model of chronic cyanosis was used to assess the effects of low oxygen tension on mitochondrial enzyme activity to address the postoperative increase in lactate and decreased ATP in the myocardium and the high incidence of low-output failure with restoration of normal oxygen tension, after technically successful corrective cardiac surgery. Chronically hypoxic cells ([Formula: see text] = 40 mmHg for 7 days) exhibited significantly reduced activities for pyruvate dehydrogenase, cytochrome- c oxidase, succinate cytochrome c reductase, succinate dehydrogenase, and citrate synthase. The activity of NADH-cytochrome c reductase was unaffected. Lactate production and the lactate-to-pyruvate ratio were significantly greater in hypoxic cardiomyocytes. Western and Northern analysis demonstrated a decrease in the levels of various mRNA and corresponding polypeptides in hypoxic cells. Thus hypoxia influences mitochondrial metabolism through acute and chronic adaptive mechanisms, reflecting allosteric (posttranscriptional) and transcriptional modulation. Transcriptional downregulation of key mitochondrial enzyme systems can explain the insufficient myocardial aerobic metabolism and low-output failure in children with cyanotic heart disease after cardiac surgery.