bluuebunny/crossref_metadata_2025 huggingface dataset:
beta 1-and beta 2-adrenergic receptors exhibit differing susceptibility to muscarinic accentuated antagonism
Authors: Aprigliano O. , Rybin V. O. , Pak E. , Robinson R. B. , Steinberg S. F.
Published: December 2017

Neonatal rat ventricular myocytes express both beta 1-and beta 2-adrenergic receptors linked to enhanced intracellular adenosine 3',5'-cyclic monophosphate (cAMP) accumulation and the modulation of contractile function. This study tests the hypothesis that muscarinic agonists act via distinct mechanisms to interfere with beta 1-and beta 2-adrenergic receptor actions. The beta 2-selective agonist zinterol (10(-7) M) elicits approximately a fourfold increase in cAMP accumulation, which is mimicked, both in magnitude and kinetics, by 10(-9) M of the mixed beta 1-receptor agonist/beta 2-receptor agonist isoproterenol. At these concentrations, isoproterenol and zinterol elicit equivalent inotropic and lusitropic (i.e., enhanced relaxation) responses. Carbachol inhibits all three responses (cAMP, inotropic, and lusitropic) elicited by isoproterenol. In contrast, carbachol does not interfere with the effect of zinterol to augment cAMP accumulation or to induce a positive inotropic response. However, carbachol inhibits the lusitropic response to zinterol via an action at an M2-muscarinic receptor linked to a pertussis toxin-sensitive pathway. Additional studies indicate that beta 2-receptor-dependent phosphorylation of troponin I and phospholamban is substantially attenuated by carbachol. We conclude that carbachol interferes with beta 1-receptor actions by reducing cAMP accumulation. In contrast, the anti-beta 2-receptor actions of carbachol are mediated by a mechanism that is distinct from inhibition of cAMP accumulation, involving an M2-muscarinic receptor coupled to a pertussis toxin-sensitive G protein, which leads to inhibition of troponin I and phospholamban phosphorylation and inhibition of the beta 2-receptor-dependent lusitropic response.
Distribution of pressure gradients along hepatic vasculature
Authors: Maass-Moreno R. , Rothe C. F.
Published: December 2017

To test the hypothesis that the hepatic sinusoidal pressure is virtually identical to the portal venous pressure (Ppv) or the abdominal vena caval pressure (Pave), microvascular pressures were measured in liver vascular networks supplied by a single portal venule near the liver surface of alpha-chloralose-urethan-anesthetized rabbits. With the use of a servo-null pressure-measuring system, the pressures in terminal portal venules, sinusoids, and initial hepatic venules averaged 5.7 +/- 0.8 (SD), 5.4 +/- 0.7, and 4.7 +/- 0.6 mmHg, respectively, relative to the middle of the right atrium. The mean Ppv was 7.7 +/- 1.1 mmHg and the Pave was 3.9 +/- 0.7 mmHg. The sinusoidal pressure (Psinu) averaged 2.33 +/- 1.04 mmHg lower than the Ppv, and 1.54 +/- 0.63 mmHg higher than the Pave. The pressure gradient across the sinusoids averaged < 1 mmHg. The fractional pressure gradient from the sinusoids to the vena cava averaged 41 +/- 15% of the total Ppv to Pave gradient. We conclude that most of the transhepatic resistance cannot be attributed to a specific vascular segment or vessel type and that sinusoidal pressures are not closely similar to either the Ppv or the Pave, as is often assumed.
Ischemia/reperfusion-induced microvascular dysfunction: role of oxidants and lipid mediators
Authors: Kurose I. , Argenbright L. W. , Wolf R. , Lianxi L. , Granger D. N.
Published: December 2017

The objective of this study was to define the role of oxidants and lipid mediators in the leukocyte-endothelial cell adhesion and albumin leakage elicited in rat mesenteric venules by ischemia-reperfusion (I/R). Intravital fluorescence microscopy was used to monitor leukocyte adherence and emigration, platelet-leukocyte aggregation, mast cell degranulation, and albumin leakage after release of a 20-min arterial occlusion. I/R elicited large increases in leukocyte-endothelial cell adhesion and albumin leakage. These responses were significantly attenuated in venules treated with either superoxide dismutase, oxypurinol (an inhibitor of xanthine oxidase), lodoxamide (a mast cell stabilizer), WEB-2086 (a platelet-activating factor antagonist), or SC-41930 (a leukotriene B4-receptor antagonist) but not by U-74006F (an inhibitor of lipid peroxidation). Platelet-leukocyte aggregates and mast cell degranulation induced by I/R were also attenuated by administration of either superoxide dismutase or lodoxamide. These results support the hypothesis that oxidants produced, in part, by xanthine oxidase promote the formation (by mast cells and endothelial cells) of platelet-activating factor and leukotriene B4, which recruit and activate leukocytes in postischemic venules. The adherent and emigrated leukocytes then mediate the increased albumin extravasation observed in the postcapillary venules.
Characterization of embryonic aortic impedance with lumped parameter models
Authors: Yoshigi M. , Keller B. B.
Published: December 2017

We systematically constructed and analyzed 18 analog circuit models to characterize embryonic arterial impedance. We measured simultaneous dorsal aortic pressure and flow, and we calculated experimental impedance in stage 24 chick embryos (n = 15). Cycle length was altered with thermal probes to improve frequency resolution of the impedance spectrum. Models were categorized according to the framework and the location of inductance and resistance terms. Models were excluded if they failed to reproduce the fundamental characteristics of the experimental impedance spectrum. We used weighted least-square parameter optimization to fit the model impedance curves to the experimental impedance data. Models that failed to converge parameters or revealed overparameterization were also excluded. We assessed goodness of fit in the frequency domain with the F-test, Akaike information criterion, and Schwarz criterion to determine the best-fit model. The addition of a serial inductance term to the traditional three-element windkessel model improved fit by reproducing modulus fluctuation and phase zero crossing (P < 0.001). Thus, despite dramatic differences in scale and geometry, the embryonic and mature vascular systems can be described using lumped parameter circuit models.
Systemic and renal hemodynamic effects of hemorrhage in conscious lambs
Authors: Smith F. G. , Abu-Amarah I.
Published: December 2017

The purpose of the present study was to investigate the systemic and renal hemodynamic effects of hemorrhage in the newborn to determine whether the newborn is capable of restoring blood pressure in the face of blood loss at hemorrhage of up to 20% of vascular volume. Experiments were carried out in conscious, chronically instrumented lambs and consisted of measurements before, during, and after hemorrhage at 0 (n = 9), 10 (n = 8), 15 (n = 8), and 20% (n = 8) of blood volume. Right atrial pressure decreased but only after 20% hemorrhage. There was a transient decrease in blood pressure at 10-15% hemorrhage and a sustained decrease in blood pressure after 20% hemorrhage (from 82 +/- 7 to 66 +/- 9 mmHg). Heart rate increased transiently after 15% hemorrhage (from 173 +/- 32 to 204 +/- 66 beats/min); heart rate remained increased for 60 min after 20% hemorrhage from 171 +/- 17 to 214 +/- 31 beats/min. There were no changes in renal vascular resistance in response to hemorrhage of up to 20% of vascular volume. These observations provide evidence that the newborn is capable of buffering blood pressure in response to blood loss of up to 20% of vascular volume and that the renal bed does not appear to contribute to the restoration of blood pressure after blood loss early in life.
Atrial natriuretic peptide expression in rats with different pulmonary hypertensive responses to hypoxia
Authors: Klinger J. R. , Wrenn D. S. , Warburton R. R. , Pietras L. , Ou L. C. , Hill N. S.
Published: December 2017

Mechanisms that regulate atrial natriuretic peptide (ANP) expression during hypoxia are not well defined. We hypothesized that plasma immunoreactive ANP (irANP) and right heart irANP and ANP mRNA levels would be greater in a strain of Sprague-Dawley rats that develops more severe hypoxic pulmonary hypertension (H rats) than another strain (M rats). After 3 wk of hypoxia (0.5 atm), right ventricular systolic pressure (RVSP) and the right ventricle (RV) weight-to-left ventricle plus septum (LV (+) S) weight ratio [RV/(LV+S)] were greater in H rats than in M rats (70 +/- 4 vs. 40 +/- 2 mmHg and 0.59 +/- 0.02 vs. 0.50 +/- 0.02, respectively; P < 0.05 for both), but plasma ANP increased twofold and RV irANP and ANP mRNA increased fivefold in both rat strains. After 3 days of normoxic recovery from chronic hypoxia, RVSP, RV/(LV+S), and RV irANP and ANP mRNA levels decreased in M rats but not in H rats. Plasma irANP decreased to baseline levels in both rat strains. We conclude that, in addition to changes in RV pressure and hypertrophy, hypoxia acts through other mechanisms to modulate RV ANP synthesis and circulating ANP levels in hypoxia-adapted rats.
Amelioration of ischemic calcium overload correlates with high-energy phosphates in senescent myocardium
Authors: Tsukube T. , McCully J. D. , Metz K. R. , Cook C. U. , Levitsky S.
Published: December 2017

Previously, we have shown that potassium and magnesium (K-Mg, 20 mM each) cardioplegia ameliorated cytosolic calcium ([Ca2+]i) accumulation and was associated with enhanced functional recovery after surgically induced global ischemia in the aged heart. K-Mg cardioplegia was also shown to enhance cytosolic cytochrome oxidase I activity and mRNA levels, suggesting that enhanced functional recovery may involve the preservation of high-energy phosphates. To investigate this hypothesis, 31P nuclear magnetic resonance was used to measure serial alterations in phosphocreatine (PCr), inorganic phosphate, nucleoside triphosphate (NTP), intracellular free magnesium (Mgf), and intracellular pH (pHi) in Langendorff-perfused, aged (135 wk) rabbit hearts during preischemia, global ischemia (30 min), and reperfusion (30 min). K-Mg cardioplegia retarded PCr depletion (P <0.05) and significantly enhanced NTP preservation (P < 0.05) during ischemia and reperfusion. K-Mg cardioplegia also attenuated the increase in Mgf during ischemia (P < 0.05). These results were correlated with amelioration of [Ca2+]i accumulation during ischemia and preservation of left ventricular function after reperfusion and suggest that optimal functional recovery from surgically induced ischemia is provided by K-Mg cardioplegia in the aged myocardium.
A novel cardioprotective function of adenosine A1 and A3 receptors during prolonged simulated ischemia
Authors: Stambaugh K. , Jacobson K. A. , Jiang J. L. , Liang B. T.
Published: December 2017

The possible cardioprotective roles of adenosine A1 and A3 receptors were investigated in a cardiac myocyte model of injury. The adenosine A3 receptor is a novel cardiac receptor capable of mediating potentially important cardioprotective functions. Prolonged hypoxia with glucose deprivation was used to simulate ischemia and to induce injury in cardiac ventricular myocytes cultured from chick embryos 14 days in ovo. When present during the prolonged hypoxia, the adenosine A3 agonists N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) and 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (CI-IB-MECA) caused a dose-dependent reduction in the extent of hypoxia-induced injury as manifested by a decrease in the amount of creatine kinase released and the percentage of myocytes killed. The adenosine A1 agonists 2-chloro-N6-cyclopentyladenosine (CCPA), N6-cyclohexyladenosine, and adenosine amine congener were also able to cause a decrease in the extent of myocyte injury. The A1 receptor-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the cardioprotective effect of the A1 but not of the A3 agonists. Conversely, the selective A3 antagonists MRS-1191 and MRS-1097 blocked the protection induced by CI-IB-MECA but had minimal effect on that caused by CCPA. Thus the cardioprotective effects of A1 and A3 agonists were mediated by their respective receptors. This study defines a novel cardioprotective function of the cardiac A3 receptor and provides conclusive evidence that activation of both A1 and A3 receptors during hypoxia can attenuate myocyte injury.
Circadian and ultradian control of cardiac output in spontaneous hypertension in rats
Authors: Oosting J. , Struijker-Boudier H. A. , Janssen B. J.
Published: December 2017

The aim of the study was to test whether circadian and ultradian variations of cardiac output (CO) in spontaneously hypertensive rats (SHR) differ from those in normotensive Wistar-Kyoto rats (WKY). Twenty-four-hour beat-to-beat recordings of CO (by electromagnetic flow probe) and mean arterial pressure (MAP) were performed in the absence and presence of cardiac autonomic blockade with metoprolol and atropine methylnitrate. Ultradian variability was analyzed by spectral analysis on beat-to-beat data series (high-frequency range) and on averaged minute-to-minute data series (low-frequency range). In general, circadian and ultradian rhythms of CO were similar in SHR (n = 10) and WKY (n = 9). Values of CO were high during the dark and low during the light period, whereas total peripheral resistance was highest during the light period. During cardiac autonomic blockade, relative differences between averaged values of CO over the dark and light periods were reduced. High-frequency spectral power of CO was mainly confined to fluctuations related to respiration and was not influenced by cardiac autonomic blockade. At low-frequency ranges, power spectra of CO lacked a dominant oscillator but showed 1/f characteristics. During cardiac autonomic blockade, low-frequency spectral power of CO fell without changing the 1/f characteristics. These findings suggest that dynamic control of CO is not altered in SHR and that autonomic effects on CO are frequency dependent. In most frequency ranges, the relative variation of CO was higher than that of MAP. Thus, over 24 h in both adult SHR and WKY, MAP is controlled within a more narrow range than CO.
Role of CD18-ICAM-1 in the entrapment of stimulated leukocytes in alveolar capillaries of perfused rat lungs
Authors: Aoki Takuya , Suzuki Yukio , Nishio Kazumi , Suzuki Kouichi , Miyata Atsusi , Iigou Yutaka , Serizawa Hiroshi , Tsumura Harukuni , Ishimura Yuzuru , Suematsu Makoto , Yamaguchi Kazuhiro
Published: December 2017

This study aimed to examine the behavior of stimulated leukocytes in the pulmonary microcirculation. The leukocyte-endothelium interaction was visualized under physiological shear rates in perfused rat lungs using high-speed confocal laser video microscopy. Leukocytes labeled with carboxyfluorescein were stimulated with cytokine-induced neutrophil chemoattractant (CINC/gro), which caused L-selectin shedding and inverse upregulation of CD18. Neither unstimulated nor stimulated leukocytes exhibited rolling in either pulmonary arterioles or venules, whereas both were sequestered in capillaries. Approximately 50% of stimulated leukocytes showed a transient cessation of movement in pulmonary capillaries. The CINC/gro stimulation, which inhibited leukocyte rolling and adhesion to mesenteric venules, reduced leukocyte velocity and increased leukocytes in pulmonary capillaries. Pretreatment with monoclonal antibodies against intercellular adhesion molecule-1 (ICAM-1) or CD18 attenuated these changes. Confocal microfluorography revealed constitutive expression of ICAM-1 not only in venules but also abundantly in capillary networks. These results suggest that selectin-independent, CD18-ICAM-1-dependent capillary sequestration is one of the major mechanisms by which activated leukocytes accumulate in the lungs.
Flow-induced dilation of rat soleus feed arteries
Authors: Jasperse Jeffrey L. , Laughlin M. Harold
Published: December 2017

Flow-induced dilation is thought to contribute to dilation of skeletal muscle arteries and arterioles during exercise hyperemia. We sought to determine whether rat soleus feed arteries (SFA) exhibit flow-induced dilation and to evaluate the potential contribution of flow-induced dilation of SFA to exercise hyperemia. Rat SFA were isolated and cannulated to allow pressure and intraluminal flow to be independently controlled. Intraluminal pressure was maintained at 90 cmH2O throughout the experiment. All SFA ( n = 13) developed spontaneous tone and dilated in response to flow. Flow of 10 and 14 μl/min produced a 34 ± 14 and 56 ± 17 μm increase above basal diameter (135 ± 12 μm), respectively. Flows >14 μl/min produced little further dilation. Maximum flow-induced dilation was 86 ± 3% of passive diameter determined in calcium-free physiological saline solution. Calculated shear stress was maintained at 4–6 dyn/cm2 at flows of 10–20 μl/min but increased at greater flows because SFA did not dilate further. To determine whether dilation in response to flows in this range may contribute to exercise hyperemia, we estimated in vivo SFA blood flows from previously published soleus blood flow data. Anesthetized rats are estimated to have flows of 10 μl/min per SFA, and conscious rats are estimated to have flows of 95 (nonexercising), 153 (walking), and 225 (running) μl/min per SFA. Corresponding shear stresses were estimated to be 26 (anesthetized), 47 (conscious, nonexercising), 75 (walking), and 111 (running) dyn/cm2. Because estimated in vivo values for both flow and wall shear stress are far greater than the flow and/or shear stresses at which maximal flow-induced dilation occurs in vitro, we conclude that flow-induced dilation contributes little to dilation of SFA during locomotory exercise.
The Frank-Starling mechanism is not mediated by changes in rate of cross-bridge detachment
Authors: Wannenburg Thomas , Janssen Paul M. L. , Fan Dongsheng , De Tombe Pieter P.
Published: December 2017

We tested the hypothesis that the Frank-Starling relationship is mediated by changes in the rate of cross-bridge detachment in cardiac muscle. We simultaneously measured isometric force development and the rate of ATP consumption at various levels of Ca2+activation in skinned rat cardiac trabecular muscles at three sarcomere lengths (2.0, 2.1, and 2.2 μm). The maximum rate of ATP consumption was 1.5 nmol ⋅ s−1⋅ μl fiber vol−1, which represents an estimated adenosinetriphosphatase (ATPase) rate of ∼10 s−1per myosin head at 24°C. The rate of ATP consumption was tightly and linearly coupled to the level of isometric force development, and changes in sarcomere length had no effect on the slope of the force-ATPase relationships. The average slope of the force-ATPase relationships was 15.5 pmol ⋅ mN−1⋅ mm−1. These results suggest that the mechanisms that underlie the Frank-Starling relationship in cardiac muscle do not involve changes in the kinetics of the apparent detachment step in the cross-bridge cycle.
Fatty acid uptake is preserved in chronically dysfunctional but viable myocardium
Authors: Mäki Maija T. , Haaparanta Merja T. , Luotolahti Matti S. , Nuutila Pirjo , Voipio-Pulkki Liisa-Maria , Bergman Jörgen R. , Solin Olof H. , Knuuti Juhani M.
Published: December 2017

Glucose uptake appears preserved or even enhanced in the chronically dysfunctional but viable myocardium. However, the use of other fuels such as free fatty acids (FFA) remains unknown. We studied FFA uptake in the chronically dysfunctional but viable myocardium in seven patients with an occluded major coronary artery and a corresponding chronic wall motion abnormality but no previous infarction. Myocardial FFA uptake kinetics in the fasting state were measured with positron emission tomography (PET) and 14( R, S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA). The FFA uptake index was calculated by multiplying the fractional [18F]FTHA uptake with serum FFA concentration. Myocardial blood flow (MBF) was measured with [15O]H2O and PET. Myocardial viability was confirmed with a static18F-labeled 2-fluoro-2-deoxy-d-glucose PET imaging and a follow-up echocardiography in the revascularized patients. Regional MBF was slightly but not significantly lower in the dysfunctional compared with normal myocardial segments (0.76 ± 0.18 vs. 0.81 ± 0.14 ml ⋅ min−1 ⋅ g−1, means ± SD; P = 0.16). The fractional [18F]FTHA uptake rates [0.11 ± 0.03 vs. 0.11 ± 0.04 ml ⋅ g−1 ⋅ min−1; not significant (NS)], and the FFA uptake indexes (5.8 ± 1.7 vs. 5.8 ± 2.1 μmol ⋅ 100 g−1 ⋅ min−1; NS) were similar in the dysfunctional but viable and in the normal myocardial regions. Thus, in the chronically dysfunctional but viable (collateral-dependent) myocardium, the fatty acid uptake probed by [18F]FTHA appears preserved. Taken together with preserved glucose uptake, the results indicate that there is uncoupling of substrate uptake and mechanical function in the chronically dysfunctional but viable myocardium.
Cardiovascular depressor responses to stimulation of substantia nigra and ventral tegmental area
Authors: Kirouac Gilbert J. , Ciriello John
Published: December 2017

Experiments were done in α-chloralose-anesthetized, paralyzed, and artificially ventilated rats to investigate the effect ofl-glutamate (Glu) stimulation of the substantia nigra (SN) and ventral tegmental area (VTA) on arterial pressure (AP) and heart rate (HR). Glu stimulation of the SN pars compacta (SNC) elicited decreases in both mean AP (MAP; −18.9 ± 1.3 mmHg; n = 52) and HR (−26.1 ± 1.6 beats/min; n = 46) at 81% of the sites stimulated. On the other hand, stimulation of the SN pars lateralis or pars reticulata did not elicit cardiovascular responses. Stimulation of the adjacent VTA region elicited similar decreases in MAP (−18.0 ± 2.6 mmHg; n = 20) and HR (−25.4 ± 3.8 beats/min; n = 17) at ∼74% of the sites stimulated. Intravenous administration of the dopamine D2-receptor antagonist raclopride significantly attenuated both the MAP (70%) and the HR (54%) responses elicited by stimulation of the transitional region where the SNC merges with the lateral VTA (SNC-VTA region). Intravenous administration of the muscarinic receptor blocker atropine methyl bromide had no effect on the magnitude of the MAP and HR responses to stimulation of the SNC-VTA region, whereas administration of the nicotinic receptor blocker hexamethonium bromide significantly attenuated both the depressor and the bradycardic responses. These data suggest that dopaminergic neurons in the SNC-VTA region activate a central pathway that exerts cardiovascular depressor effects that are mediated by the inhibition of sympathetic vasoconstrictor fibers to the vasculature and cardioacceleratory fibers to the heart.
Low-intensity exercise training decreases cardiac output and hypertension in spontaneously hypertensive rats
Authors: Véras-Silva Acácio Salvador , Mattos Katt Coelho , Gava Nilo Sérgio , Brum Patricia Chakur , Negrão Carlos Eduardo , Krieger Eduardo Moacyr
Published: December 2017

The decrease in cardiac sympathetic tone and heart rate after low-intensity exercise training may have hemodynamic consequences in spontaneously hypertensive rats (SHR). The effects of exercise training of low and high intensity on resting blood pressure, cardiac output, and total peripheral resistance were studied in sedentary ( n = 17), low- ( n = 17), and high-intensity exercise-trained ( n = 17) SHR. Exercise training was performed on a treadmill for 60 min, 5 times per week for 18 weeks, at 55% or 85% maximum oxygen uptake. Blood pressure was evaluated by a cannula inserted into the carotid artery, and cardiac output was evaluated by a microprobe placed around the ascending aorta. Low-intensity exercise-trained rats had a significantly lower mean blood pressure than sedentary and high-intensity exercise-trained rats (160 ± 4 vs. 175 ± 3 and 173 ± 2 mmHg, respectively). Cardiac index (20 ± 1 vs. 24 ± 1 and 24 ± 1 ml ⋅ min−1 ⋅ 100 g−1, respectively) and heart rate (332 ± 6 vs. 372 ± 14 and 345 ± 9 beats/min, respectively) were significantly lower in low-intensity exercise-trained rats than in sedentary and high-intensity exercise-trained rats. No significant difference was observed in stroke volume index and total peripheral resistance index in all groups studied. In conclusion, low-intensity, but not high-intensity, exercise training decreases heart rate and cardiac output and, consequently, attenuates hypertension in SHR.
Longitudinal position matrix of the pig coronary vasculature and its hemodynamic implications
Authors: Kassab Ghassan S. , Pallencaoe Edith , Schatz Amy , Fung Yuan-Cheng B.
Published: December 2017

Hemodynamic analysis of coronary blood flow must be based on a statistically valid geometric model of the coronary vasculature. We have previously developed a diameter-defined Strahler model for the arterial and venous trees and a network model for the capillaries. A full set of data describing the geometric properties of the porcine coronary vasculature was given. The order number, diameter, length, connectivity matrix [ m,n] (CM), and parallel-series features were measured for all orders of vessels of the right coronary artery (RCA), left anterior descending artery (LAD), left circumflex artery (LCX), and coronary venous system. The purpose of the present study is to present another feature of the branching pattern of the coronary vasculature: the longitudinal position matrix [ m,n] (LPM), whose component in row m and column n is the fractional longitudinal position of the branch point on vessels of order n at which vessels of order m branch off ( m ≤ n). The LPM of the pig RCA, LAD and LCX arterial trees, as well as the coronary sinusal and thebesian venous trees, are presented. The hemodynamic implications of the LPM are illustrated by comparing two kinds of circuits: one, the CM + LPM model, simulates the mean data on the morphology (diameters, lengths, and numbers), CM, and LPM of vessels, whereas the other, the CM model, simulates the mean data on the morphology and CM without considering the LPM. We found that the LPM affects the hemodynamics of coronary blood flow especially with regard to the nonuniformity or dispersion of flow distribution.
Vagal modulation of heart rate during exercise: effects of age and physical fitness
Authors: Tulppo Mikko P. , Mäkikallio Timo H. , Seppänen Tapio , Laukkanen Raija T. , Huikuri Heikki V.
Published: December 2017

This study was designed to assess the effects of age and physical fitness on vagal modulation of heart rate (HR) during exercise by analyzing the instantaneous R-R interval variability from Poincaré plots (SD1) at rest and at different phases of a bicycle exercise test in a population of healthy males. SD1 normalized for the average R-R interval (SD1n), a measure of vagal activity, was compared at rest and during exercise among subjects of ages 24–34 (young, n = 25), 35–46 (middle-aged, n = 30), and 47–64 yr (old, n = 25) matched for peak O2 consumption (V˙o 2 peak) and among subjects withV˙o 2 peak of 28–37 (poor, n = 25), 38–45 (average, n = 36), and 46–60 ml ⋅ kg−1 ⋅ min−1(good, n = 25) matched for age. SD1n was higher at rest in the young subjects than in the middle-aged or old subjects (39 ± 14, 27 ± 16, and 21 ± 8, respectively; P < 0.001), but the age-related differences in SD1n were smaller during exercise [e.g., 11 ± 5, 9 ± 5, and 8 ± 4 at the level of 100 W; P = not significant (NS)]. The age-matched subjects with good, average, and poor V˙o 2 peakshowed no difference in SD1n at rest (32 ± 17, 28 ± 13, and 26 ± 11, respectively; P = NS), but SD1n differed significantly among the groups from a low to a moderate exercise intensity level (e.g., 13 ± 6, 10 ± 5, and 6 ± 3 for good, average, and poor fitness groups, respectively; P < 0.001, 100 W). These data show that poor physical fitness is associated with an impairment of cardiac vagal function during exercise, whereas aging itself results in more evident impairment of vagal function at rest.
Total arterial compliance estimated by stroke volume-to-aortic pulse pressure ratio in humans
Authors: Chemla Denis , Hébert Jean-Louis , Coirault Catherine , Zamani Karen , Suard Isabelle , Colin Patrice , Lecarpentier Yves
Published: December 2017

On the basis of the windkessel model, the stroke volume-to-aortic pulse pressure ratio (SV/PP) has been proposed as an estimate of total arterial compliance, but recent studies have questioned this approximation. Aortic pressure was obtained at rest in 31 adults undergoing cardiac catheterization (47 ± 14 yr): controls ( n = 7), patients with dilated cardiomyopathy ( n = 10), and patients with other cardiac diseases ( n = 14). We calculated PP, mean aortic pressure (MAoP), heart period ( T), SV (thermodilution cardiac output/heart rate), total peripheral resistance ( R), total arterial compliance estimated by area method ( Carea), and the time constant of aortic pressure decay in diastole ( RCarea). In the overall population ( n = 31), there was no significant difference between SV/PP and Carea. SV/PP was linearly related to Carea(SV/PP = 0.99 Carea+ 0.05; r = 0.98; P < 0.001); the slope and intercept did not differ from unity and zero, respectively. Similar results were obtained in the three subgroups. These results implied that PP/MAoP and T/ RCareawere proportionally related ( T/ RCarea= 1.18PP/MAoP − 0.07; r = 0.96; P < 0.001). We conclude that for humans at rest 1) SV/PP gave a reliable estimate of Carea, and 2) T normalized by the time constant of aortic pressure decay in diastole was proportionally related to PP/MAoP. This last relationship could be considered an aspect of the coupling between the left ventricle and its load.
Myocardial adenosine A1-receptor sensitivity during juvenile and adult stages of maturation
Authors: Sawmiller Darrell R. , Fenton Richard A. , Dobson James G.
Published: December 2017

In the heart, endogenous adenosine attenuates the β-adrenergic-elicited increase in contractile performance via activation of adenosine A1 receptors. It has been recently reported that this function of adenosine becomes more pronounced with myocardial maturation. The purpose of the present study was to determine whether mature hearts possess a greater sensitivity than immature hearts to this antiadrenergic effect of adenosine. Isolated perfused hearts or atria from immature (ca. 23 days) and mature (ca. 80 days) rats were stimulated with isoproterenol (Iso), a β-adrenergic agonist, at 10−8 M and concomitantly exposed to increasing concentrations of 2-chloroN6-cyclopentyladenosine (CCPA), a highly selective and potent adenosine A1-receptor agonist, from 10−12 to 10−6 M. CCPA at 10−10–10−6M dose dependently reduced the Iso-elicited contractile response more in immature than in mature hearts or atria. At 10−6 M, CCPA reduced the Iso-elicited contractile response by 103% in immature hearts and by 55% in mature hearts. These effects of CCPA were attenuated by the adenosine A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine at 10−7 M. In additional experiments, CCPA exhibited similar effectiveness in reducing the spontaneous heart rate of immature and mature hearts, an effect also mediated by activation of adenosine A1 receptors. Similar to CCPA, the adenosine A1-receptor agonist R- N 6-(2-phenylisopropyl)adenosine reduced the Iso-elicited contractile response more in immature than in mature hearts, albeit with less effectiveness than CCPA. In agreement with these results, CCPA reduced Iso-elicited adenylyl cyclase activity more in immature than in mature hearts. Overall, in contrast with our original hypothesis, these results indicate that immature hearts display greater sensitivity than mature hearts to the antiadrenergic effect of adenosine A1-receptor activation.
Coculture conditions alter endothelial modulation of TGF-β1 activation and smooth muscle growth morphology
Authors: Powell Richard J. , Bhargava Jaya , Basson Marc D. , Sumpio Bauer E.
Published: December 2017

We examined whether endothelial cells (ECs) inhibit smooth muscle cell (SMC) transforming growth factor-β1 (TGF-β1) activation in bilayer coculture. Western analysis showed that SMCs cocultured with ECs as a bilayer had lower amounts of active TGF-β1 protein compared with SMCs cultured alone and SMCs cocultured with ECs as a monolayer. EC inhibition of TGF-β1 activation could be blocked with plasminogen activator inhibitor-1 (PAI-1) antibody. Similarly, SMC hill-and-valley growth, a marker for TGF-β1 activity, was present in SMCs cultured alone and SMCs cocultured with ECs as a monolayer but was absent in SMCs cocultured as a bilayer. SMCs cocultured with ECs as a bilayer migrated at a greater rate than SMCs cultured either alone or cocultured as a monolayer. The EC effect on SMC migration was inhibited by the addition of 5 ng/ml TGF-β1. ECs had no effect on SMC RNA levels of TGF-β1. PAI-1 levels were increased in ECs and ECs cocultured with SMCs compared with SMCs cultured alone. ECs inhibit TGF-β1 activation in bilayer coculture. This appears to be mediated through an increase in EC PAI-1 release. Alterations in coculture conditions, in particular the degree of EC-SMC cell contact, have profound effects on this process.
Receptor mechanisms of serotonin-induced prenodal lymphatic constriction in the canine forelimb
Authors: Dobbins David E.
Published: December 2017

Numerous endogenous vasoactive agents have been shown to cause lymphatic smooth muscle contraction. In this study, we assessed the ability of serotonin (5-HT) to alter lymphatic smooth muscle activity and elucidated the receptor mechanisms of 5-HT’s actions. Both intralymphatic and intra-arterial administration of 5-HT significantly increased lymphatic smooth muscle activity in lymphatics perfused at constant flow, as indicated by an increase in lymphatic perfusion pressure. The 5-HT-induced increase in lymphatic perfusion pressure is attenuated but not blocked by the intra-arterial infusion of phentolamine, suggesting the involvement of α-adrenoreceptors and 5-HT receptors. Intralymphatic infusion of the 5-HT2-receptor-agonist α-methylserotonin significantly increased lymphatic perfusion pressure, either alone or when administered into an α-receptor blocked preparation, whereas the 5-HT1-receptor-agonist carboxyamidotryptamine maleate did not effect the prenodal lymphatics. These data indicate that the lymphatic smooth muscle contraction produced by 5-HT is mediated both by lymphatic α-adrenoreceptors and 5-HT2 receptors.
Theoretical optimization of pulmonary-to-systemic flow ratio after a bidirectional cavopulmonary anastomosis
Authors: Santamore William P. , Barnea Ofer , Riordan Christopher J. , Ross Mitchell P. , Austin Erle H.
Published: December 2017

A univentricle with parallel pulmonary and systemic circulations is inherently inefficient because mixing of pulmonary and systemic venous return occurs. Thus a cavopulmonary anastomosis is used as a staged palliative procedure to reduce volume overload in patients with cyanotic congenital heart disease. On the basis of oxygen uptake and consumption, an equation was derived that related cardiac output, pulmonary venous oxygen saturation, upper body oxygen consumption, and superior-to-inferior vena caval blood flow ratio (QSVC/QIVC) to oxygen delivery. The primary findings were as follows. 1) As QSVC/QIVCincreases, total body oxygen delivery and arterial and superior vena caval oxygen saturations increase. 2) As QSVC/QIVCincreases, lower body oxygen delivery and inferior vena caval oxygen saturation initially increase, then peak, and then decrease. 3) As the percentage of lower body oxygen consumption increases, oxygen delivery and saturation decrease. 4) A cavopulmonary anastomosis decreases the required cardiac output for a given oxygen delivery. Thus we concluded that a high systemic arterial oxygen saturation after cavopulmonary anastomosis requires a high percentage of upper body oxygen consumption and a high QSVC/QIVCand that the cavopulmonary anastomosis reduces the volume load on the single ventricle.
Fluorescence measurement of calcium transients in perfused rabbit heart using rhod 2
Authors: Del Nido Pedro J. , Glynn Paul , Buenaventura Percival , Salama Guy , Koretsky Alan P.
Published: December 2017

Surface fluorescence spectroscopy of the beating heart to measure cytosolic calcium has been limited by the need to use ultraviolet excitation light for many of the commonly used calcium indicators. Ultraviolet light in the heart produces a high level of background fluorescence and is highly absorbed, limiting tissue penetration. Visible wavelength fluorescence dyes such as rhod 2 are available; however, the lack of spectral shift with calcium binding precludes the use of ratio techniques to account for changes in cytosolic dye concentration. We have developed a method for in vivo quantitation of cytosolic rhod 2 concentration that in conjunction with calcium-dependent fluorescence measurements permits estimation of cytosolic calcium levels in perfused rabbit hearts. Reflective absorbance of excitation light by rhod 2 loaded into myocardium was used as an index of dye concentration and the ratio of fluorescence intensity to absorbance as a measure of cytosolic calcium concentration. Endothelial cell loading of rhod 2 was found to be minimal (<5%), and dye leak rate out of the cytosol was slow, with ∼5% loss of dye fluorescence occurring between 10 and 30 min after dye loading. Rhod 2 loading into subcellular compartments, determined by manganese quenching, was also minimal (<5%). The dissociation constant of rhod 2 for calcium was measured in vitro to be 500 nM, and this value increased to 710 nM in the presence of 0.5 mM myoglobin. On the basis of this value and in vivo fluorescence measurements, cytosolic calcium concentration in the rabbit heart was found to be 229 ± 90 nM at end diastole and 930 ± 130 nM at peak systole, with peak fluorescence preceding peak ventricular pressure by ∼40 ms. This technique should facilitate detailed analysis of calcium transients from the whole heart.
Application of HPLC to counting of colored microspheres in determination of regional blood flow
Authors: Mazoit Jean Xavier , Le Guen Régine , Decaux Anne , Albaladejo Pierre , Samii Kamran
Published: December 2017

Colored microspheres have become popular compared with radioactive microspheres because they do not use radioactivity. However, they suffer from a much greater variability in their determination. We have developed a new method for assaying the dye using high-performance liquid chromatography (HPLC) with internal standard. This technique permits accurate determination of ≤400 spheres in rat blood, heart, kidney, liver, and brain with a relative error [coefficient of variation (CV)] <10%. To date, only three colors (white, yellow, and red) may be used because, of the five colors tested, one (violet) served as internal standard and another (blue) exhibited marked degradation during extraction. Compared with the classical spectrophotometric technique, HPLC allows a three to five times improvement in reproducibility with a relative error significantly lower ( P < 0.01) than with direct spectrophotometry. Although this new technique appears to be more time consuming than the classical method, its use seems to be preferable because of the improvement in measurement sensitivity.
Pressure-overload hypertrophy is unabated in mice devoid of AT1Areceptors
Authors: Hamawaki Masayoshi , Coffman Thomas M. , Lashus Andrew , Koide Masaaki , Zile Michael R. , Oliverio Michael I. , Defreyte Gilberto , Cooper George , Carabello Blase A.
Published: December 2017

Mechanisms controlling cardiac growth are under intense investigation. Among these, the renin-angiotensin system has received great interest. In the current study, we tested the hypothesis that the renin-angiotensin system was not an obligate factor in cardiac hypertrophy. We examined the left ventricular hypertrophic response to a pressure overload in mice devoid of the AT1Areceptor, the putative major effector of the growth response of the renin-angiotensin system. Aortic banding produced similar transband gradients in wild-type and AT1Aknockout mice. The left ventricular mass-to-body weight ratio increased from 3.44 ± 0.08 to 5.62 ± 0.25 in wild-type ascending aortic-banded mice. The response in the knockout mice was not different (from 2.97 ± 0.13 to 5.24 ± 0.37). We conclude that the magnitude of cardiac hypertrophy is not affected by the absence of the AT1Areceptor and its signaling pathway and that this component of the renin-angiotensin system is not necessary in cardiac hypertrophy.
Inhibition of rat ventricularIK1with antisense oligonucleotides targeted to Kir2.1 mRNA
Authors: Nakamura Tomoe Y. , Artman Michael , Rudy Bernardo , Coetzee William A.
Published: December 2017

The cardiac inward rectifying K+current ( IK1) is important in maintaining the maximum diastolic potential. We used antisense oligonucleotides to determine the role of Kir2.1 channel proteins in the genesis of native rat ventricular IK1. A combination of two antisense phosphorothioate oligonucleotides inhibited heterologously expressed Kir2.1 currents in Xenopus oocytes, either when coinjected with Kir2.1 cRNA or when applied in the incubation medium. Specificity was demonstrated by the lack of inhibition of Kir2.2 and Kir2.3 currents in oocytes. In rat ventricular myocytes (4–5 days culture), these oligonucleotides caused a significant reduction of whole cell IK1(without reducing the transient outward K+current or the L-type Ca2+current). Cell-attached patches demonstrated the occurrence of multiple channel events in control myocytes (8, 14, 21, 35, 43, and 80 pS). The 21-pS channel was specifically knocked down in antisense-treated myocytes (fewer patches contained this channel, and its open frequency was reduced). These results demonstrate that the Kir2.1 gene encodes a specific native 21-pS K+-channel protein and that this channel has an essential role in the genesis of cardiac IK1.
Induction ofHSP 32gene in hypoxic cardiomyocytes is attenuated by treatment withN-acetyl-l-cysteine
Authors: Borger D. R. , Essig D. A.
Published: December 2017

Increased synthesis of stress proteins may enhance myocardial viability during periods of low oxygen delivery. Our purpose was to determine if the oxidative stress protein heme oxygenase-1 [heat stress protein 32 (HSP 32)] was induced in hypoxic cardiomyocytes and whether this induction might be mediated by a redox-sensitive mechanism. Primary rat neonatal cardiomyocytes, cultured to express a tissuelike phenotype, responded to 12 h of hypoxia (<0.5% ambient oxygen) with an approximately fivefold (range 3- to 7.5-fold; P < 0.05) increase in HSP 32 mRNA and a threefold ( P < 0.05) increase in HSP 32 protein content. Exposure to 80 μM H2O2for 3 h increased HSP 32 mRNA content to a similar extent. Expression of heme oxygenase-2 mRNA was unaffected by H2O2or hypoxic treatments. Inclusion of 20 mM N-acetyl-l-cysteine in the medium during hypoxia reduced the increase in HSP 32 mRNA and protein expression by 25–50% compared with hypoxia alone. The data suggest that induction of HSP 32 protein may lead to an improved antioxidant defense in cardiomyocytes during hypoxia and that a redox-sensitive pathway mediates at least a portion of the hypoxic induction of the HSP 32gene.
Brain “ouabain,” ANG II, and sympathoexcitation by chronic central sodium loading in rats
Authors: Huang Bing S. , Veerasingham Shereeni J. , Leenen Frans H. H.
Published: December 2017

Both brain ouabain-like activity (“ouabain”) and brain angiotensin II (ANG II) contribute to the sympathoexcitatory and pressor responses to high sodium intake in spontaneously hypertensive (SHR) and Dahl salt-sensitive (Dahl S) rats. To assess whether increases in cerebrospinal fluid (CSF) sodium can mimic this pattern of changes, Wistar rats were chronically infused with artificial CSF (aCSF) or sodium-rich aCSF (0.8 or 1.2 M sodium) intracerebroventricularly through osmotic minipumps for 14 days. Sodium-rich aCSF (0.8 M) was also infused intracerebroventricularly for 2 wk concomitantly with either antibody Fab fragments that bind ouabain and related steroids with high affinity, γ-globulins as control (200 μg/day for both), or the AT1blocker losartan (1 mg ⋅ kg−1 ⋅ day−1). Sodium-rich aCSF increased CSF sodium from 146 ± 2 to 152 ± 2 (0.8 M) and 160 ± 3 (1.2 M) mmol/l, and increased brain “ouabain” in the hypothalamus, pituitary, and pons. In conscious rats, sodium-rich aCSF increased baseline mean arterial pressure (MAP), enhanced MAP, heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to intracerebroventricular α2-adrenoceptor agonist guanabenz and air stress, and desensitized arterial and cardiopulmonary baroreflex control of HR and RSNA. These effects were largely prevented by intracerebroventricular Fab fragments or losartan. Thus, in Wistar rats, both brain “ouabain” and the brain renin-angiotensin system contribute to sympathoexcitation, impairment of baroreflexes, and hypertension caused by chronically increased CSF sodium. The similar patterns of changes caused by CSF sodium in Wistar rats and by high sodium intake in SHR and Dahl S rats indicate that if high sodium intake increases central sodium, such changes may contribute to sympathoexcitation and hypertension.
Noradrenergic neurotransmission at PVN in locus ceruleus-induced baroreflex suppression in rats
Authors: Hwang Kuo-Rue , Chan Samuel H. H. , Chan Julie Y. H.
Published: December 2017

We investigated the role of ascending noradrenergic projections from the locus ceruleus (LC) to the paraventricular nucleus (PVN) of the hypothalamus in LC-induced suppression of the baroreceptor reflex (BRR) response in adult Sprague-Dawley rats maintained under pentobarbital anesthesia. On the basis of in vivo microdialysis and high-performance liquid chromatography-electrochemical detection, microinjection ofl-glutamate (5 nmol) into the LC resulted in a site-specific increase in norepinephrine (NE) concentration in the dialysate collected from the parvocellular subnucleus of the PVN. The temporal course of this increase in extracellular NE concentration in the PVN coincided with the time course of inhibition elicited by the LC on the BRR response. Microinfusion of NE (10, 50, or 100 nM) into the parvocellular subnucleus of the PVN by reverse microdialysis also promoted a parallel increase in NE at the PVN and a reduction in the BRR response. Inhibition of the BRR response induced by microinjection into the PVN of the α1-adrenoceptor agonist phenylephrine (10 nmol) or chemical activation of the LC was reversed by bilateral PVN microinjection of prazosin (100 pmol). However, local application to the PVN of the α2- or β-adrenoceptor agonist guanabenz (10 nmol) or isoproterenol (10 nmol) was ineffective. Our results suggest that NE released from the LC-PVN noradrenergic projection may participate in LC-induced suppression of the BRR response by activating the α1-adrenoceptors at the parvocellular subnucleus of the PVN.
Apparent arterial compliance
Authors: Quick Christopher M. , Berger David S. , Noordergraaf Abraham
Published: December 2017

Recently, there has been renewed interest in estimating total arterial compliance. Because it cannot be measured directly, a lumped model is usually applied to derive compliance from aortic pressure and flow. The archetypical model, the classical two-element windkessel, assumes 1) system linearity and 2) infinite pulse wave velocity. To generalize this model, investigators have added more elements and have incorporated nonlinearities. A different approach is taken here. It is assumed that the arterial system 1) is linear and 2) has finite pulse wave velocity. In doing so, the windkessel is generalized by describing compliance as a complex function of frequency that relates input pressure to volume stored. By applying transmission theory, this relationship is shown to be a function of heart rate, peripheral resistance, and pulse wave reflection. Because this pressure-volume relationship is generally not equal to total arterial compliance, it is termed “apparent compliance.” This new concept forms the natural counterpart to the established concept of apparent pulse wave velocity.