bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender differences in endothelium-dependent relaxations do not involve NO in porcine coronary arteries
Authors: Barber Dustan A. , Miller Virginia M.
Published: December 2017

Experiments were designed to determine whether normal fluctuations in endogenous sex steroid hormones and/or gender affect endothelium-dependent relaxations in coronary arteries, and, if so, to identify endothelium-derived factors contributing to these differences. Coronary arteries from sexually mature, gonadally intact male and female pigs or ovariectomized pigs were prepared either for study of isometric force in organ chambers or for measurement of prostanoids and activity of nitric oxide (NO) synthase. In organ chamber studies, neither the magnitude nor the sensitivity of endothelium-dependent relaxations correlated with endogenous estrogen or progesterone in female pigs. However, relaxations to bradykinin and UK-14304 were significantly greater and/or shifted leftward in arterial rings from female compared with male pigs. Indomethacin (10−5 mol/l) increased endothelium-dependent relaxations only in arteries from male pigs. N G-monomethyl-l-arginine reduced endothelium-dependent relaxations to a similar extent in coronary arteries from either sex. Neither production nor response to thromboxane A2 or prostacyclin differed in coronary arteries from male compared with female pigs. Activity for calcium-dependent or -independent NO synthase was similar in both sexes. These results suggest that normal fluctuations in endogenous sex steroid hormones do not affect endothelium-dependent relaxations in coronary arteries from female pigs. There are, however, gender differences in endothelium-dependent relaxations that are indomethacin sensitive and may be due to cyclooxygenase products other than thromboxane A2 or prostacyclin.
Relaxation effect of CGP-48506, EMD-57033, and dobutamine in ejecting and isovolumically beating rabbit hearts
Authors: Slinker Bryan K. , Green Henry W. , Wu Yiming , Kirkpatrick Robert D. , Campbell Kenneth B.
Published: December 2017

Because it is not known whether ejection influences the negative effect of the Ca2+-sensitizing drugs on ventricular relaxation, we extended our previous analysis of stress-dependent relaxation in isovolumic beats to encompass ejecting beats and evaluated the relationships between both the time of onset of relaxation and the rate of relaxation and wall stress in a broader analysis framework. Furthermore, because the sites of action of the Ca2+-sensitizing drugs CGP-48506 and EMD-57033 may be different, and thus CGP-48506 may have fewer adverse effects on resting muscle length or force, we compared these two drugs to test the hypothesis that CGP-48506 would have less effect than EMD-57033 on relaxation in the isolated buffer-perfused rabbit heart. This analysis of stress-dependent relaxation in both ejecting and isovolumic beats readily differentiates between the negative lusitropic effect of 2 × 10−6 M EMD-57033, the negligible lusitropic effect of 6 × 10−6 M CGP-48506, and the positive lusitropic effect of 1.25 × 10−6 M dobutamine. Furthermore, comparison of the effect of the two Ca2+-sensitizing drugs in ejecting versus isovolumic contractions shows that CGP-48506 affects relaxation differently in ejecting contractions than it does in isovolumic contractions, whereas EMD-57033 affects relaxation similarly in both ejecting and isovolumic contractions.
Rostral ventrolateral medullary opioid receptor activation modulates pressor response to muscle contraction
Authors: Caringi Daryl , Mokler David J. , Koester David M. , Ally Ahmmed
Published: December 2017

The effects of an opioid agonist, [d-Ala2]methionine enkephalinamide (DAME), administered into the rostral ventrolateral medulla (rVLM) or caudal ventrolateral medulla (cVLM) on cardiovascular responses to isometric muscle contraction were determined in anesthetized rats. A 30-s contraction evoked by tibial nerve stimulation increased mean arterial pressure (MAP) and heart rate (HR) by 34 ± 6 mmHg and 40 ± 7 beats/min, respectively, with a developed tension of 322 ± 30 g, after bilateral insertion of microdialysis probes into the rVLM. Thirty-minute dialysis of DAME (10 and 100 μM) attenuated the contraction-evoked cardiovascular changes dose dependently (10 μM: MAP = 25 ± 4 mmHg, HR = 27 ± 3 beats/min, tension = 333 ± 25 g; 100 μM: MAP = 14 ± 4 mmHg, HR = 16 ± 5 beats/min, tension = 330 ± 34 g). Preadministration of an opioid antagonist, naloxone (100 μM), augmented contraction-evoked MAP and HR responses and blocked effects of 100 μM DAME. Microdialysis of DAME into the cVLM produced no changes in the pressor response to contraction. At end of each experiment, tibial nerve stimulation after neuromuscular blockade evoked no MAP or HR change. Results demonstrate that opioid receptor activation within the rVLM modulates cardiovascular responses to isometric muscle contraction.
PEEP only partly restores disturbed distribution of regional pulmonary blood flow in lung injury
Authors: Kleen M. , Zwissler B. , Messmer K.
Published: December 2017

The effects of lung injury, positive end-expiratory pressure (PEEP), and norepinephrine on heterogeneity of regional pulmonary blood flow (rPBF, radioactive microspheres) were investigated. We hypothesized that lung injury increases heterogeneity of rPBF and that PEEP ventilation reduces these effects. Heterogeneity of rPBF is scale dependent and was therefore assessed in detail. Local correlation (ρ), relative dispersion (RD), fractal dimension (D), perfusion gradients, and histograms of rPBF each measures a different aspect of heterogeneity. In eight anesthetized dogs, lung injury was induced with oleic acid and glass bead injection. Afterward, PEEP of 10–20 cmH2O was instituted. Norepinephrine was infused at 20 cmH2O PEEP. Heterogeneity increased upon lung injury (ρ, 0.44 ± 0.09 vs. 0.24 ± 0.09; RD, 0.36 ± 0.06 vs. 0.64 ± 0.12; both P ≤ 0.05), but fractal dimension remained constant. PEEP did not change ρ, RD, or D. Perfusion gradients were reversed after lung injury (right, −27 ± 18 vs. 196 ± 115%; left, −24 ± 18 vs. 282 ± 184%; P ≤ 0.05). PEEP (10 cmH2O) reduced gradients (116 ± 73 and 143 ± 62%, respectively; P ≤ 0.05). Norepinephrine, in part, further reduced gradients (right, 50 ± 58%; P ≤ 0.05; left, 102 ± 94%; P = NS). We conclude that oleic acid- and glass bead-induced lung injury produces abnormal distribution of rPBF. Of these changes, application of PEEP only reverses perfusion gradients.
Alternative promoters and cardiac muscle cell-specific expression of the Na+/Ca2+exchanger gene
Authors: Nicholas Susanne B. , Yang Weidong , Lee Shwu-Luan , Zhu Hong , Philipson Kenneth D. , Lytton Jonathan
Published: December 2017

Many studies have investigated the regulation of the Na+/Ca2+exchanger, NCX1, but limited data exist on transcriptional regulation of the NCX1 gene. We have identified the transcription start sites of three tissue-specific alternative promoters of NCX1 transcripts from rat heart, kidney, and brain. We have characterized the cardiac NCX1 promoter, from which the most abundant quantities of NCX1 transcripts are expressed. Transfection of primary cardiac myocytes, CHO cells, and COS-7 cells with overlapping genomic DNA fragments spanning the NCX1 cardiac transcription start site has uncovered a cardiac cell-specific minimum promoter from −137 to +85. The cardiac NCX1 promoter is TATA-less but has putative binding sites for cardiac-specific GATA factors, an E box, and an Inr as well as multiple active enhancers. The kidney NCX1 promoter has a typical TATA box and binding sites for several tissue-specific factors. The brain NCX1 promoter is very GC-rich and possesses several Sp-1 binding sites consistent with its ubiquitous expression.
Ca2+waves during triggered propagated contractions in intact trabeculae
Authors: Miura Masahito , Boyden Penelope A. , Ter Keurs Henk E. D. J.
Published: December 2017

Triggered propagated contractions (TPCs) starting from damaged regions travel along multicellular cardiac muscle preparations. We have reported that octanol (100 μM) inhibits TPCs. The inhibitory effect of octanol on propagation of TPCs could be due to an effect of octanol on Ca2+-induced Ca2+release (CICR) mediated by Ca2+diffusion inside the single cell or on the diffusion of Ca2+from cell to cell via gap junctions (GJs). Therefore, we studied the regional changes in intracellular Ca2+concentration ([Ca2+]i) during TPCs and the effect of octanol on the permeability of gap junctions ( PGJ) in rat cardiac trabeculae. [Ca2+]iwas measured using electrophoretically injected fura 2 and an image-intensified charge-coupled device camera. PGJwas calculated from the diffusion coefficient for fura 2 in trabeculae ( Dtrab) and in the myoplasm ( Dmyop). After 1- and 3-h superfusion with 100 μM 1-octanol, Dmyopshowed no significant changes, whereas Dtrabwas reduced significantly. Therefore, calculated PGJwas reduced from 4.15 × 10−5to 2.10 × 10−5and 0.86 × 10−5cm/s, respectively. The propagation velocity of the regional increases in [Ca2+]iduring TPCs was constant, averaging 1.69 ± 1.48 mm/s (range 0.34–5.47 mm/s, n = 10). These observations support the hypothesis that TPCs are initiated near the damaged ends of trabeculae and are propagated by CICR from the sarcoplasmic reticulum mediated by diffusion of Ca2+through cells and from cell to cell through GJs.
Changes in protein kinase C in early cardiomyopathy and in gracilis muscle in the BB/Wor diabetic rat
Authors: Giles Thomas D. , Ouyang Jie , Kerut E. Kenneth , Given Michael B. , Allen Gayle Eileen , McIlwain Elizabeth F. , Greenberg Stan S.
Published: December 2017

Hyperglycemia can upregulate protein kinase C (PKC), which may be an important mediator of the progression from normal heart and muscle function to diabetic myopathy in the myocardium and skeletal muscle in type 1 insulin-dependent diabetes mellitus (IDM). We evaluated this possibility during the early stage of IDM in BB/Wor diabetic (D) rats and age-matched BB/Wor diabetes-resistant (DR) rats. Interventricular septal thickness, E wave peak velocity of tricuspid inflow (both minimum and maximum), and left ventricular (LV) weight index were increased, and the rate of change in LV pressure (LV dP/d t) decreased in D rats subjected to M-mode and two-dimensional echocardiography and hemodynamic recording of heart rate, LV pressure (LVP), +LV dP/d t, −LV dP/d t, and LV end-diastolic pressure (LVEDP) in vivo and in vitro 41 days after the onset of hyperglycemia. Whole ventricle basal PKC activity was increased by 44.4 and 18.4% in the particulate and soluble fractions, respectively, from D rats compared with that from DR rats using r-32P phosphorylation of appropriate peptide substrates. When measured by Western blot gel densitometry, particulate PKC-α and PKC-δ content increased by 89 and 24%, respectively, but soluble PKC-β and soluble and particulate PKC-ε were unchanged compared with that of DR rats. Similarly, gracilis muscle PKC activity and PKC-α and PKC-δ were elevated in the gracilis muscle, whereas that of the circulating neutrophil did not differ between the D and DR rats. Thus, in vivo, the early diabetic cardiomyopathy of the D rat is characterized by a restrictive LV with increased septal thickness and is associated with elevated PKC activity and increased amounts of myocardial particulate PKC-α and PKC-δ, which are also seen in the skeletal muscle. We conclude that increased PKC isozymes may play a pivotal role during IDM in the development of diabetic cardiomyopathy and skeletal muscle myopathy.
IL-1β alters the expression of the receptor tyrosine kinase gene r-EphA3 in neonatal rat cardiomyocytes
Authors: Li Yun You , McTiernan Charles F. , Feldman Arthur M.
Published: December 2017

To identify proinflammatory cytokine responsive genes in the myocardium, we used differential display to study RNA isolated from neonatal rat cardiac myocytes treated with tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Sequence analysis of differential display products confirmed by reverse Northern blots revealed one clone as the partial sequence of an Eph-related receptor tyrosine kinase (r-EphA3). In cardiac myocytes, 36-h exposure to TNF-α and IL-1β reduced r-EphA3 transcripts to 59.9% ( P < 0.01) of control levels; this effect was largely dependent on IL-1β. Western blot analysis showed that changes in r-EphA3 protein levels reflect that seen for transcripts. Cardiac nonmyocytes expressed substantially lower levels of r-EphA3. Full-length r-EphA3 cDNA clone (3,077 base pair) yielded an amino acid sequence with 90–98% homology to the Eph receptor human EphA3, chick EphA3, and mouse EphA3. In the adult rat, r-EphA3 transcripts were most abundant in the heart, brain, and lung. These results suggest that IL-1β may exert its effect on cardiac myocytes at least in part by altering r-EphA3 expression.
Central methysergide prevents renal sympathoinhibition and bradycardia during hypotensive hemorrhage
Authors: Scrogin Karie E. , Veelken Roland , Johnson Alan Kim
Published: December 2017

Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were measured in conscious rats during either hemorrhage or cardiopulmonary chemoreceptor stimulation with phenylbiguanide (PBG) after intracerebroventricular injection of the 5-HT1/5-HT2-receptor antagonist, methysergide (40 μg). Progressive hemorrhage caused an initial rise (109 ± 33%) followed by a fall in RSNA (−60 ± 7%) and a fall in HR (−126 ± 7 beats/min). Methysergide delayed the hypotension and prevented both the sympathoinhibitory and bradycardic responses to hemorrhage. Systemic 5-HT3-receptor blockade did not influence responses to hemorrhage. The PBG infusion caused transient depressor (−25 ± 6 mmHg), bradycardic (−176 ± 40 beats/min), and renal sympathostimulatory (182 ± 47% baseline) responses that were not affected by central methysergide (−20 ± 6 mmHg, −162 ± 18 beats/min, 227 ± 46% baseline). These data indicate that a central serotonergic receptor-mediated component contributes to the sympathoinhibitory and bradycardic responses to hypotensive hemorrhage in conscious rats. Furthermore, the same central 5-HT-receptor populations involved in reflex responses to hypotensive hemorrhage probably do not mediate the sympathoinhibitory response to cardiopulmonary chemosensitive 5-HT3 receptors.
Lack of beneficial effects of growth hormone treatment in conscious dogs during development of heart failure
Authors: Shen You-Tang , Woltmann R. F. , Appleby S. , Prahalada S. , Krause S. M. , Kivilghn S. D. , Johnson R. G. , Siegl P. K. , Lynch J. J.
Published: December 2017

The effects of chronic treatment with growth hormone (porcine GH, 0.56 mg ⋅ kg−1 ⋅ day−1sc) were examined in dogs with heart failure induced by rapid ventricular pacing (240 beats/min) for 4 wk. Fourteen conscious dogs were studied 2–3 wk after surgical instrumentation with catheters in the descending aorta and left atrium, a pressure gauge in the left ventricle (LV), a flow probe around the ascending aorta, pacing leads on the ventricular free wall and left atrium, and ultrasonic crystals on the opposing anterior and posterior endomyocardium of the LV. GH treatment for 4 wk significantly increased both body weight and plasma insulin-like growth factor 1 (IGF-1) compared with vehicle-treated dogs ( P < 0.01, +2.0 ± 0.5 vs. +0.3 ± 1.1 kg; 1,043 ± 218 vs. 241 ± 64 ng/ml, respectively). However, the changes in resting LV systolic (i.e., both isovolumic and ejection phases) and diastolic function (i.e., isovolumic relaxation time constant τ) and the systemic vascular resistance were similar for the GH- and vehicle-treated groups during the development of heart failure. LV contractile reserve, assessed with step infusion of isoproterenol or dobutamine challenge, was markedly attenuated after heart failure, but there were no differences between the GH- and vehicle-treated groups. During the progression of heart failure, the increases in plasma atrial natriuretic peptide correlated ( P < 0.01) directly with left atrial pressure and inversely with LV circumferential fiber shortening. However, GH treatment did not substantially modify these relationships. In addition, renal function and myocardial ultrastructure at the advanced stage of heart failure also showed similar changes for the GH- and vehicle-treated groups. We conclude that in conscious dogs during the development of congestive heart failure produced by rapid ventricular pacing, GH at a dose that increases body weight and plasma IGF-1 levels does not affect LV performance or systemic vascular dynamics.
Mitral valve opening in the ovine heart
Authors: Karlsson Matts O. , Glasson Julie R. , Bolger Ann F. , Daughters George T. , Komeda Masashi , Foppiano Linda E. , Miller D. Craig , Ingels Neil B. ,   (With the Technical Assistance of Carol W. Mead, Mary K. Zasio, Erin M. Schultz, and Terrence Tye)
Published: December 2017

To study the three-dimensional size, shape, and motion of the mitral leaflets and annulus, we surgically attached radiopaque markers to sites on the mitral annulus and leaflets in seven sheep. After 8 days of recovery, the animals were sedated, and three-dimensional marker positions were measured by computer analysis of biplane videofluorograms (60/s). We found that the oval mitral annulus became most elliptical in middiastole. Both leaflets began to descend into the left ventricle (LV) during the rapid fall of LV pressure (LVP), before leaflet edge separation. The anterior leaflet exhibited a compound curvature in systole and maintained this shape during opening. The central cusp of the posterior leaflet was curved slightly concave to the LV during opening. Markers at the border of the “rough zone” were separated by 10 mm during systole. We conclude that coaptation occurs very near the leaflet edges, that the annulus and leaflets move toward their open positions during the rapid fall of LVP, and that leaflet edge separation, the last event in the opening sequence, occurs near the time of minimum LVP.
Reduction in arterial compliance alters carotid baroreflex control of cardiac output in a model of hypertension
Authors: Potts Jeffrey T. , McKeown Kelly P. , Shoukas Artin A.
Published: December 2017

Baroreflex regulation of cardiac output is determined by the performance of the heart as well as the available blood flow returning to the heart (i.e., venous return). We hypothesized that a decrease in arterial compliance (Ca) would affect carotid baroreflex control of cardiac output by altering the slope of the venous return curve (VR curve). Baroreflex control of systemic arterial pressure (Pa), central venous pressure (Pv), heart rate, cardiac output (CO), and peripheral vascular resistance ( R) were determined during bilateral carotid occlusion (BCO) in spontaneously hypertensive (hypertensive, HT) and Sprague-Dawley (normotensive, NT) rats. Ca was determined from the rate of arterial pressure decay when CO was transiently stopped, and the VR curve was obtained during graded inflation of a vascular balloon positioned in the right atrium. The inverse slope of the VR curve was used as an index of the resistance to venous return (RVR). The baseline slope of the VR curve was −50.5 ± 3.3 vs. −35.5 ± 2.6 ml ⋅ kg−1 ⋅ min−1 ⋅ mmHg−1in NT vs. HT, respectively ( P < 0.05). Control values of Pa (96 ± 5 vs. 124 ± 8 mmHg) and R[0.43 ± 0.04 vs. 0.80 ± 0.07 peripheral resistance units (PRU)] were reduced in NT, whereas Ca (0.062 ± 0010 vs. 0.036 ± 0.003 ml ⋅ kg−1 ⋅ mmHg−1) was elevated in NT vs. HT, respectively ( P < 0.05). Analysis of the pressure dependence of Ca demonstrated that Ca was a nonlinear function of Pa, and the exponential decay constant for the Ca-Parelationship was reduced in HT (0.0055 ± 0.0012 vs. 0.0012 ± 0.0002 min, NT vs. HT, P < 0.05). Baroreflex activation by BCO significantly increased Pa(ΔPa, 20 ± 4 vs. 28 ± 3 mmHg) and R(Δ R, 0.16 ± 0.04 vs. 0.24 ± 0.06 PRU) in NT vs. HT, respectively. However, BCO significantly decreased CO in NT but not HT (ΔCO, −24 ± 5 vs. −4 ± 6 ml ⋅ kg−1 ⋅ min−1, P < 0.05). In NT, RVR was increased 39 ± 9% during BCO ( P < 0.05), whereas RVR increased 8 ± 3% in HT ( P = NS). From these findings, we conclude that the difference in baroreflex control of CO is mediated, in part, by the reduction in Ca, which minimized the baroreflex-evoked increase in RVR.
Physical basis of pressure transfer from periphery to aorta: a model-based study
Authors: Stergiopulos Nikos , Westerhof Berend E. , Westerhof Nico
Published: December 2017

We propose a new method to derive aortic pressure from peripheral pressure and velocity by using a time domain approach. Peripheral pressure is separated into its forward and backward components, and these components are then shifted with a delay time, which is the ratio of wave speed and distance, and added again to reconstruct aortic pressure. We tested the method on a distributed model of the human systemic arterial tree. From carotid and brachial artery pressure and velocity, aortic systolic and diastolic pressure could be predicted within 0.3 and 0.1 mmHg and 0.4 and 1.0 mmHg, respectively. The central aortic pressure wave shape was also predicted accurately from carotid and brachial pressure and velocity (root mean square error: 1.07 and 1.56 mmHg, respectively). The pressure transfer function depends on the reflection coefficient at the site of peripheral measurement and the delay time. A 50% decrease in arterial compliance had a considerable effect on reconstructed pressure when the control transfer function was used. A 70% decrease in arm resistance did not affect the reconstructed pressure. The transfer function thus depends on wave speed but has little dependence on vasoactive state. We conclude that central aortic pressure and the transfer function can be derived from peripheral pressure and velocity.
Intrinsic ANG II type 1 receptor stimulation contributes to recovery of postischemic mechanical function
Authors: Ford William R. , Clanachan Alexander S. , Lopaschuk Gary D. , Schulz Richard , Jugdutt Bodh I.
Published: December 2017

To determine whether intrinsic angiotensin II (ANG II) type 1 receptor (AT1-R) stimulation modulates recovery of postischemic mechanical function, we studied the effects of selective AT1-R blockade with losartan on proton production from glucose metabolism and recovery of function in isolated working rat hearts perfused with Krebs-Henseleit buffer containing palmitate, glucose, and insulin. Aerobic perfusion (50 min) was followed by global, no-flow ischemia (30 min) and reperfusion (30 min) in the presence ( n = 10) or absence ( n = 14) of losartan (1 μmol/l) or the cardioprotective adenosine A1receptor agonist N 6-cyclohexyladenosine (CHA, 0.5 μmol/l, n = 11). During reperfusion in untreated hearts (controls), left ventricular (LV) minute work partially recovered to 38% of aerobic baseline, whereas proton production increased to 155%. Compared with controls, CHA improved recovery of LV work to 79% and reduced proton production to 44%. Losartan depressed recovery of LV work to 0% without altering proton production. However, exogenous ANG II (1–100 nmol/l) in combination with losartan restored recovery of LV work during reperfusion in a concentration-dependent manner, suggesting that postischemic recovery of function depends on intrinsic AT1-R stimulation.
Effect of chronic sensory denervation on Ca2+-induced relaxation of isolated mesenteric resistance arteries
Authors: Mupanomunda Maria M. , Wang Yanlin , Bukoski Richard D.
Published: December 2017

We recently reported that Ca2+-induced relaxation could be linked to a Ca2+ receptor (CaR) present in perivascular nerves. The present study assessed the effect of chronic sensory denervation on Ca2+-induced relaxation. Mesenteric resistance arteries were isolated from rats treated as neonates with capsaicin (50 mg/kg), vehicle, or saline. The effect of cumulative addition of Ca2+ was assessed in vessels precontracted with 5 μM norepinephrine. Immunocytochemical studies showed that capsaicin treatment significantly reduced the density of nerves staining positively for calcitonin gene-related peptide (CGRP) and for the CaR (CGRP density: control, 51.1 ± 3.9 μm2/mm2; capsaicin treated, 31.4 ± 2.8 μm2/mm2, P = 0.01; control CaR density, 46 ± 4 μm2/mm2, n = 7; capsaicin-treated CaR density, 24 ± 4 μm2/mm2, n = 8, P = 0.002). Dose-dependent relaxation to Ca2+ (1–5 mM) was significantly depressed in vessels from capsaicin-treated rats (overall P < 0.001, n = 6 or 7), whereas the relaxation response to acetylcholine remained intact. These data support the hypothesis that Ca2+-induced relaxation is mediated by activation of the CaR associated with capsaicin-sensitive perivascular neurons.
Arterial vasomotion: effect of flow and evidence of nonlinear dynamics
Authors: Stergiopulos N. , Porret C.-A. , De Brouwer S. , Meister J.-J.
Published: December 2017

Vasomotion has been studied on segments of rat mesenteric and femoral arteries perfused in vitro. We have investigated 1) the effect of perfusion flow on the characteristics of vasomotion and 2) the nature and patterns of vasomotion. We have found that perfusion flow is not a control parameter that contributes to the genesis of vasomotion but that it affects, in most cases only slightly, the frequency and amplitude of vasomotion. We have found evidence that vasomotion is low-dimensional chaotic. The correlation dimension ranged between 2 and 4, and the average Lyapunov’s coefficient was ∼0.1. A great variety of vasomotion patterns was observed with features that are typical of nonlinear deterministic systems: regular and irregular vasomotion, quasiperiodicity, period doubling and higher-order periods, intermittency, mixed modes, and bursting activity. Vasomotion patterns appeared occasionally to be highly sensitive to perturbations in perfusion flow, which also supported the existence of nonlinear dynamics. Finally, entrainment (phase locking) was observed when arteries were perfused with oscillatory flow with frequency in the neighborhood of the frequency of vasomotion.
Chronic activation of brain areas by high-sodium diet in Dahl salt-sensitive rats
Authors: Budzikowski Adam S. , Vahid-Ansari Faranak , Leenen Frans H. H.
Published: December 2017

To map changes in neuronal activity in the brains of Dahl salt-sensitive (Dahl S) vs. salt-resistant (Dahl R) rats by high-sodium diet, we used immunohistochemical detection of Fra-like proteins as a marker for long-term neuronal activation. Compared with Dahl R rats during regular sodium intake, Dahl S rats showed modestly higher expression of Fra-like immunoreactivity (Fra-LI) in the supraoptic nucleus, anterior hypothalamic area (AHA), central gray, and nucleus of solitary tract (NTS) at 5, 6, and 9 wk of age but clearly elevated Fra-LI in the magnocellular part of the paraventricular nucleus (PVN) at 6 wk of age (but not at 5 and 9 wk). In the median preoptic nucleus (MnPO) Fra-LI was lower at 9 wk of age and no differences were observed in the parvocellular PVN and subfornical organ in Dahl S vs. Dahl R rats on regular sodium intake. Compared with Dahl S rats on a regular-sodium diet, Dahl S rats on a high-sodium diet from 4 to 9 wk of age had significantly increased blood pressure and experienced transient activation of magnocellular PVN and MnPO and virtually no changes in the activity of the parvocellular PVN, AHA, and NTS. In contrast, Dahl R rats showed marked activation in the magnocellular PVN after 1 and 2 wk on a high-sodium diet compared with Dahl R rats on a regular-sodium diet. The present study demonstrates that Dahl S rats show differential activation of brain areas participating in regulation of osmotic and cardiovascular homeostasis during development of sodium-sensitive hypertension.
Estrogen restores role of basal nitric oxide in control of vascular tone in rats with chronic heart failure
Authors: Nekooeian Ali Akbar , Pang Catherine C. Y.
Published: December 2017

This study examined the cardiovascular effects of 17β-estradiol in ovariectomized rats with heart failure. Two groups (50–60 days old) were implanted with 60-day-release pellets containing 17β-estradiol (25 μg/day) or vehicle at 7 days before ligation of the left coronary artery. Another group was sham operated and given vehicle pellets. After 7 wk, they were studied under pentobarbital anesthesia. Relative to sham-operated rats, ligated rats had reduced mean arterial pressure (MAP, −24 ± 6 mmHg), cardiac output (−27 ± 4 ml/min), left ventricular (LV) end-systolic pressure (−29 ± 8 mmHg), depressor responses to ACh (−6 ± 4 mmHg at 7.2 μg/kg) and sodium nitroprusside (SNP, −22 ± 6 mmHg at 9 μg/kg), and pressor responses to N G-nitro-l-arginine methyl ester (l-NAME, −14 ± 6 mmHg at 8 mg/kg) and increased LV end-diastolic pressure (LVEDP, 10.3 ± 0.8 mmHg) but no change in total peripheral resistance (TPR). Treatment of ligated rats with 17β-estradiol reduced TPR (−0.19 ± 0.06 mmHg ⋅ min ⋅ ml−1), LVEDP (−3.6 ± 1 mmHg), and responses to ACh (−16 ± 4 mmHg) and augmented responses tol-NAME (14 ± 3 mmHg) but did not alter other variables. Therefore, 17β-estradiol reduces preload and afterload and restores the vasodilator role of basal nitric oxide in ovariectomized rats with chronic heart failure.
Influence of gender on control of arterial tone in experimental hypertension
Authors: Kähönen Mika , Tolvanen Jari-Petteri , Sallinen Kirsimarja , Wu Xiumin , Pörsti Ilkka
Published: December 2017

Endothelial dysfunction has been found to be less severe in female than in male spontaneously hypertensive rats (SHR), which could contribute to the gender differences observed in the extent and rate of progression of hypertension in SHR. However, the influence of gender on the roles of different endothelium-derived mediators in the arterial responses in hypertension have not been evaluated in detail. Therefore, contractile and relaxation responses of mesenteric arterial rings in vitro were studied in female and male SHR, with normotensive female and male Wistar-Kyoto rats (WKY) serving as controls. In norepinephrine (NE)-precontracted arterial rings, endothelium-dependent relaxations to ACh as well as endothelium-independent dilations to sodium nitroprusside were more pronounced in female than in male SHR, whereas relaxations to the β-adrenoceptor agonist isoproterenol remained equally impaired in female and male SHR. The cyclooxygenase inhibitor diclofenac, which reduces the synthesis of dilating and constricting prostanoids, markedly enhanced the relaxations to ACh in male SHR but not in the other groups. The nitric oxide (NO) synthase inhibitor N G-nitro-l-arginine methyl ester attenuated the relaxations to ACh more effectively in female SHR and WKY than in the male groups. However, when endothelium-dependent hyperpolarization was prevented by precontracting the preparations with KCl, no significant differences were found in relaxations to ACh among the study groups. In conclusion, release of cyclooxygenase-derived constricting factors appeared to be more pronounced in male than in female SHR. In addition, the relative role of NO in endothelium-dependent arterial relaxation seemed to be higher in female than in male SHR, and relaxation induced by an NO donor also was more pronounced in female than in male SHR.
Long-term effects of nonpeptide vasopressin V2 antagonist OPC-31260 in heart failure in the rat
Authors: Burrell Louise M. , Phillips Paddy A. , Risvanis John , Chan Robert K. , Aldred Kathryn L. , Johnston Colin I.
Published: December 2017

The hormone arginine vasopressin (AVP) contributes to water retention and vasoconstriction in congestive heart failure (CHF) through effects at the V2 and V1a receptors, respectively. The effect of long-term V2 receptor (V2R) blockade using OPC-31260 was assessed in a rat model of postinfarction-induced CHF. Rats underwent coronary artery ligation or sham operation and were treated for 6 mo with oral OPC-31260 (10 mg ⋅ kg−1 ⋅ day−1) or vehicle. CHF was characterized by left ventricular remodeling and impaired systolic function, increased cardiac and lung weight, and elevated plasma atrial natriuretic peptide; plasma AVP and plasma renin activity were not increased. Chronic V2R blockade increased urine volume ( P < 0.01) and decreased urine osmolality ( P < 0.01) but had no natriuretic effects. V2R blockade did not activate the renin-angiotensin system but increased plasma AVP in CHF ( P < 0.01). V2R blockade did not influence cardiac remodeling, cardiac function, or survival. These results suggest that AVP plays a major role in water retention through the renal V2R in a rat model of CHF. V2R blockade using OPC-31260 may represent an alternative to standard diuretic therapy in the management of water retention that characterizes heart failure.
Ischemic tolerance in skeletal muscle: role of nitric oxide
Authors: Pudupakkam S. , Harris K. A. , Jamieson W. G. , DeRose G. , Scott J. A. , Carson M. W. , Schlag M. G. , Kvietys P. R. , Potter R. F.
Published: December 2017

We tested the hypothesis that ischemic preconditioning (PC) of skeletal muscle provided tolerance to a subsequent ischemic event 24 h later, and that such protection was due to nitric oxide (NO). Male Wistar rats, anesthetized with halothane, were randomly assigned to groups: ischemic (no PC; n = 11), PC ( n = 11), PC + N-nitro-l-arginine methyl ester (l-NAME; 100 μmol/l; n = 5), PC + N-nitro-d-arginine methyl ester (100 μmol/l; n= 4), PC + aminoguanidine (AMG; 100 μmol/l; n = 4), ischemic +l-NAME ( n= 4), or ischemic + AMG ( n = 4). PC consisted of 5× 10 min of ischemia and reperfusion, and, 24 h later, 2 h of ischemia were induced by a tourniquet applied to the limb. With the use of intravital microscopy, the number of perfused capillaries ( N pc) in the extensor digitorum longus (EDL) muscle was measured over a 90-min reperfusion period. The ratio of ethidium bromide- to bisbenzimide-labeled nuclei was used to estimate tissue injury. PC preserved N pc(23.6 ± 2.5) following 2 h of ischemia compared with sham muscles (11.5 ± 5.1), significantly elevating inducible NO synthase (iNOS) activity (81% increase), but did not afford protection to the parenchyma.l-NAME and AMG prevented ischemia-reperfusion-induced reduction in N pc in muscles without PC. However, after 90 min of reperfusion,l-NAME ( N pc = 15.0 ± 1.7), but not AMG ( N pc = 22.8 ± 3.1), significantly reduced the microvascular protection afforded by PC. We conclude that PC of the EDL muscle resulted, 24 h later, in protection to microvascular perfusion only, and that such protection was due to NO from sources other than iNOS.
Exercise-induced muscle injury augments forearm vascular resistance during leg exercise
Authors: Ray Chester A. , Mahoney Edward T. , Hume Keith M.
Published: December 2017

The purpose of the present investigation was to examine the effect of exercise-induced muscle injury on hemodynamic responses during exercise. Ten subjects performed unilateral isometric knee extensions (IKE) at 30% of preinjury maximum voluntary contraction to fatigue and for 3 min before and 48 h after muscle injury. Muscle injury was elicited by performing 8 sets of 10 repetitions of eccentric muscle actions of the knee extensor muscles (i.e., quadriceps muscles) by lowering a weight equivalent to 75% of eccentric maximum load. Exercise time to fatigue for IKE at 30% of maximum voluntary contraction in the injured leg was significantly decreased from preinjury to postinjury IKE (257 ± 21 to 203 ± 23 s; n = 10), but was unchanged in the control leg (244 ± 16 to 254 ± 20 s; n = 7). With the use of a 10-cm visual analog scale, ratings of muscle soreness in the injured leg increased from 0 to 5.1 ± 0.7 cm ( P < 0.001) but were not changed in the control leg (0 both times). Both heart rate and mean arterial pressure responses to exercise were unchanged following muscle injury. Forearm blood flow and forearm vascular resistance were not different at rest and during the first minute of exercise before and after muscle injury. However, after muscle injury, forearm blood flow was significantly lower and forearm vascular resistance was significantly higher ( P < 0.03) during the second and third minutes of exercise. There were no significant changes in any variables with the contralateral control leg. In four subjects, resting magnetic resonance images demonstrated a 23% greater relative cross-sectional area of the knee extensor muscles with an elevated transverse relaxation time in the injured versus control leg. The results indicate that forearm vascular resistance is augmented during isometric knee extension following muscle injury of the knee extensor muscles. The data suggest that muscle injury alters vascular control to non-exercising skeletal muscle during exercise.
CNP causes receptor-mediated positive dromotropic effects in anesthetized dog hearts
Authors: Hirose Masamichi , Furukawa Yasuyuki , Miyashita Yusuke , Kurogouchi Fumio , Nakajima Koichi , Tsuboi Masato , Chiba Shigetoshi
Published: December 2017

No data are available for the direct effect of C-type natriuretic peptide (CNP) on atrioventricular (AV) conduction in mammalian hearts. Thus we studied the dromotropic effects of CNP-22 injected into the AV node artery in autonomically decentralized hearts in open-chest, anesthetized dogs. CNP decreased AV interval (AV conduction time) in a dose-dependent manner with increase in coronary artery blood flow rate in six anesthetized dogs. Isosorbide dinitrate did not affect AV interval, but it increased coronary artery blood flow rate. A guanylyl cyclase-linked natriuretic peptide receptor antagonist, HS-142–1, inhibited the decreases in AV interval and the increases in coronary blood flow rate in response to CNP, whereas propranolol did not affect the positive dromotropic response to CNP. These results demonstrate that CNP decreases AV interval and increases coronary artery blood flow rate mediated by a guanylyl cyclase-linked natriuretic peptide receptor, but not β-adrenoceptor, in the dog heart.
Cardiac sympathetic afferent stimulation by bradykinin in heart failure: role of NO and prostaglandins
Authors: Wang Wei
Published: December 2017

I have shown that cardiac sympathetic afferent stimulation by epicardial application of bradykinin (BK) was significantly enhanced in pacing-induced heart failure (HF) dogs. This enhancement appeared to be mediated by prostaglandins. The present study was to determine whether nitric oxide is involved in this enhancement. Under α-chloralose (100 mg/kg iv) anesthesia, the renal sympathetic nerve activity (RSNA) response to BK was determined in 15 HF and 15 sham dogs in the sinoaortic-denervated and vagotomized state. The RSNA response to BK was significantly enhanced in HF. This enhanced RSNA response to BK was significantly reduced in the HF dogs after administration of the cycloxygenase inhibitor indomethacin (5 mg/kg iv), but no significant change was found in the sham group. In contrast, RSNA responses to BK were significantly reduced in the sham dogs after administration of the nitric oxide synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME, 30 mg/kg iv), but no significant change was found in the HF group. These data suggest that the RSNA response to BK is mediated by nitric oxide to a large degree in the normal state but is primarily mediated by prostaglandins in the HF state.
Hydrogen peroxide relaxes porcine coronary arteries by stimulating BKCachannel activity
Authors: Barlow Robert S. , White Richard E.
Published: December 2017

It has been known for a number of years that neutrophils and macrophages secrete H2O2while fighting disease, and the levels obtained within the vasculature under these conditions can reach several hundred micromolar. Because the effect of H2O2on vascular smooth muscle is not fully understood, the present study examined the cellular effects of H2O2on coronary arteries. Under normal ionic conditions, H2O2relaxed arteries that were precontracted with prostaglandin F2α or histamine (EC50 = 252 ± 22 μM). The effect of H2O2was concentration dependent and endothelium independent. In contrast, H2O2did not relax arteries contracted with 80 mM KCl, suggesting involvement of K+ channels. Single-channel patch-clamp recordings revealed that H2O2increased the activity of the large-conductance (119 pS), Ca2+- and voltage-activated K+(BKCa) channel. This response was mimicked by arachidonic acid and inhibited by eicosatriynoic acid, a lipoxygenase blocker, suggesting involvement of leukotrienes. Further studies on intact arteries demonstrated that eicosatriynoic acid not only blocked the vasodilatory response to H2O2but unmasked a vasoconstrictor effect that was reversed by blocking cyclooxygenase activity with indomethacin. These findings identify a novel effector molecule, the BKCachannel, which appears to mediate the vasodilatory effect of H2O2, and suggest that a single signaling pathway, arachidonic acid metabolism, can mediate the vasodilatory and vasoconstrictor effects of H2O2and possibly other reactive oxygen species.
Effect of Total-Body X-Irradiation on Fat Balance and Liver Lipids in the Rhesus Monkey
Authors: Coniglio John G. , Darby W. J. , Efner J. Ann , Fleming Jim , Hudson Granville W.
Published: December 2017

Fat balance studies were done on rhesus monkeys irradiated with 325, 400 and 650 r total-body x-irradiation. The postirradiational results were compared with the preirradiational values of the same monkeys and with those obtained in pair-fed controls. No defect in fat absorption was found due to the irradiation. Increased fecal fat loss after irradiation was observed in both irradiated and nonirradiated animals. Monkeys given 650 r had liver lipid concentrations similar to their pair-fed controls. These analyses were done at 12, 96 and 229 days after irradiation. Changes in body weight in all animals paralleled decreases in food intake immediately after irradiation and subsequent increases with recovery. Hematologic studies showed the usual decrease in leucocyte count after irradiation. One monkey given 650 r was killed 12 days postirradiation because death was imminent; all other animals survived the irradiation.
Detection of Dietary Cholesterol-4-C14 in the Hepatic Reticulo-Endothelial Cell of the Rat
Authors: Friedman Meyer , Byers Sanford O. , St. George Shirley
Published: December 2017

Separation and isolation of hepatic parenchymal from reticulo-endothelial cells of rats given cholesterol-4-C14 was accomplished. Radioactivity was found in both cell types 6 and 24 hours following oral administration, indicating that the reticulo-endothelial cells play a role in the disposition of dietary derived cholesterol.
Dynamics of Hypothermic Heart Muscle (Heart-Lung Preparation)
Authors: Reissmann Kurt R. , Kapoor Sitaram
Published: December 2017

The work performance of the hypothermic heart muscle and its possible relationship to ventricular fibrillation was studied in 42 canine heart-lung preparations. With lowering of temperature the work capacity of the heart declined proportional to the decline in heart rate. The maximum stroke volume remained uniformly high over a wide range of hypothermia, until arrhythmia interfered at temperatures around 22°C. Although the work capacity gradually decreased with lower temperature, it was found to be considerably higher than the work load the heart has to cope with in an intact animal at the same temperature. Spontaneous ventricular fibrillation occurred at the same temperature range in denervated heart-lung preparations as in intact hypothermic animals. No relationship was found between the onset of fibrillation and the work load of the heart prior to its onset. Myocardial mechanical failure is therefore not considered to be the cause of ventricular fibrillation in hypothermia. The increased blood viscosity at lower temperatures did not account for the marked prolongation of the ejection phase. Variations in stroke volume likewise did not effect significantly its duration. Epinephrine markedly shortened both ejection and relaxation phase of the hypothermic heart. Epinephrine had a marked inotropic effect upon the hypothermic heart, while the accelerator effect decreased with lowering of temperature. At 22°C or below, where sinus rhythm was no longer present, epinephrine induced ectopic impulse formation in multiple foci which led to ventricular fibrillation.
General and Specific Characteristics of Physiological Adaptations
Authors: Adolph E. F.
Published: December 2017

Adaptations (adaptates) were induced when individual rats were exposed to a particular stressor. They are modifications of function that outlast the stressor. Quantitative data chiefly concerned the effects of prolonged exposures to cold air, to simulated altitude, or of repeated administration of cold air, low oxygen, water, sodium chloride or sucrose. Adaptations to several stressors could be compared kinetically. Some adaptates were alike in their courses of development; but varied latencies, rates and directions of modifications were also found. Most manifestations of adaptation gradually disappeared (deadapted) in the absence of further exposure. The disappearance was usually slower than the development. The initial state of the function measured was reattained. Hence, adaptations were believed to superimpose upon more stable patterns of regulation. The combination of modifications that resulted when a given stressor impinged was found empirically but could not be predicted. The adaptates studied were more often specific to one stressor than general to more than one.
Aldosterone Secretion After Hypophysectomy
Authors: Rauschkolb Elizabeth W. , Farrell Gordon L. , Koletsky Simon
Published: December 2017

Adrenal venous blood was collected from hypophysectomized and sham-hypophysectomized dogs 6 days postoperatively. 17-Hydroxycorticosterone, corticosterone, 11-desoxy-17-hydroxycorticosterone and aldosterone were isolated by paper chromatography. Histological examination of the sellar and suprasellar regions of the hypophysectomized dogs demonstrated the absence of pituitary tissue. The adrenal glands of the hypophysectomized dogs showed cortical atrophy which did not involve the zona glomerulosa. The rate of secretion of aldosterone by the hypophysectomized dogs was found to be approximately 66% of that of the control, sham hypophysectomized, dogs. The rates of secretion of 17-hydroxycorticosterone, corticosterone and 11-desoxy-17-hydroxycorticosterone were found to be approximately 10% of that of the controls. The ability of the hypophysectomized dog to remain in electrolyte balance appears to be due in large measure to the continued secretion of aldosterone.
Metabolism of Carbon14-Labeled Pyruvate by the Newborn Rat
Authors: Kimmelstiel Ruth , Villee Claude A.
Published: December 2017

Pyruvate labeled with carbon-14 was administered intraperitoneally to newborn rats which were subsequently subjected to periods of aerobiosis or anaerobiosis. Expired air was analyzed for carbon dioxide, and blood, liver and carcass were analyzed for pyruvate, lactate, glycogen and total lipids. Small quantities of CO2 were produced anaerobically but this was not derived from the direct decarboxylation of pyruvate. Anaerobiosis resulted in a five-fold increase in blood lactate. The liver glycogen content of 10–24-hr-old rats treated anaerobically was only 10% of that of those kept in oxygen. The premature and newborn rats were apparently unable to mobilize glycogen in response to anoxia. The amounts of liver or carcass lipids were not significantly different after aerobic or anaerobic conditions. Lipogenesis occurred anaerobically at a rate not greatly different from that observed in aerobic conditions. In contrast, the data suggest that the utilization of lipids is reduced by anaerobiosis. No gross changes were found that could entirely explain the ability of neonates to survive prolonged oxygen deprivation but part, at least, of the energy for survival was provided by accelerated glycolysis.