bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of central AT1 and V1 receptors in cardiovascular adaptation to hemorrhage in SD and renin TGR rats
Authors: Paczwa Piotr , Szczepańska-Sadowska Ewa , Ganten Slawomir Łoń, Ursula , Ganten Detlev
Published: December 2017

In acute experiments, intracranially applied angiotensin II and vasopressin elicit significant cardiovascular effects. The purpose of the present study was to find out whether chronic intrabrain elevation of these peptides, occurring in the renin transgenic TGR(mRen2)27 (TGR) rats, results in an alteration of the cardiovascular control. Mean arterial blood pressure (MAP) and heart rate responses to hypovolemia were examined in hypertensive TGR and normotensive Sprague-Dawley (SD) rats under control conditions and during blockade of central AT1 or V1 receptors. Both groups received cerebroventricular infusions of either 1) cerebrospinal fluid ( series 1), 2) AT1 receptors antagonist (AT1ANT, series 2), or 3) V1 receptors antagonist (V1ANT, series 3). Blockade of AT1 and V1 receptors decreased MAP in TGR but not in SD rats. In SD rats, bleeding elicited a similar decrease of MAP in each series and a transient increase of heart rate in series 3. In TGR, hemorrhage caused bradycardia and decrease of MAP, which was greater than in SD rats. Hemorrhagic hypotension in TGR was abolished by V1ANT and bradycardia by V1ANT or AT1ANT. The results demonstrate remarkable differences in cardiovascular adjustment to hemorrhage in SD and TGR rats and provide evidence for enhanced involvement of central V1 and AT1 receptors in the regulation of blood pressure during hypovolemia in TGR. Central V1 vasopressin receptors play a crucial role in eliciting posthemorrhagic hypotension and bradycardia in this strain.
Increases in oxygen tension stimulate expression of ICAM-1 and VCAM-1 on human endothelial cells
Authors: Willam Carsten , Schindler Ralf , Frei Ulrich , Eckardt Kai-Uwe
Published: December 2017

Leukocyte infiltration plays a major role in ischemia-associated organ dysfunction and damage. A crucial step for extravasation of white blood cells is binding of leukocyte β-integrins to endothelial adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1). To test for direct effects of oxygen on this process we studied ICAM-1 and VCAM-1 expression in human dermal microvascular and umbilical vein endothelial cells (EC) exposed to different oxygen tensions in the absence or presence of tumor necrosis factor-α (TNF-α). Hypoxia (95% N2-5% CO2) resulted in a downregulation of basal but not TNF-α-induced expression of ICAM-1 and VCAM-1. Subsequent rises in oxygen (21, 40, or 95% O2) led to marked increase of ICAM-1 and VCAM-1 cell surface and mRNA expression in both EC types, which after 16 h amounted to about one-third to one-half of maximal TNF-α-induced expression. This increase was greatest after 0.5-h hypoxia and was blunted with prolonged hypoxic preincubation. Exposure of cells preincubated under “normoxic” (21% O2) conditions to hyperoxia (40 or 95% O2) also enhanced expression of both adhesion molecules, but the increase was lower than in cells preexposed to hypoxia. The nitric oxide synthesis inhibitor NG-nitro-l-arginine methyl ester (l-NAME) enhanced ICAM-1 and VCAM-1 expression under basal and hypoxic conditions, but in the presence of l-NAME, levels in reoxygenated cells were not higher than basal levels. Moreover, the oxygen-induced rise could be mimicked by addition of H2O2to normoxic cells, and the oxygen-induced expression of VCAM-1 but not of ICAM-1 was inhibited by addition of the free radical scavengers superoxide dismutase, N-acetyl-l-cysteine, and pyrrolidinedithiocarbamate. These data indicate that an increase in oxygen availability stimulates ICAM-1 and VCAM-1 expression on micro- and macrovascular EC, which may contribute to adhesion and transmigration of different leukocyte populations in ischemia-reperfusion injuries.
Effects of calcitonin gene-related peptide on vascular resistance in rats: role of sex steroids
Authors: Grewal Michelle , Cuevas Janis , Chaudhuri Gautam , Nathan Lauren
Published: December 2017

It has been demonstrated in reflex-intact animals that the sensitivity to calcitonin gene-related peptide (CGRP) is increased during pregnancy and that this action is mediated by sex steroids but not by nitric oxide (NO). We assessed the effects of CGRP in the following groups of anesthetized ganglion-blocked rats: 1) pregnant, 2) ovariectomized, and 3) ovariectomized and treated with estradiol and progesterone. Changes in mean arterial pressure (MAP) were assessed after the administration of varying doses of CGRP. Decreases in MAP after CGRP administration were significantly greater in pregnant rats and ovariectomized rats administered sex steroids than in ovariectomized controls. The CGRP antagonist CGRP8–37 produced a pressor response of similar magnitude in both pregnant and ovariectomized rats. We also assessed the effects of CGRP and the modulating role of NO in the isolated uterine vascular bed preparation. CGRP reduced perfusion pressure to a greater degree in ovariectomized animals treated with sex steroids than in ovariectomized animals. This response was attenuated by pretreatment with an NO synthesis inhibitor. CGRP8–37 produced a similar increase in perfusion pressure in both groups. We conclude that 1) the increased vascular sensitivity observed during pregnancy or after treatment with sex steroids is in part mediated by NO, and 2) CGRP8–37 has a vasoconstrictor action of its own.
Participation of PI3K and atypical PKC in Na+-K+-pump stimulation by IGF-I in VSMC
Authors: Li Dailin , Sweeney Gary , Wang Qinghua , Klip Amira
Published: December 2017

The activity of the Na+-K+-pump is intricately linked to the maintenance of vascular tone. Here we demonstrate that insulin-like growth factor I (IGF-I) increases Na+-K+-pump activity in the vascular smooth muscle cell (VSMC) clone A7r5 in a time- and dose-dependent manner. This stimulatory effect of IGF-I was prevented by the tyrosine kinase inhibitor genistein (5 μM) and by the specific phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin (100 nM) and LY-294002 (25 μM). IGF-I activated a wortmannin-sensitive PI3K and its purported effector, the atypical protein kinase C (PKC)-ζ. Stimulation of PKC-ζ was prevented by the generic PKC inhibitor GF109203x (bisindolylmaleimide, 10 μM). Downregulation of diacylglycerol-sensitive (conventional and novel) PKCs by 24-h pretreatment with 1 μM phorbol 12-myristate 13-acetate had no effect on IGF-I-stimulated Na+-K+-pump activity. Similarly, inhibition of only conventional and novel PKCs with GF109203x (1 μM) had no effect on IGF-I-stimulated Na+-K+-pump activity. In contrast, a concentration of GF109203x (10 μM) that also inhibits the atypical PKCs abolished Na+-K+-pump stimulation by IGF-I. Neither the Na+-K+-2Cl−cotransporter inhibitor bumetanide (100 μM) nor the Na+/H+exchanger inhibitor HOE-694 (5 μM) affected the Na+-K+-pump stimulation by IGF-I, suggesting that a rise in intracellular Na+concentration is not necessary for increased Na+-K+-pump activity. These results suggest that IGF-I directly stimulates the Na+-K+pump via a signaling pathway involving PI3K and atypical PKC (ζ).
CaM kinase augments cardiac L-type Ca2+current: a cellular mechanism for long Q-T arrhythmias
Authors: Wu Yuejin , MacMillan Leigh B. , McNeill R. Blair , Colbran Roger J. , Anderson Mark E.
Published: December 2017

Early afterdepolarizations (EAD) caused by L-type Ca2+current ( ICa,L) are thought to initiate long Q-T arrhythmias, but the role of intracellular Ca2+in these arrhythmias is controversial. Rabbit ventricular myocytes were stimulated with a prolonged EAD-containing action potential-clamp waveform to investigate the role of Ca2+/calmodulin-dependent protein kinase II (CaM kinase) in ICa,Lduring repolarization. ICa,Lwas initially augmented, and augmentation was dependent on Ca2+from the sarcoplasmic reticulum because the augmentation was prevented by ryanodine or thapsigargin. ICa,Laugmentation was also dependent on CaM kinase, because it was prevented by dialysis with the inhibitor peptide AC3-I and reconstituted by exogenous constitutively active CaM kinase when Ba2+was substituted for bath Ca2+. Ultrastructural studies confirmed that endogenous CaM kinase, L-type Ca2+channels, and ryanodine receptors colocalized near T tubules. EAD induction was significantly reduced in current-clamped cells dialyzed with AC3-I (4/15) compared with cells dialyzed with an inactive control peptide (11/15, P = 0.013). These findings support the hypothesis that EADs are facilitated by CaM kinase.
Activated macrophages decrease rat cardiac myocyte contractility: importance of ICAM-1-dependent adhesion
Authors: Simms Matthew G. , Walley Keith R.
Published: December 2017

Macrophages are found in the heart as part of the inflammatory response. To determine whether macrophages could contribute to myocardial dysfunction, rat ventricular myocytes were isolated and cocultured with elicited peritoneal macrophages in media containing tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, or endotoxin for 4 h. Cardiac myocytes were electrically stimulated, and fractional shortening was determined using videomicroscopy. When myocytes alone or myocytes in coculture with macrophages separated by a membrane were challenged with TNF-α, lipopolysaccharide, or IL-1, fractional shortening did not decrease. When macrophages were allowed to contact myocytes, fractional shortening decreased from 20.1 ± 0.9% in unchallenged macrophage-myocyte cocultures to 15.5 ± 0.9, 16.3 ± 0.8, and 15.8 ± 0.6% when challenged for 4 h with TNF-α, endotoxin, or IL-1β, respectively ( P < 0.05). Myocytes had a mean adherence of 4.2 ± 0.2 macrophages after TNF-α challenge compared with 2.6 ± 0.3 for controls ( P < 0.05). The number of adherent macrophages was associated with the decrease in fractional shortening. Anti-intercellular adhesion molecule-1 (ICAM-1) reduced macrophage adherence and prevented the decrease in fractional shortening. This decrease was also prevented by desferoxamine, superoxide dismutase, and nitro-l-arginine methyl ester. This suggests that activated macrophages adhere to myocytes via ICAM-1, and adherent macrophages decrease their contractile function via TNF-α, oxygen free radicals, and nitric oxide.
Potentiation of stretch-induced atrial natriuretic peptide secretion by intracellular acidosis
Authors: Tavi Pasi , Laine Mika , Voutilainen Sari , Lehenkari Petri , Vuolteenaho Olli , Ruskoaho Heikki , Weckström Matti
Published: December 2017

We sought to investigate whether atrial myocyte contraction and secretion of the atrial natriuretic peptide (ANP) are affected in the same manner by intervention in intracellular Ca2+handling by acidosis. The effects of propionate (20 mM)-induced intracellular acidosis on the stretch-induced changes in ANP secretion, contraction force, and intracellular Ca2+concentration ([Ca2+]i) were studied in the isolated rat atrium. The stretch of the atrium was produced by increasing the intra-atrial pressure of the paced and superfused preparation. Contraction force was estimated from pressure pulses generated by the contraction of the atrium. Intracellular Ca2+was measured from indo 1-AM-loaded atria, and ANP was measured by radioimmunoassay from the perfusate samples collected during interventions. Intracellular pH of the atrial myocytes was measured by a fluorescent indicator (BCECF)-based imaging system. Intracellular acidification caused by 20 mM propionic acid (0.18 pH units) potentiated the stretch-induced (intra-atrial pressure from 1 to 4 mmHg) ANP secretion, causing a twofold secretion compared with nonacidotic controls. Simultaneously, the responsiveness of the atrial contraction to stretch was reduced ( P < 0.05, n = 7). Stretch augmented the systolic indo 1-AM transients in acidic ( P < 0.05, n = 6) and nonacidic atria ( P < 0.05, n = 6). However, during acidosis this was accompanied by an increase of the diastolic indo 1-AM ratio ( P < 0.05, n = 6). Cooccurrence of stretch and acidosis caused an increase in systolic and diastolic [Ca2+]iand potentiated the stretch-induced ANP secretion, whereas the contraction force and its stretch sensitivity were decreased. This mechanism may be involved in ischemia-induced ANP secretion, suggesting a role for ANP secretion as an indicator of contractile dysfunction.
Expression of FAS adjacent to fibrotic foci in the failing human heart is not associated with increased apoptosis
Authors: Filippatos Gerasimos , Leche Carlos , Sunga Ruben , Tsoukas Anthony , Anthopoulos Prodromos , Joshi Iravati , Bifero Antonio , Pick Ruth , Uhal Bruce D.
Published: December 2017

Fibrosis in the heart may result from loss of myocytes, which are replaced by collagens. Apoptosis is now known to contribute to myocyte loss in the failing human heart. The mechanisms underlying the induction of cardiomyocyte apoptosis, and thus the expansion of fibrotic foci in the failing heart, are poorly understood. We hypothesized that viable heart cells adjacent to fibrotic foci might become “predisposed” to apoptosis by expression of the receptor FAS (APO1, CD95). We therefore studied the spatial relationship of FAS expression and fibrosis in patients with heart failure. Left ventricular biopsies were obtained from seven patients undergoing coronary artery bypass grafting. All patients had reduced ejection fraction but varied in New York Heart Association class score at the time of surgery. Heart cell apoptosis, fibrosis, and FAS expression were studied by propidium iodide and in situ end labeling (ISEL) of DNA, Picrosirius red staining, and immunohistochemistry. All patient samples exhibited, albeit to varying degrees, apoptosis detected by ISEL, chromatin condensation, and nuclear fragmentation. In all samples, fibrosis (collagen) was evident both perivascular and in isolated regions of scarring. Regardless of the extent of fibrosis or detectable apoptosis, FAS expression was observed in regions immediately adjacent to the fibrosis, but not in regions distal to fibrosis, nor in fibrotic areas devoid of nuclei. Expression of FAS was found adjacent to both perivascular and diffuse fibrosis, and ISEL-positive nuclei were found within cells reacting positively with anti-FAS antibodies. However, ISEL-positive nuclei were no more abundant in FAS-positive regions (67.6 ± 5.8% of total nuclei) than in FAS-negative areas (69.5 ± 9.8%). We conclude that expression of FAS occurs in remaining heart cells adjacent to fibrosis of either perivascular or presumed reparative origin. Although this phenomenon could contribute to the expansion of fibrotic foci, FAS-induced apoptosis in the failing heart may not be more prevalent than apoptosis initiated by other signaling mechanisms.
Permeation of the luminal capillary glycocalyx is determined by hyaluronan
Authors: Henry Charmaine B. S. , Duling Brian R.
Published: December 2017

The endothelial cell glycocalyx influences blood flow and presents a selective barrier to movement of macromolecules from plasma to the endothelial surface. In the hamster cremaster microcirculation, FITC-labeled Dextran 70 and larger molecules are excluded from a region extending almost 0.5 μm from the endothelial surface into the lumen. Red blood cells under normal flow conditions are excluded from a region extending even farther into the lumen. Examination of cultured endothelial cells has shown that the glycocalyx contains hyaluronan, a glycosaminoglycan which is known to create matrices with molecular sieving properties. To test the hypothesis that hyaluronan might be involved in establishing the permeation properties of the apical surface glycocalyx in vivo, hamster microvessels in the cremaster muscle were visualized using video microscopy. After infusion of one of several FITC-dextrans (70, 145, 580, and 2,000 kDa) via a femoral cannula, microvessels were observed with bright-field and fluorescence microscopy to obtain estimates of the anatomic diameters and the widths of fluorescent dextran columns and of red blood cell columns (means ± SE). The widths of the red blood cell and dextran exclusion zones were calculated as one-half the difference between the bright-field anatomic diameter and the width of the red blood cell column or dextran column. After 1 h of treatment with active Streptomyces hyaluronidase, there was a significant increase in access of 70- and 145-kDa FITC-dextrans to the space bounded by the apical glycocalyx, but no increase in access of the red blood cells or in the anatomic diameter in capillaries, arterioles, and venules. Hyaluronidase had no effect on access of FITC-Dextrans 580 and 2,000. Infusion of a mixture of hyaluronan and chondroitin sulfate after enzyme treatment reconstituted the glycocalyx, although treatment with either molecule separately had no effect. These results suggest that cell surface hyaluronan plays a role in regulating or establishing permeation of the apical glycocalyx to macromolecules. This finding and our prior observations suggest that hyaluronan and other glycoconjugates are required for assembly of the matrix on the endothelial surface. We hypothesize that hyaluronidase creates a more open matrix, enabling smaller dextran molecules to penetrate deeper into the glycocalyx.
Alterations in sarcoplasmic reticulum function and gene expression in ischemic-reperfused rat heart
Authors: Temsah Rana M. , Netticadan Thomas , Chapman Donald , Takeda Satoshi , Mochizuki Seibu , Dhalla Naranjan S.
Published: December 2017

In view of the critical role of sarcoplasmic reticular (SR) Ca2+release and the Ca2+pump in cardiac contraction-relaxation, this study was undertaken to assess the status of SR function, protein content, and gene expression in isolated rat hearts subjected to global ischemia for 30 min followed by 60 min of reperfusion (I/R). Attenuated recovery of contractile function in the I/R hearts was associated with reduced SR Ca2+uptake, Ca2+release, and ryanodine-binding activities. mRNA levels and protein contents for SR Ca2+pump ATPase and Ca2+release channels were markedly depressed in the I/R hearts. Perfusion of hearts with superoxide dismutase plus catalase, well-known scavengers of oxyradicals, prevented the I/R-induced alterations in cardiac function and partially prevented SR Ca2+transport activities and mRNA abundance. In hearts perfused with xanthine plus xanthine oxidase or H2O2, changes similar to those in the I/R hearts were observed. These results indicate that oxyradicals may participate in depressing the SR Ca2+handling and gene expression in the I/R heart. It is suggested that treatment of hearts with antioxidants may improve the recovery of cardiac function by preserving the SR function and partially protecting the SR gene expression.
Ischemic muscle chemoreflex response elevates blood flow in nonischemic exercising human forearm muscle
Authors: Tschakovsky M. E. , Hughson R. L.
Published: December 2017

We tested the hypothesis that forearm blood flow (FBF) might be reduced during forearm exercise when a vasoconstrictor response was evoked by calf exercise during calf ischemia (CE + I). In nine healthy subjects, brachial artery FBF and finger-cuff mean arterial pressure (MAP) were measured beat by beat during rest and forearm exercise. CE + I initiated before 5 min of forearm exercise ( condition A) increased MAP by 24% and reduced resting forearm vascular conductance (FVC) by 24% such that FBF remained at the same level as without CE + I (control, condition C). With the onset of forearm exercise, the difference in FVC between condition A and condition C was abolished; consequently, the FBF adaptation to exercise was greater after 3 min of exercise in condition A (247.0 ± 14.8 ml/min) than in condition C(197.1 ± 9.4 ml/min, P< 0.05) because of the elevated MAP. Gradual stimulation of the chemoreflex by the addition of CE + I at 3 min of a 9-min bout of forearm exercise ( condition B) did not affect FVC such that progressive elevations in MAP resulted in proportional increases in FBF. We concluded that chemoreflex-mediated increases in systemic sympathetic nervous activity appear to affect resting FVC. Evidence from this study suggests that local factors responsible for initiating and maintaining vasodilation during moderate, small-muscle mass exercise can quickly override this vasoconstrictor influence such that FBF is elevated during exercise in direct proportion to the elevation in MAP.
Visible-light photon migration through myocardium in vivo
Authors: Gandjbakhche Amir H. , Bonner Robert F. , Arai Andrew E. , Balaban Robert S.
Published: December 2017

Empirical data between 510 and 590 nm of diffuse reflected light from the pig heart in vivo have shown that myoglobin and cytochrome c absorption peaks with little apparent contribution of red blood cell (RBC) Hb. Monte Carlo simulations of photon migration in tissue were performed to compare the effects of myoglobin and cytochromes with those of blood Hb on photon pathlengths and diffuse reflectance of visible wavelengths (450–600 nm) from the pig heart in vivo. Wavelength dependence of the input parameters, including the transport-corrected scattering coefficients (1.1–1.2 mm−1) and the absorption coefficients of blood-free solubilized heart tissue (0.43–1.47 mm−1), as well as the absorption coefficients of Hb, were determined by an integrating sphere method and standard spectrophotometry, respectively. The Monte Carlo simulations indicate that in the 510- to 590-nm range the mean path length within the myocardium for diffusely reflected light varies from 1.4 to 1.2 mm, whereas their mean penetration depth within the epicardium is only 330–400 μm for blood-free heart tissue. Analysis shows that the blood Hb absorption extrema are only observable between 510 and 590 nm when RBC concentration in tissue is >0.5%. Blood within vessels much larger than capillaries does not contribute significantly to the spectral features, because virtually all light in this spectral range is absorbed during transit through large vessels (>100 μm). This analysis suggests that diffuse reflected light in the 510- to 590-nm region will show spectral features uniquely associated with myoglobin and cytochrome c oxygenation states within 400 μm of the surface of the heart in situ as long as the capillary RBC concentration remains <0.5%.
Rise in endothelium-derived NO after stimulation of rat perivascular sympathetic mesenteric nerves
Authors: Boric Mauricio P. , Figueroa Xavier F. , Donoso M. Verónica , Paredes Alfonso , Poblete Inés , Huidobro-Toro J. Pablo
Published: December 2017

To evaluate whether sympathetic activity induces nitric oxide (NO) production, we perfused the rat arterial mesenteric bed and measured luminally accessible norepinephrine (NE), NO, and cGMP before, during, and after stimulation of perivascular nerves. Electrical stimulation (1 min, 30 Hz) raised perfusion pressure by 97 ± 7 mmHg, accompanied by peaks of 23 ± 3 pmol NE, 445 ± 48 pmol NO, and 1 pmol cGMP. Likewise, perfusion with 10 μM NE induced vasoconstriction coupled to increased NO and cGMP release. Electrically elicited NO release depended on stimulus frequency and duration. Endothelium denudation with saponin abolished the NO peak without changing NE release. Inhibition of NO synthase with 100 μM N ω-nitro-l-arginine reduced basal NO and cGMP release and blocked the electrically stimulated and exogenous NE-stimulated NO peak while enhancing vasoconstriction. Blocking either sympathetic exocytosis with 1 μM guanethidine or α1-adrenoceptors with 30 nM prazosin abolished the electrically evoked vasoconstriction and NO release. α2-Adrenoceptor blockade with 1 μM yohimbine reduced both vasoconstriction and NO peak while increasing NE release. In summary, sympathetically released NE induces vasoconstriction, which triggers a secondary release of endothelial NO coupled to cGMP production.
Mitochondrial transporter responsiveness and metabolic flux homeostasis in postischemic hearts
Authors: O’Donnell J. Michael , White Lawrence T. , Lewandowski E. Douglas
Published: December 2017

The transport of metabolites between mitochondria and cytosol via the α-ketoglutarate-malate carrier serves to balance flux between the two spans of the tricarboxylic acid (TCA) cycle but is reduced in stunned myocardium. To examine the mechanism for reduced transporter activity, we followed the postischemic response of metabolite influx/efflux from mitochondria to stimulation of the malate-aspartate (MA) shuttle. Isolated rabbit hearts were either perfused with 2.5 mM [2-13C]acetate ( n = 7) or similarly reperfused ( n = 5) after 10-min ischemia. In other hearts, the MA shuttle was stimulated with a high cytosolic redox state (NADH) induced by 2.5 mM lactate in normal ( n = 6) or reperfused hearts ( n = 7). In normal hearts, the MA shuttle response accelerated transport from 8.3 ± 3.4 to 16.2 ± 5.0 μmol ⋅ min−1⋅ g dry wt−1. Although transport was reduced in stunned hearts, the MA shuttle was responsive to cytosolic NADH load, increasing transport from 3.4 ± 1.0 to 9.8 ± 3.7 μmol ⋅ min−1⋅ g dry wt−1. Therefore, metabolite exchange remains intact in stunned myocardium but responds to changes in TCA cycle flux regulation.
Physiological and molecular characterization of the Na+/Ca2+exchanger in human platelets
Authors: Kimura Masayuki , Jeanclos Elisabeth M. , Donnelly Robert J. , Lytton Jonathan , Reeves John P. , Aviv Abraham
Published: December 2017

In this report, we have demonstrated that Na+/Ca2+exchanger activity in a human megakaryocytic cell line (CHRF-288 cells) is K+dependent, similar to the properties previously described for Na+/Ca2+exchange activity in human platelets. With the use of RT-PCR techniques and mRNA, the exchanger expressed in CHRF-288 cells was found to be identical to that expressed in human retinal rods. Northern blot analysis of the mRNA for the human retinal rod exchanger in CHRF-288 cells revealed a major transcript at 5.8 kb with two minor bands at 4.9 and 6.8 kb. mRNA for the retinal rod exchanger was also identified in human platelets. Using Ba2+influx as a measure of Na+/Ca2+exchange activity in human platelets, we have demonstrated that exchange activity is driven by the transmembrane gradient for K+as well as that for Na+. We propose that the K+dependence of the platelet Na+/Ca2+exchanger could make platelets especially sensitive to daily fluctuations in salt intake.
Lack of age-associated elevations in 24-h systolic and pulse pressures in women who exercise regularly
Authors: Seals Douglas R. , Stevenson Edith T. , Jones Pamela P. , DeSouza Christopher A. , Tanaka Hirofumi ,   (With the Technical Assistance of Cyndi Long and Mary Jo Reiling)
Published: December 2017

We tested the hypothesis that the elevations in 24-h arterial systolic (SBP) and pulse (PP) pressures with age in sedentary adult females are absent or smaller in women who exercise regularly. Four groups of healthy normotensive women were studied: premenopausal ( n = 12; 29 ± 1 yr, mean ± SE) and postmenopausal ( n = 20; 62 ± 1) sedentary, and premenopausal ( n = 14; 30 ± 1) and postmenopausal ( n= 12; 58 ± 1) endurance-exercise trained (distance runners). In the sedentary group, 24-h SBP and PP (Spacelabs ambulatory monitor 90207) were ∼10 mmHg higher ( P < 0.05) in the postmenopausal women than in the premenopausal controls; this was because of higher daytime and nighttime SBP and PP levels in the postmenopausal women. In contrast, 24-h, daytime and nighttime SBP and PP were not different with age in the endurance-trained women. SBP variability and SBP load (% of all recordings > 140 mmHg) generally were greater with age in the sedentary women (e.g., SBP load = 14 ± 4 vs. 3 ± 1%, P < 0.05) but not in the endurance-trained women. In the pooled population, 24-h SBP and PP were related to waist-to-hip ratio (measure of abdominal adiposity) ( r = 0.48 and 0.49, respectively, P < 0.001) and carotid augmentation index (measure of arterial stiffness) ( r = 0.43 and 0.53, P < 0.005). In the sedentary women, accounting for the influence of either of these factors eliminated the significant age-associated differences in 24-h SBP and PP ( P > 0.3). Our results suggest that the elevations in 24-h SBP and PP with age in sedentary adult females may not occur in women who regularly perform endurance exercise. This appears to be related to the absence of age-associated increases in abdominal adiposity and arterial stiffness in the exercising women.
Mechanism for the effects of extracellular acidification on HERG-channel function
Authors: Jiang Min , Dun Wen , Tseng Gea-Ny
Published: December 2017

Human ether-à-go-go-related gene ( HERG) encodes a K channel similar to the rapid delayed rectifier channel current ( I Kr) in cardiac myocytes. Modulation of I Kr by extracellular acidosis under pathological conditions may impact on cardiac electrical activity. Therefore, we studied the effects of extracellular acidification on I Kr function and the underlying mechanism, using HERGexpressed in Xenopus oocytes as a model. Acidification [extracellular pH (pHo) 8.5–6.5] accelerated HERG deactivation (at −80 mV, the time constant τ of the major component of deactivation was 253 ± 17, 158 ± 10, and 65 ± 5 ms at pHo 8.5, 7.5, and 6.5, respectively; n = 7–10 each), with no effects on other gating kinetics except a modest acceleration of recovery from inactivation (at −80 mV, τ of recovery was 4.7 ± 0.3, 3.8 ± 0.3, and 1.3 ± 0.2 ms at pHo 8.5, 7.5, and 6.5, respectively; n = 4–7 each). The following were ruled out as the underlying mechanisms: 1) voltage shift in channel activation, 2) pore blockade by protons, 3) protonation of histidines on the extracellular domain of HERG, 4) acceleration of recovery from C-type inactivation, and 5) interaction between an external H+binding site and the cytoplasmic NH2-terminal domain (a key determinant of HERG deactivation rate). Extracellular application of diethylpyrocarbonate caused an irreversible acceleration of HERG deactivation and prevented further acceleration by external acidification. Our data suggest that side chains accessible to the extracellular solution mediated the effects of elevating extracellular H+ concentration on channel deactivation.
Cardiac autonomic responses to volume overload in normal subjects and in patients with dilated cardiomyopathy
Authors: Spinelli L. , Petretta M. , Marciano F. , Testa G. , Rao M. A. E. , Volpe M. , Bonaduce D.
Published: December 2017

This study evaluated the effects of acute isotonic volume expansion on heart rate variability (HRV) in 10 patients with dilated cardiomyopathy (DCM) and in 10 age- and sex-matched normal volunteers. Echocardiographic left ventricular volumes and HRV measurements by continuous Holter recording were assessed at baseline, at 60 and 120 min during intravenous saline load (0.9% NaCl, 0.25 ml ⋅ kg−1 ⋅ min−1), and 60 min after infusion was terminated. Data analysis was performed by repeated-measures ANOVA. After volume expansion, left ventricular ejection fraction increased ( F = 9.8; P < 0.001) in normal subjects and decreased ( F = 8.7; P < 0.001) in DCM patients. During volume expansion a significant difference was also detectable between the two groups in root-mean-square successive difference ( F = 25.2; P < 0.001), percentage of differences between successive normal R-R intervals >50 ms ( F = 97.6; P < 0.001), high-frequency power ( F = 50.1; P < 0.001), and low-frequency power ( F = 41.6; P < 0.001), all of which reflect parasympathetic modulation of heart rate; in fact, these measurements increased in normal subjects and decreased in DCM patients. In normal subjects, the increase in HRV measurements during volume expansion suggests a parasympathetic activation, mediated by stimulation of cardiopulmonary and arterial mechanoreceptors. On the contrary, in DCM patients the parasympathetic withdrawal, already detectable at baseline, increases during volume expansion.
Dynamic adaptation of cardiac oxidative phosphorylation is not mediated by simple feedback control
Authors: van Beek J. H. G. M. , van Wijhe M. H. , Eijgelshoven M. H. J. , Hak J. B.
Published: December 2017

The classic idea about regulation of cardiac oxidative phosphorylation (OxPhos) was that breakdown products of ATP (ADP and Pi) diffuse freely to the mitochondria to stimulate OxPhos. On the basis of this metabolic feedback control system, the response time of OxPhos ( tmito) is predicted to be inversely proportional to the mitochondrial aerobic capacity (MAC). We determined tmitoduring steps in heart rate in isolated perfused rabbit hearts ( n = 16) before and after reducing MAC with nonsaturating doses of oligomycin. The reduction of MAC was quantified in mitochondria isolated from each perfused heart, dividing oligomycin-sensitive, ADP-stimulated state 3 respiration by oligomycin-insensitive uncoupled respiration. The tmitoto heart rate steps from 60 to 70 and 80 beats/min was 5.6 ± 0.6 and 7.2 ± 0.8 s (means ± SE) and increased an estimated 34 and 40% for a 50% decrease in MAC ( P < 0.05), respectively, which is much less than the 100% predicted by the feedback hypothesis. For steps to 100 or 120 beats/min, tmitowas 8.3 ± 0.5 and 11.2 ± 0.6 s and was not reduced with decreases in MAC ( P > 0.05). We conclude that immediate feedback control by quickly diffusing ADP and Picannot explain the dynamic regulation of cardiac OxPhos. Because calcium entry into the mitochondria also cannot explain the first fast phase of OxPhos activation, we propose that delay of the energy-related signal in the cytoplasm dominates the response time of OxPhos.
Role of cytochromeP-450 4A in oxygen sensing and NO production in rat cremaster resistance arteries
Authors: Kerkhof Cornel J. M. , Bakker Erik N. T. P. , Sipkema Pieter
Published: December 2017

The role of arachidonic acid metabolism and nitric oxide (NO) in hypoxia-induced changes of vascular tone was investigated in first-order cannulated rat cremaster muscle resistance arteries. Spontaneous tone reduced arterial diameter from 179 ± 2 μm (fully dilated) to 98 ± 3 μm under normoxia ([Formula: see text] = 150 mmHg). Hypoxia ([Formula: see text] 5–10 mmHg) had no significant effect on arterial diameter under conditions of spontaneous tone. The effect of hypoxia was not changed after blockade of cyclooxygenase with indomethacin or after blockade of lipoxygenase with nordihydroguaiaretic acid. However, after partial blockade of cytochrome P-450 4A enzymes with 17-octadecynoic acid (17-ODYA), hypoxia increased the diameter by 65 ± 6 μm ( P < 0.05). This increase could be inhibited by NG-nitro-l-arginine (l-NNA) or 20-hydroxyeicosatetraenoic acid (20-HETE). 17-ODYA induced a concentration-dependent dilation under normoxia, which could be blocked by endothelium removal orl-NNA. 17-ODYA did not increase smooth muscle sensitivity to NO. We conclude that, under conditions of spontaneous tone and in the absence of luminal flow, hypoxia (5–10 mmHg) has no effect on the diameter of resistance arteries from the rat cremaster muscle. Inhibition of the cytochrome P-450 4A pathway of arachidonic acid metabolism under normoxia induces NO production by the endothelium. Hypoxia induces an NO-mediated dilation when cytochrome P-450 4A enzymes are partially inhibited.
Sustained JNK activation induces endothelial apoptosis: studies with colchicine and shear stress
Authors: Hu Ying-Li , Li Song , Shyy John Y.-J. , Chien Shu
Published: December 2017

The disruption of microtubules by treating bovine aortic endothelial cells with 10−7–10−5M colchicine caused apoptosis, as evidenced by DNA laddering and TdT-mediated dUTP nick end labeling fluorescence staining. Colchicine treatment also induced a sustained activation of c-Jun NH2-terminal kinase (JNK) that lasted for ≥12 h. The blockade of JNK activity by using the negative interfering mutant JNK(K-R) markedly decreased the apoptosis induced by colchicine. Exposure of bovine aortic endothelial cells to laminar shear stress (12 dyn/cm2) caused a transient (<2 h) activation of JNK, and there was no induction of apoptosis. The sustained activation of JNK may play a significant role in the apoptosis induced by colchicine.
Ca2+-dependent Cl−channels in mouse and rabbit aortic smooth muscle cells: regulation by intracellular Ca2+and NO
Authors: Hirakawa Yoji , Gericke Marion , Cohen Richard A. , Bolotina Victoria M.
Published: December 2017

Ca2+-dependent Cl−([Formula: see text]) channels and their regulation by intracellular Ca2+concentration ([Ca2+]i) and nitric oxide (NO) were characterized in mouse and rabbit aortic smooth muscle cells (SMC) using patch clamp and fura 2 imaging. Single channels (1.8 pS) and whole cell[Formula: see text] currents were activated by caffeine-induced Ca2+release. Single [Formula: see text] channels were also activated by ≥200 nM Ca2+in inside-out membrane patches and remained active for >5 min in ≤1 μM Ca2+but showed rapid rundown in 2 mM Ca2+. Authentic NO or S-nitroso- N-acetylpenicillamine (SNAP) did not affect their activation or rundown in inside-out patches. In the whole cell, SNAP (100 μM) and 8-(4-chlorophenylthio)-guanosine 3′,5′-cyclic monophosphate (50 μM) did not affect [Formula: see text]current, but at a higher concentration SNAP (1 mM) induced a sustained [Ca2+]irise, accompanied by a dramatic decrease in caffeine-induced Ca2+release and[Formula: see text] current. These results indicate that 1) mouse and rabbit aortic SMC possess 1.8-pS [Formula: see text]channels that are activated by Ca2+release from the stores, 2) both activation and rundown of single [Formula: see text] channels depend on [Ca2+]i, and 3) NO does not affect[Formula: see text] channels directly or via cGMP but can inhibit their activation indirectly by decreasing Ca2+release from the stores.
Musical rhythms in heart period dynamics: a cross-cultural and interdisciplinary approach to cardiac rhythms
Authors: Bettermann H. , Amponsah D. , Cysarz D. , van Leeuwen P.
Published: December 2017

The purpose of this study was to expand classic heart period analysis methods by techniques from ethnomusicology that explicitly take complex musical rhythm principles into consideration. The methods used are based on the theory of African music, the theory of symbolic dynamics, and combinatorial theory. Heart period tachograms from 192 24-h electrocardiograms of 96 healthy subjects were transformed into binary symbol sequences that were interpretable as elementary rhythmic (percussive) patterns, the time lines in African music. Using a hierarchical rhythm pattern scheme closely related to the Derler Rhythm Classification (from jazz theory), we calculated the predominance and stability of pattern classes. The results show that during sleep certain classes, specific to individuals, occurred in a cyclically recurrent manner and many times more often than expected. Simultaneously, other classes disappeared more or less completely. Moreover, the most frequent classes obviously originate from phase-locking processes in autonomic regulation (e.g., between respiratory and cardiac cycles). In conclusion, the new interdisciplinary method presented here demonstrates that heart period patterns, in particular those occurring during night sleep, can be interpreted as musical rhythms. This method may be of great potential use in music therapy research.
cAMP production by piglet cerebral vascular smooth muscle cells: pHo, pHi, and permissive action of PGI2
Authors: Leffler Charles W. , Balabanova Liliya , Williams K. Keven
Published: December 2017

In newborn pig pial arterioles and cocultures of cerebral microvascular endothelial and smooth muscle cells, hypercapnia increases cAMP. In the intact cerebral circulation, both the increase in cAMP and the accompanying vasodilation require the presence of PGI2. Using piglet cerebral microvascular smooth muscle in primary culture, we addressed the hypothesis that, in the presence of PGI2, hypercapnia-induced changes in extracellular pH cause increases in cAMP. The stable PGI2-receptor agonist iloprost did increase production of cAMP in response to combined extracellular pH and pHi (11 ± 6 vs. 32 ± 10% in the absence and presence of 10−10 M iloprost, respectively). However, there was no positive dose-response relationship between iloprost concentration and stimulation of cAMP production by acidosis (e.g., 58 ± 9 vs. 41 ± 5% in the presence of 10−12 and 10−9 M iloprost, respectively). Rapid decreases in pHi stimulate the cAMP production. Decreases in extracellular pH do not appear to contribute further. The G protein inhibitor pertussis toxin did not augment cAMP production in response to decreasing pHi. We conclude that PGI2 receptor activation permits another mechanism to enhance cAMP generation in response to intracellular, but not extracellular, acidosis and that the mechanism of the permissive effect of PGI2 does not involve inhibition of a pertussis toxin-sensitive G protein.
A3adenosine receptor activation attenuates neutrophil function and neutrophil-mediated reperfusion injury
Authors: Jordan James E. , Thourani Vinod H. , Auchampach John A. , Robinson Jill A. , Wang Ning-Ping , Vinten-Johansen Jakob
Published: December 2017

This study tested the hypothesis that A3adenosine receptors inhibit neutrophil (PMN) function and PMN-mediated reperfusion injury. 2-Chloro- N6-(3-iodobenzyl)adenosine-5′- N-methyluronamide (Cl-IB-MECA), an A3agonist, did not attenuate superoxide production or myeloperoxidase release from stimulated PMNs. However, Cl-IB-MECA reduced platelet-activating factor-stimulated PMN adherence to coronary endothelium at low concentrations: 52 ± 27, 45 ± 10, and 87 ± 23 PMNs/mm2at 0.1, 1.0, and 10 nM vs. 422 ± 64 PMNs/mm2with platelet-activating factor alone. This inhibition was not blocked by A1(5 μM KW-3902) or A2a(5 μM KF-21326) antagonists: 44 ± 3 and 43 ± 2 PMNs/mm2, respectively. Endothelial pretreatment with 1 nM Cl-IB-MECA reduced PMN adherence, which was reversed by the A3antagonist MRS-1220 (100 nM). PMN-mediated reperfusion injury was initiated in isolated rabbit hearts by infusion of 28 × 106PMNs/min for 10 min early in reperfusion. PMNs caused a significant decrease in recovery of left ventricular developed pressure and positive and negative time derivatives of pressure (23 ± 3, 25 ± 3, and 23 ± 3% of baseline, respectively) vs. buffer-perfused hearts (43 ± 7, 44 ± 7, and 45 ± 6%, respectively). Cl-IB-MECA (10 nM) given at reperfusion attenuated the PMN-mediated loss of contractile recovery (40 ± 3, 46 ± 5, and 42 ± 4% of baseline). Cl-IB-MECA reduced myeloperoxidase release activity (5.3 ± 0.6 absorbance units/min) and CD18-positive cells (54 ± 9 cells/slide) compared with the untreated PMN group (17.9 ± 1.7 absorbance units/min and 183 ± 68 cells/slide). We conclude that Cl-IB-MECA attenuates reperfusion injury by decreasing PMN-endothelial cell interactions. These results suggest that the A3adenosine receptor may be a novel therapeutic target for treatment of myocardial ischemia and reperfusion.
Limitation of arteriolar myogenic activity by local nitric oxide: segment-specific effect of dietary salt
Authors: Nurkiewicz Timothy R. , Boegehold Matthew A.
Published: December 2017

The purpose of this study was to determine if local nitric oxide (NO) activity attenuates the arteriolar myogenic response in rat spinotrapezius muscle. We also investigated the possibility that hypertension, dietary salt, or their combination can alter any influence of local NO on the myogenic response. Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) fed low-salt (0.45%, LS) or high-salt (7%, HS) diets were enclosed in a ventilated airtight box with the spinotrapezius muscle exteriorized for intravital microscopy. Mean arterial pressure was unaffected by dietary salt in WKY but was significantly higher and augmented by dietary salt in SHR. In all experiments, elevation of microvascular pressure by box pressurization caused a 0–30% decrease in the diameter of large (arcade bridge) arterioles and a 21–27% decrease in the diameter of intermediate (arcade) arterioles. Inhibition of NO synthase with N G-monomethyl-l-arginine (l-NMMA) significantly enhanced myogenic responsiveness of arcade bridge arterioles in WKY-LS and SHR-LS but not in WKY-HS and SHR-HS.l-NMMA significantly enhanced the myogenic responsiveness of arcade arterioles in all four groups. Excess l-arginine reversed this effect of l-NMMA in all cases, and arteriolar responsiveness to the NO donor sodium nitroprusside was not different among the four groups. High-salt intake had no effect on the passive distension of arterioles in either strain during box pressurization. We conclude that 1) local NO normally attenuates arteriolar myogenic responsiveness in WKY and SHR, 2) dietary salt impairs local NO activity in arcade bridge arterioles of both strains, and 3) passive arteriolar distensibility is not altered by a high-salt diet in either strain.
Effect of pacing site on ventricular fibrillation initiation by shocks during the vulnerable period
Authors: Idriss Salim F. , Wolf Patrick D. , Smith William M. , Ideker Raymond E.
Published: December 2017

The critical point hypothesis for the upper limit of vulnerability (ULV) states that the site of S1 pacing should not affect the ULV S2 shock strength for a single S2 shock electrode configuration but may affect the S1-S2 interval at which sub-ULV shocks induce ventricular fibrillation (VF). Furthermore, early post-S2 activations leading to VF should arise in areas with low potential gradients of similar magnitude, regardless of the S1 site. This hypothesis was tested in 10 pigs by determining ULVs for three S1 sites [left ventricular apex (LVA), LV base (LVB), and right ventricular outflow tract (RVOT)] with one S2 configuration (LVA patch to superior vena cava catheter). T-wave scanning was performed with biphasic S2 shocks incremented from 60 V in 40-V steps and stepped up or down in 20- and 10-V steps. Activations and S2 potential gradients were recorded at 528 epicardial sites. Although shocks just below the ULV induced VF significantly earlier in the T wave when the S1 site was the RVOT than when it was the LVA or LVB, ULVs were not significantly different for the three S1 pacing sites. Early post-S2 activations arose closer to the S2 electrode for weak S2s but moved to distant low potential gradient areas as the S2 strengthened. Just below the ULV, early post-S2 activations arose in the RVOT when the S1 site was the LVA or LVB but arose along the RV base when the S1 site was the RVOT. Early site potential gradients were not significantly different just below the ULV (LVA: 8.2 ± 4.1 V/cm; LVB: 8.6 ± 4.9 V/cm; RVOT: 8.7 ± 4.4 V/cm). At the ULV, early post-S2 activations arose from the same areas but did not induce VF. The results support the critical point hypothesis for the ULV. For this S2 configuration, no single point in the T wave could be used to determine the ULV for all S1 sites.