bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences in rate dependence of transient outward current in rabbit and human atrium
Authors: Fermini B. , Wang Z. , Duan D. , Nattel S.
Published: December 2017

Both human and rabbit atrial cells possess a large 4-aminopyridine-sensitive transient outward current (I(to1)). However, the slow reactivation of this current in rabbits suggests that its role may be limited to very slow heart rates. We used whole cell voltage-clamp recordings to evaluate the rate dependency of I(to1) in rabbit and human atrial myocytes. Our results show that at physiological temperatures in human atrium, I(to1) is rate independent at rates between 0.1 and 4.0 Hz. Peak I(to1) at 4.0 Hz in rabbit was 3.4 +/- 1.4% (mean +/- SE) of current at 0.1 Hz (P < 0.001, n = 8), whereas in humans, peak I(to1) at 4.0 Hz averaged 88.8 +/- 6.1% of the current at 0.1 Hz (P > 0.05, n = 7). These differences were due to marked discrepancies in reactivation time course, which was biexponential with time constants that averaged 650 +/- 159 ms and 8.4 +/- 1.1 s in rabbit (n = 8) compared with a single exponential time constant of 33.6 +/- 6.8 ms (n = 8) in human atrium (both at 30 degrees C). These findings suggest that I(to1) can contribute importantly to atrial repolarization at all physiological heart rates in humans. Furthermore, these results emphasize that there are important interspecies variations in the rate dependence of I(to1), which need to be considered in understanding the physiological and pharmacological regulation of atrial repolarization.
Blood viscosity in tube flow: dependence on diameter and hematocrit
Authors: Pries A. R. , Neuhaus D. , Gaehtgens P.
Published: December 2017

Since the original publications by Martini et al. (Dtsch. Arch. Klin. Med. 169: 212–222, 1930) and Fahraeus and Lindqvist (Am. J. Physiol. 96: 562–568, 1931), it has been known that the relative apparent viscosity of blood in tube flow depends on tube diameter. Quantitative descriptions of this effect and of the dependence of blood viscosity on hematocrit in the different diameter tubes are required for the development of hydrodynamic models of blood flow through the microcirculation. The present study provides a comprehensive data base for the description of relative apparent blood viscosity as a function of tube diameter and hematocrit. Data available from the literature are compiled, and new experimental data obtained in a capillary viscometer are presented. The combined data base comprises measurements at high shear rates (u > or = 50 s-1) in tubes with diameters ranging from 3.3 to 1,978 microns at hematocrits of up to 0.9. If corrected for differences in suspending medium viscosity and temperature, the data show remarkable agreement. Empirical fitting equations predicting relative apparent blood viscosity from tube diameter and hematocrit are presented. A pronounced change in the hematocrit dependence of relative viscosity is observed in a range of tube diameters in which viscosity is minimal. While a linear hematocrit-viscosity relationship is found in tubes of < or = 6 microns, an overproportional increase of viscosity with hematocrit prevails in tubes of > or = 9 microns. This is interpreted to reflect the hematocrit-dependent transition from single- to multifile arrangement of cells in flow.
Cellular Vmax reflects both membrane properties and the load presented by adjoining cells
Authors: Spach M. S. , Heidlage J. F. , Darken E. R. , Hofer E. , Raines K. H. , Starmer C. F.
Published: December 2017

This study was designed to test the hypothesis that the electrical load seen at a microelectrode impalement site is sensitive to the direction of propagation of the approaching wavefront as a reflection of an altered spatial relationship between the impalement site and the surrounding microscopic electrical boundaries located up- and downstream. These boundaries correspond to the different sizes and shapes of the impaled and surrounding cells as well as to the distribution of the associated electrical connections between the cells. The effects of changes in these geometric relationships on maximum rate of rise of transmembrane potential (Vmax) were investigated in canine ventricular muscle by measuring Vmax in different cells while the direction of propagation was changed from along the longitudinal axis to the transverse axis of the fibers or the direction of conduction was reversed along either of these axes. Comparison of the Vmax values for longitudinal propagation (LP) and transverse propagation (TP), each in one direction, showed that TP Vmax was significantly greater than LP Vmax (P < 0.001). However, the values of Vmax were different from cell to cell during LP (93–139 V/s) and TP (110–181 V/s). The absolute values of LP Vmax and TP Vmax at the same site varied independently of each other, e.g., some of the lowest LP Vmax values occurred at the same site as the highest TP Vmax values. Furthermore, at the same site, Vmax changed considerably when propagation was maintained along the longitudinal axis but the direction of conduction was reversed. Similar prominent changes in Vmax occurred when the direction was reversed along the transverse axis.(ABSTRACT TRUNCATED AT 250 WORDS)
Antibodies to SPARC inhibit albumin binding to SPARC, gp60, and microvascular endothelium
Authors: Schnitzer J. E. , Oh P.
Published: December 2017

Albumin, through its binding to the endothelial glycocalyx, functions as a major determinant of capillary permeability and as a carrier for various small molecules in its transcytosis across continuous endothelium via plasma-lemmal vesicles. Several albumin-binding proteins (ABP) have been identified: three membrane-associated ABP, which we call gp60, gp30, and gp18, and one secreted protein, acidic and rich in cysteine (SPARC). In this study, we used antiserum raised against bovine SPARC (BON) to investigate the possible interrelationships among ABP to better understand their role in binding and transcytosis. BON not only interacted with SPARC secreted by cultured endothelium but also recognized gp60 in lysates of cultured rat, human, and bovine endothelial cells. Purified SPARC inhibited BON interaction with gp60. BON immunoglobulin (Ig)G specifically inhibited albumin binding to both SPARC and gp60 extracts. This effect was eliminated by preabsorption of BON to immobilized SPARC. BON also significantly inhibited albumin binding to cultured microvascular endothelial cells via its interaction with gp60. Anti-SPARC peptide sera were also tested, and one serum raised against a peptide encompassing an NH2-terminal region of SPARC recognized both SPARC and gp60 but did not inhibit albumin binding; gp30 and gp18 were not recognized by any of these anti-SPARC antibodies. These results suggest that SPARC and gp60 are functionally and immunologically related ABP that may share a common albumin-binding domain. gp60 appears to be the major mediator of albumin binding to microvascular endothelium.
Noninvasive quantification of principal strains in normal canine hearts using tagged MRI images in 3-D
Authors: Azhari H. , Weiss J. L. , Rogers W. J. , Siu C. O. , Zerhouni E. A. , Shapiro E. P.
Published: December 2017

Previous studies of myocardial strains have been largely limited to invasive procedures in isolated regions. Utilizing images from tagged magnetic resonance imaging (MRI) in three dimensions (3-D), we noninvasively quantified in vivo endocardial (endo) and epicardial (epi) principal strains (PS) throughout the left ventricle (LV) and tested their uniformity. Seven normal hearts in paced reclosed-chest dogs were studied. Combining long- and short-axis images, 24 myocardial cuboids were tagged at end diastole (ED), imaged at end systole and ED, and reconstructed in 3-D. The cuboids were circumferentially arranged in three parallel approximately 1-cm-thick short-axis slices (8 cuboids/slice). By application of finite strain analysis to each cuboid, the major PS (i.e., magnitude and angle with respect to the circumferential direction of maximal shortening) was calculated for each face. when strains are averaged globally (i.e., using all regions), the average magnitude of endo PS exceeded epi PS approximately twofold: -0.24 +/- 0.07 (SD) vs. -0.11 +/- 0.05 (P < 0.05). On the other hand, the PS angle with respect to the circumferential direction at epi exceeded the angle at endo (P < 0.05) by 33 +/- 36 degrees. Average PS direction at epi, 59 +/- 32 degrees, aligned with the expected fiber direction but was perpendicular to it at endo, 26 +/- 30 degrees. However, significant regional variations were observed from wall to wall and from apex to base. When variations in location were accounted for, the pooled SD for the PS magnitudes dropped to 0.032 and for the direction to only 15 degrees. Furthermore, it was found that the anterior-posterior pair of walls contracted differently (P < 0.05) from the septal-lateral pair of walls. These observations indicate that regional myocardial function is heterogeneous and is location dependent.
Possible equilibration of portal venous and central venous pressures during circulatory arrest
Authors: Tabrizchi R. , Lim S. L. , Pang C. C.
Published: December 2017

The mean circulatory filling pressure technique has been used to assess total body venous tone. It involves measuring central venous pressure (CVP) at 5-8 s following circulatory arrest. This study examines if CVP and portal venous pressure (PVP) equilibrate when circulation is stopped by inflating a balloon implanted in the right atrium. CVP and PVP were measured in the control condition and after intravenous bolus injections of norepinephrine (NE, 1.6 microgram/kg), angiotensin II (ANG II, 1.3 microgram/kg), and isoproterenol (Iso, 0.5 microgram/kg) in conscious and pentobarbital-anesthetized rats. In conscious rats, CVP was similar to PVP after circulatory arrest under conditions of normal, elevated, or reduced vascular tone. In anesthetized rats, CVP was similar to PVP in the control condition and after intravenous bolus injection of NE and Iso but was less than PVP after the administration of ANG II. Therefore, mean circulatory filling pressure may not fully reflect total body venous tone in anesthetized, surgically stressed rats.
Role of PGI2 and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid
Authors: Rosolowsky M. , Campbell W. B.
Published: December 2017

Metabolites of arachidonic acid regulate several physiological processes, including vascular tone. The purpose of this study was to determine which metabolites of arachidonic acid are produced by bovine coronary arteries and which may regulate coronary vascular tone. Arachidonic acid induced a concentration-related, endothelium-dependent relaxation [one-half maximum effective concentration (EC50) of 2 x 10(-7) M and a maximal relaxation of 91 +/- 2% at 10(-5) M] of bovine coronary arteries that were contracted with U-46619, a thromboxane mimetic. The concentration of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), a metabolite of prostaglandin I2 (PGI2), increased from 82 +/- 6 to 328 +/- 24 pg/ml with arachidonic acid (10(-5) M). Treatment with the cyclooxygenase inhibitor indomethacin attenuated arachidonic acid-induced relaxations by approximately 50% and blocked the synthesis of 6-keto-PGF1 alpha. PGI2 caused a concentration-related relaxation (EC50 of 10(-8) M and a maximal relaxation of 125 +/- 11% at 10(-7) M). BW755C, a cyclooxygenase and lipoxygenase inhibitor, inhibited arachidonic acid-induced relaxation to the same extent as indomethacin. When vessels were treated with both indomethacin and BW755C, the inhibition of relaxation was the same as either inhibitor alone. SKF 525a, a cytochrome P-450 inhibitor, reduced arachidonic acid-induced relaxation by approximately 50%. When SKF 525a was given in combination with indomethacin, the relaxation by arachidonic acid was almost completely inhibited. SKF 525a inhibited the synthesis of epoxyeicosatrienoic acids (EETs).(ABSTRACT TRUNCATED AT 250 WORDS)
Age-related changes in endothelial permeability and distribution volume of albumin in rat aorta
Authors: Belmin J. , Corman B. , Merval R. , Tedgui A.
Published: December 2017

Age-related changes in macromolecular transport across the arterial wall were investigated in 10-, 20-, and 30-mo-old WAG/Rij rats. Animals were injected with 125I- and 131I-labeled albumin, 90 and 5 min before they were killed, respectively. The transmural distribution of relative concentration of tracers in the aortic wall was obtained using en face serial sectioning technique. The apparent endothelial permeability to albumin calculated from the distribution of 5-min 131I-labeled albumin concentrations was significantly enhanced in 20- and 30-mo-old rats compared with 10-mo-old rats. The apparent distribution volume of albumin within the media, estimated as the mean medial 125I-labeled albumin concentration, was not significantly changed in 20-mo-old rats but was significantly decreased in the 30-mo-old animals. These age-related changes in the macromolecular transport suggest that the entry of plasma macromolecules in the aged arterial wall might be enhanced, whereas the efflux through the media may be impeded, possibly contributing to their trapping in the subendothelium.
Competition between palmitate and ketone bodies as fuels for the heart: study with positron emission tomography
Authors: Vanoverschelde J. L. , Wijns W. , Kolanowski J. , Bol A. , Decoster P. M. , Michel C. , Cogneau M. , Heyndrickx G. R. , Essamri B. , Melin J. A.
Published: December 2017

To test the ability of ketone bodies to inhibit myocardial fatty acid oxidation in vivo, the myocardial clearance kinetics of [1–11C]palmitate was assessed with positron emission tomography in six fasted volunteers and six instrumented dogs, studied repeatedly before and during infusion of 3-hydroxybutyrate (17 mumol.kg-1 x min-1). With the use of multiexponential fitting of tissue time-activity curves, the size, half time (T1/2), and index of the early rapid phase of 11C myocardial clearance, reflecting palmitate oxidation, were calculated. In humans, the relative size (-28%, P < 0.001) and index (-37%, P < 0.01) of the early rapid phase decreased significantly during infusion of 3-hydroxybutyrate, consistent with decreased fatty acid oxidation. Paradoxically, T1/2 decreased from 10.1 +/- 1.6 to 7.4 +/- 1.1 min (P < 0.01). To elucidate possible mechanisms, multiple coronary arteriovenous samples were obtained from the dogs to assess the efflux of oxidized and nonmetabolized tracer. Infusion of 3-hydroxybutyrate resulted in decreased myocardial [11C]CO2 production (-40%, P < 0.05) and reduced palmitate retention (-38%, P < 0.05). In three dogs, the arteriovenous difference in radiolabeled palmitate became negative 10 min after injection, indicating backdiffusion of nonmetabolized tracer from the myocardium. Thus a steady-state infusion of 3-hydroxybutyrate, resulting in physiological plasma levels, alters [1-11C]palmitate kinetics in vivo by decreasing myocardial long-chain fatty acid oxidation and by increasing backdiffusion of nonmetabolized tracer.
Spontaneous contractions of isolated bat wing venules are inhibited by luminal flow
Authors: Davis M. J.
Published: December 2017

The hypothesis that spontaneous contractions of bat wing venules could be modulated by luminal flow was tested. Single venules (114 +/- 5 microns diam) from the wings of anesthetized pallid bats were dissected, cannulated, and pressurized in vitro. A dual reservoir system was used to independently control luminal pressure and flow. In the absence of flow, and with pressure set to 10 cmH2O, all venules contracted spontaneously at rates between 20 and 40 cycles/min. Pressure elevation over the range of 3-10 cmH2O caused a rapid increase in contraction frequency and decrease in amplitude; pressure reduction caused a rapid decrease in contraction frequency and increase in amplitude. In contrast, initiation of flow resulted in a delayed and gradual reduction of contraction amplitude and/or frequency (sometimes to zero). The net effect of flow was to increase mean diameter and decrease the product of frequency x cross-sectional area. Flow-induced inhibition of venular contraction was eliminated by endothelial denudation but persisted in the presence of NG-monomethyl-L-arginine (10(-4) M) or indomethacin (10(-5) M) in concentrations that blocked the effects of exogenously applied ATP or arachidonic acid, respectively. The flow-induced venular response also persisted in the presence of superoxide dismutase (55 U/ml). Denuded venules responded to flow when placed downstream (i.e., perfused in series) from venules with intact endothelium. These results indicate that luminal flow can modulate the contractile function of bat wing venules via release of a transferable substance from the endothelium. The exact nature of the substance is not yet known but it does not appear to be classical endothelium-derived relaxing factor, a prostaglandin, or an oxygen radical.
Characterization of CBF response to somatosensory stimulation: model and influence of anesthetics
Authors: Lindauer U. , Villringer A. , Dirnagl U.
Published: December 2017

We investigated the cerebral blood flow (CBF) response to somatosensory stimulation. Stimulation of neuronal activity was performed by deflection (2-3/s) of the mystacial vibrissae in rats over a period of 60 s, and regional cortical CBF was measured continuously in the contralateral somatosensory cortex with laser-Doppler flowmetry. CBF within the somatosensory cortex was studied through the parietal bone thinned to translucency (n = 7) or through a closed cranial window with the dura mater removed (n = 7). In addition, the differential effect of anesthetics (halothane-N2O, n = 5; thiobutabarbiturate, n = 5; and alpha-chloralose, n = 7) on the CBF response to stimulation was investigated. After a rapid increase after stimulation onset (maximum reached within 2-3 s), CBF remained above baseline with a slight tendency to decrease despite continued stimulation. On termination of stimulation, CBF fell to near prestimulation values within 2-3 s. The following mean CBF responses above baseline during the 60-s stimulation period were obtained: halothane-N2O anesthesia, 25.4 +/- 5.9%; thiobutabarbiturate anesthesia, 10.6 +/- 2.4%; and alpha-chloralose anesthesia, 16.9 +/- 2.3 (through the translucent bone) and 16.2 +/- 2.9% (closed cranial window, dura removed). We conclude that coupling of CBF to neuronal function has a very high temporal resolution (< 3 s) and that whisker deflection in rats provides a physiological stimulus to study coupling with laser-Doppler flowmetry.
Loss of cardiac myofibrils: mechanism of contractile deficits induced by taurine deficiency
Authors: Lake N.
Published: December 2017

It is well established that taurine deficiency is associated with myocardial contractile dysfunction; however, the mechanism is unknown. As a follow-up to finding reduced force generation in taurine-depleted rat cardiac trabeculae, using either calcium or strontium activation, this study examined alterations in ventricular fine structure and contractile proteins in animals made taurine deficient by in vivo treatment with a taurine transport antagonist, guanidinoethane sulfonate. Observations of ventricular ultrastructure showed disordered contractile filaments and clear losses of myofibrillar bundles in association with taurine deficiency. Biochemical analyses of ventricular contractile proteins using polyacrylamide gel electrophoresis confirmed losses of the major sarcomeric proteins, myosin and actin. These findings provide a possible mechanism for the contractile deficits and cardiomyopathy described in taurine-deficient animals.
Hypercapnia slightly raises blood volume and sizably elevates flow velocity in brain microvessels
Authors: Bereczki D. , Wei L. , Otsuka T. , Hans F. J. , Acuff V. , Patlak C. , Fenstermacher J.
Published: December 2017

The increase in local cerebral blood flow (LCBF) caused by hypercapnia may be mainly accomplished by raising the velocity of plasma and/or red blood cell (RBC) flow through the microvessels and not by perfusing more capillaries. This suggestion was tested in awake rats exposed to 8% CO2 and in control rats. LCBF was measured by the 14C-labeled iodoantipyrine method. The volume of blood in small parenchymal microvessels was estimated from the distribution spaces of 125I-labeled serum albumin (RISA) and 55Fe-labeled RBCs. Hypercapnia elevated LCBF 2.0- to 3.5-fold in the 40 brain areas studied, marginally raised the RBC spaces, and significantly increased the RISA and whole blood distribution spaces (approximately 25 and 19%, respectively). These changes in microvessel distribution volumes could be the result of perfusing a slightly larger fraction of capillaries (recruitment), increasing microvessel diameter somewhat, or both. With hypercapnia, the mean transit times fell to approximately 45% of control, which indicated that LCBF was mainly increased by raising the velocity of RBC and plasma flow through already perfused microvessels. Overall, few, if any, capillaries or other microvessels were recruited by hypercapnia.
Influence of pericardium on left atrial compliance and pulmonary venous flow
Authors: Hoit B. D. , Shao Y. , Gabel M. , Walsh R. A.
Published: December 2017

We studied seven open-chest anesthetized dogs to test the hypothesis that left atrial (LA) compliance is increased after pericardiectomy and to determine the effect of pericardiectomy on left atrial reservoir and conduit function. Two orthogonal sonomicrometer crystal pairs were used to estimate LA volume, and LA filling was assessed with a pulmonary vein (PV) flow probe. The left ventricular (LV) systolic (JFTI) and diastolic (KFTI) PV flow integrals were used as indexes of LA reservoir and conduit function, respectively. Diastolic LV transmitral flow was assessed with transesophageal Doppler echocardiography. Data were acquired over a wide range of intracardiac pressures and volumes obtained by intravenous hetastarch infusion both before and after pericardiectomy. The mean dynamic stiffness constant of the LA diastolic pressure-volume relation was significantly greater before pericardiectomy than afterwards (0.15 +/- 0.04 vs. 0.08 +/- 0.03 ml-1, P < 0.05). Data were analyzed before and after pericardiectomy at three matched levels of left atrial pressure (LAP; 7, 13, and 20 mmHg). The J-to-KFTI ratio increased significantly with volume infusion and was significantly less after pericardiectomy than before (1.2 +/- 0.7 vs. 1.2 +/- 0.6, 1.8 +/- 0.6 vs. 2.2 +/- 0.9, and 2.0 +/- 0.8 vs. 2.6 +/- 0.9 at low, mid, and high levels of LAP, respectively; P < 0.05 at mid and high levels of LAP). Peak early transmitral velocity increased with both volume infusion and pericardiectomy. We conclude that pericardiectomy increases LA compliance and early LV filling rate and is accompanied by a relatively greater augmentation in conduit than reservoir function of the left atrium.
Influence of sodium intake on in vivo left ventricular anatomy in experimental renovascular hypertension
Authors: de Simone G. , Devereux R. B. , Camargo M. J. , Wallerson D. C. , Laragh J. H.
Published: December 2017

The effect of different dietary salt contents (0.0035, 0.4, and 4%) on in vivo left ventricular (LV) geometry was studied by necropsy-validated echocardiographic methods in groups of 30 two-kidney, one-clip (2K, 1C) and one-kidney, one-clip (1K, 1C) male Wistar rats and two-kidney (2K) and one-kidney (1K) shams 9 wk after surgery. The salt-deficient diet was associated with lower body weight, higher plasma renin activity in both 2K,1C and 2K shams (P < 0.004) and higher hematocrit in 2K,1C (P < 0.02). Blood pressure was increased by high-salt diet in experimental groups but not in shams (P < 0.01). Increase in dietary sodium content was associated with increased cross-sectional area index (CSAI) and LV mass index in 2K rats independently of renal artery stenosis (P < 0.0007) and also in 1K shams (P < 0.01). LV end-diastolic dimension was greater in 1K,1C and 1K shams than in 2K,1C and 2K shams at every level of sodium intake and was directly related to atrial natriuretic factor levels in both 1K,1C (r = 0.68) and 2K,1C (r = 0.59). LV hypertrophy was independently predicted by blood pressure (P < 0.0006) and high-sodium diet (P < 0.05) in 1K rats (multiple r = 0.57, P < 0.001) and by high-sodium diet (P < 0.0001) and low hematocrit (P < 0.05) in 2K rats (multiple r = 0.76, P < 0.0001). Thus provision of normal or high sodium content in the diet was a more consistent stimulus to LV hypertrophy than the level of blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Ca(2+)-dependent fluorescence transients and phosphate metabolism during low-flow ischemia in rat hearts
Authors: Camacho S. A. , Figueredo V. M. , Brandes R. , Weiner M. W.
Published: December 2017

To determine whether cytosolic free calcium ([Ca2+]i) rises during low-flow ischemia and to determine the mechanisms responsible for contractile dysfunction, isolated rat hearts were studied during graded reductions of coronary flow. Indo1 fluorescence at 385- and 456-nm wave-lengths (F385/456) was used as an index of [Ca2+]i. 31P-magnetic resonance spectroscopy (MRS) was used to measure free energy of ATP hydrolysis (delta GATP), intracellular pH (pHi), and Pi in parallel experiments to determine whether these factors may be responsible for increasing diastolic [Ca2+]i or altering the [Ca2+]i-pressure relationship. When coronary flow was reduced to 20 and 10% of control, diastolic F385/456 increased by 14 +/- 3 and 39 +/- 5%, respectively. Although developed pressure markedly decreased when coronary flow was reduced, there was no change of the F385/456 transient amplitude (systolic minus diastolic). During low-flow ischemia there was a significant decrease of delta GATP and increase of Pi that may lead to increased [Ca2+]i. Furthermore, there was a close inverse relationship between Pi and developed pressure, suggesting that Pi is an important regulator of contractility.
Responses of cerebral arterioles in diabetic rats to activation of ATP-sensitive potassium channels
Authors: Mayhan W. G. , Faraci F. M.
Published: December 2017

The goal of this study was to determine whether responses of pial arterioles to activation of ATP-sensitive potassium channels are altered during diabetes mellitus. We measured changes in diameter of pial arterioles in vivo in nondiabetic and diabetic rats (streptozotocin; 50–60 mg/kg ip; studied 3–4 mo after streptozotocin) in response to RP52891, an activator of ATP-sensitive potassium channels. RP52891 (1.0 microM) dilated pial arterioles in nondiabetic rats by 16 +/- 1% but constricted pial arterioles in diabetic rats by 2 +/- 2% (means +/- SE; P < 0.05 vs. response in nondiabetic rats). Dilatation of pial arterioles in nondiabetic rats in response to RP52891 was inhibited by glibenclamide (1.0 microM) but was not altered by NG-monomethyl-L-arginine (1.0 microM), apamin (0.1 microM), or charybdotoxin (50 nM). Thus dilatation of pial arterioles in response to RP52891 appears to be due to activation of ATP-sensitive potassium channels and does not involve nitric oxide or calcium-activated potassium channels. To determine whether impaired dilatation of pial arterioles in response to RP52891 in diabetic rats was related to a nonspecific effect of diabetes mellitus on vasodilatation, we measured diameter of pial arterioles in nondiabetic and diabetic rats in response to nitroglycerin. Nitroglycerin (1.0 microM) dilated pial arterioles by 12 +/- 1% in nondiabetic rats and 16 +/- 2% in diabetic rats (P > 0.05). Thus impaired dilatation of pial arterioles in diabetic rats in response to RP52891 also is not related to a nonspecific effect of diabetes mellitus on vasodilatation.(ABSTRACT TRUNCATED AT 250 WORDS)
Activated complement directly modifies the performance of isolated heart muscle cells from guinea pig and rat
Authors: Berger H. J. , Taratuska A. , Smith T. W. , Halperin J. A.
Published: December 2017

The complement system has been implicated in the pathogenesis of cardiovascular disorders including ischemia and atherosclerosis. Selective deposition of C5b-9, the membrane attack complex of complement, has been histochemically documented in human myocardium early after reperfusion of ischemic areas and in infarcted zones. However, functional sequelae of the C5b-9 complex binding to myocardial cells have not been identified. Insertion of C5b-9 complexes into the membrane of other cell types can generate transient changes in membrane permeability in the absence of cell lysis. We demonstrate in beating isolated adult guinea pig and rat cardiac myocytes that human derived C5b-9 can transiently augment in a dose-dependent manner both basal cytosolic calcium concentration and calcium transients, resulting in a temporary increase in contractility. If similar changes occur in human heart cells in vivo, they could significantly affect myocardial performance and contribute to functional abnormalities seen in ischemia and other pathological conditions associated with complement activation.
Fluid shear stress stimulates platelet-derived growth factor expression in endothelial cells
Authors: Mitsumata M. , Fishel R. S. , Nerem R. M. , Alexander R. W. , Berk B. C.
Published: December 2017

Fluid flow and the associated shear stress play a critical role in vascular growth and remodeling. Recent data suggest that increased endothelial cell expression of platelet-derived growth factor (PDGF) A- and B-chain by flow may participate in these events. In the present study, we examined the mechanism for flow-induced PDGF expression, focusing on protein kinase C (PKC). Bovine aortic endothelial cells were exposed to flow (shear stress = 30 dyn/cm2) in a parallel-plate flow chamber. Increases in PDGF B-chain, but not PDGF A-chain, were observed within 3 h, maximal within 6 h (13-fold increase), and sustained for 24 h. PKC appeared to be involved because phorbol 12-myristate 13-acetate induced PDGF B-chain mRNA. Activation of PKC alone, however, was insufficient to induce PDGF mRNA because the selective PKC activator, 1-oleoyl-2-acetyl-sn-glycerol, did not induce PDGF expression. A PKC-independent pathway was suggested by the fact that inhibition of PKC (downregulation with phorbol 12,13-dibutyrate or exposure to staurosporine) failed to block PMA or flow-induced PDGF B-chain expression. These results demonstrate flow-induced PDGF B-chain expression in endothelial cells that appears to be mediated, in part, by a PKC-independent pathway.
Activation of cardiac sympathetic afferents: effects of exogenous adenosine and adenosine analogues
Authors: Dibner-Dunlap M. E. , Kinugawa T. , Thames M. D.
Published: December 2017

Adenosine is released during myocardial ischemia and can cause angina-like chest pain when given by intracoronary administration. We tested the hypothesis that intracoronary adenosine activates cardiac sympathetic afferent fibers and results in reflex sympathoexcitation. In dogs with sinoaortic denervation and vagotomy, we administered 2 mg of adenosine into the left anterior descending artery over 2 min. Before dipyridamole infusion, intracoronary adenosine resulted in no change in blood pressure or renal sympathetic nerve activity. After dipyridamole infusion, which blocks adenosine uptake, intracoronary adenosine resulted in a peak increase in sympathetic activity of 34 +/- 7%. We also investigated the adenosine-receptor subtype responsible for this sympathoexcitatory response. We found that the adenosine1 agonist N6-cyclopentyladenosine elicited a dose-dependent sympathoexcitatory response similar to adenosine but that the adenosine2 agonist 5'-(N-cyclopropyl)carboxamidoadenosine failed to elicit a sympathoexcitatory response. We conclude that adenosine activates cardiac sympathetic afferent fibers and leads to a sympathoexcitatory response due to activation of adenosine1 receptors.
Albumin modulation of capillary permeability: role of endothelial cell [Ca2+]i
Authors: He P. , Curry F. E.
Published: December 2017

Albumin is required in vascular perfusates to maintain the normal permeability of microvessel walls. The most common mechanism proposed for action of albumin involves binding to the endothelial cell surface to increase the resistance to water and solute flows through hydraulic pathways across the capillary wall. The results of the present experiments do not conform to this simple adsorption model. Ringer perfusion increased the hydraulic conductivity (Lp) of the wall of single perfused frog mesenteric microvessels by 4.0 +/- 0.5-fold. The increase in Lp was associated with an increase of cytoplasmic calcium concentration ([Ca2+]i) from 59 +/- 5 nM when albumin was in the perfusate to a transient peak of 181 +/- 13 nM, 1–2 min after Ringer perfusion. [Ca2+]i then fell back to close to 100 nM. Processes that reduced Ca2+ influx into endothelial cells (removal of extracellular Ca2+, membrane depolarization) reduced Ca2+ influx and attenuated the increase in [Ca2+]i. The same processes abolished the increase in Lp after Ringer perfusion and restored Lp to close to control values during Ringer perfusion. Thus Ca2+ entry into endothelial cells is required to initiate and maintain the increased permeability during Ringer perfusion.
Free cytosolic Ca2+ measured with Ca(2+)-selective electrodes and fura 2 in rat mesenteric resistance arteries
Authors: Jensen P. E. , Mulvany M. J. , Aalkjaer C. , Nilsson H. , Yamaguchi H.
Published: December 2017

Free cytosolic Ca2+ was measured with sub-micrometer-tip, double-barrelled, Ca(2+)-selective electrodes and fura 2 in rat mesenteric resistance arteries. The purpose was to establish intracellular free Ca2+ concentration ([Ca2+]i) values in resting and stimulated vessels. Isolated vessels were mounted for isometric force measurements. Measured with electrodes, mean [Ca2+]i was 115 and 708 nM under resting and norepinephrine-activated conditions, respectively. Fura 2 was calibrated intracellularly including determination of the intracellular dissociation constant (Kd) of the fura 2:Ca2+ complex. The intracellular Kd was 342 nM. With this value of Kd, fura 2 measurements of mean [Ca2+]i were 129 and 537 nM under resting and norepinephrine-activated conditions, respectively. The values measured with the two techniques were thus in good accordance.
Adult rat ventricular myocytes cultured in defined medium: phenotype and electromechanical function
Authors: Ellingsen O. , Davidoff A. J. , Prasad S. K. , Berger H. J. , Springhorn J. P. , Marsh J. D. , Kelly R. A. , Smith T. W.
Published: December 2017

We studied primary short-term cultures of adult rat ventricular myocytes in defined medium to determine whether phenotype and electromechanical function are maintained in rod-shaped, quiescent cells. Although > 80% of the myocytes retained their rod-shaped in vivo morphology for up to 72 h, contractile function as measured by cell edge motion declined 30-50% from 6 to 24 h, paralleling a 68% shortening of action potential duration. From 24 to 72 h, contractility remained unchanged. Ca2+ channel current density increased 55% after 24-48 h and then returned to the level of freshly isolated cells (9 +/- 1 pA/pF, mean +/- SE). Resting membrane potential (-71 +/- 1 mV) and action potential overshoot (34 +/- 3 mV) did not change. The ratio of alpha- to beta-myosin heavy chain mRNA and the level of cardiac alpha-actin mRNA were maintained for 8 days. Thus quiescent adult rat ventricular myocytes in defined medium undergo extensive phenotypic adaptation within 72 h of isolation, despite maintenance of a rod-shaped morphology and stable levels of contractile protein mRNA, which may limit their suitability for electrophysiological and contractile function studies.
Excitatory amino acid receptors within NTS mediate arterial chemoreceptor reflexes in rats
Authors: Zhang W. , Mifflin S. W.
Published: December 2017

The nucleus tractus solitarius (NTS) is the primary site of termination of arterial baroreceptor and chemoreceptor afferent fibers. Excitatory amino acid (EAA) receptors within NTS have been shown to play an important role in the mediation of arterial baroreceptor reflexes; however, the importance of EAA receptors within NTS in the mediation of arterial chemoreceptor reflexes remains controversial. Therefore, in chloralose-urethan-anesthetized, mechanically ventilated, paralyzed rats, 4 nmol of the broad-spectrum EAA receptor antagonist kynurenic acid (Kyn) was injected into the NTS to observe the effects of EAA receptor blockade on the pressor responses evoked by either activation of ipsilateral carotid body chemoreceptors (by close arterial injection of CO2-saturated bicarbonate) or electrical stimulation of ipsilateral carotid sinus nerve (CSN). Under control conditions, activation of carotid body chemoreceptors and CSN stimulation evoked increases in arterial pressure of 27 +/- 2 (n = 24 sites) and 28 +/- 3% (n = 8), respectively. Kyn microinjection into NTS significantly reduced the pressor responses evoked by activation of carotid body chemoreceptors and electrical stimulation of the CSN for 20 and 25 min, respectively. Attenuation of pressor responses evoked by chemoreceptor activation were maximal at 20 min post-Kyn injection (13 +/- 2%), whereas CSN-evoked pressor responses were maximally attenuated at 15 min (6 +/- 4%). Microinjection into NTS of 4 nmol of xanthurenic acid, a structural analogue of Kyn with no EAA receptor antagonist properties, had no effect on chemoreceptor reflexes. We conclude that EAA receptors within NTS play an important role in the mediation of arterial chemoreceptor reflexes.
Role of sympathetic nerves in the vascular effects of local temperature in human forearm skin
Authors: Pergola P. E. , Kellogg D. L. , Johnson J. M. , Kosiba W. A. , Solomon D. E.
Published: December 2017

The role of adrenergic nerve function in the cutaneous vascular response to changes in local skin temperature in the human forearm was examined using three protocols: 1) blocking release of norepinephrine presynaptically by local iontophoresis of bretylium (BT), 2) altering background adrenergic tone by changing whole body skin temperature, and 3) blocking cutaneous nerves by proximal infiltration of local anesthetic. Forearm skin blood flow was measured by laser-Doppler flowmetry (LDF) and cutaneous vascular conductance (CVC) was calculated as LDF/blood pressure. In protocol 1, local cooling (29 degrees C) elicited a rapid and sustained fall in CVC at control sites (-43 +/- 8%) in contrast to a biphasic response at BT-treated sites, consisting of an initial vasodilation followed by a vasoconstriction (percent change CVC = 28 +/- 13 and -34 +/- 18, respectively). Local warming (39 degrees C) increased CVC at control and at BT-treated sites by 331 +/- 46 and 139 +/- 31%, respectively. In protocol 2, at a neutral, cool, or warm whole body skin temperature, local cooling (29 degrees C) elicited similar reductions in CVC (-34 +/- 8, -29 +/- 5, and -30 +/- 4%, respectively), and local warming (38 degrees C) produced similar increases in CVC (89 +/- 15, 85 +/- 21, and 74 +/- 22%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of an increase in systemic blood pressure on nailfold capillary pressure in humans
Authors: Shore A. C. , Sandeman D. D. , Tooke J. E.
Published: December 2017

Moderate autoregulation of capillary pressure occurs during changes in arterial and/or venous pressure in animals. Whether an increase in systemic blood pressure is transmitted to capillaries in humans is unknown. Eight healthy volunteers performed isometric handgrip exercise (30% of maximum) while nailfold capillary pressure (CP) and digital arterial blood pressure (DBP) were measured in the contralateral hand. CP was measured for 40 s before exercise and 40-100 s during exercise. Only experiments with no change in pipette position and no artifactual changes in flow were accepted. Basal DBP was stable [91.5 +/- 12.7 mmHg (-40 to -20 s basal) and 91.3 +/- 11.8 mmHg (-20 to 0 s basal)], and isometric exercise increased DBP [100.4 +/- 13.9 mmHg (0-20 s exercise) and 103.1 +/- 15.3 mmHg (20-40 s exercise); P < 0.05]. CP was unchanged during the first 40 s of exercise [18.9 +/- 4.9 mmHg (-40 to 20 s basal), 18.9 +/- 5.2 mmHg (-20 to 0 s basal), 18.4 +/- 4.7 mmHg (0-20 s exercise), and 18.3 +/- 5.3 mmHg (20-40 s exercise)] and remained unchanged for up to 100 s (n = 5), despite a continued elevation of DBP. These data suggest that protective mechanisms minimize the transmission of increases in systemic blood pressure to the capillary bed in humans.
Postural vascular response in human skin: passive and active reactions to alteration of transmural pressure
Authors: Jepsen H. , Gaehtgens P.
Published: December 2017

Laser-Doppler (LD) fluxmetry was performed in the palmar finger skin of healthy subjects to study the mechanisms contributing to the postural vascular response. Local transmural pressure in the skin blood vessels of the region studied was altered for 1 min in two experimental series either by passive movement of the arm to different vertical hand positions relative to heart level or by application of external pressure (-120-180 mmHg) to the finger. Heart and respiratory rate, arterial blood pressure, and LD flux in the contralateral finger (kept at heart level) were measured. The measurements suggest a compound reaction of local (myogenic) and systemic (neurogenic) mechanisms: the local regulatory component appears as a graded active vascular response elicited by passive vessel distension or compression. A systemic component, associated with a single deep inspiration, is frequently observed during the actual movement of the arm. In addition, prolonged holding of the test hand in a given vertical position also elicits a delayed vascular response in the control hand at heart level, which may be generated by volume receptors in the intrathoracic low-pressure system.
Pulmonary endothelial nitric oxide production is developmentally regulated in the fetus and newborn
Authors: Shaul P. W. , Farrar M. A. , Magness R. R.
Published: December 2017

To define the role of endothelial nitric oxide (NO) in developmental changes in pulmonary vascular resistance and oxygen responsiveness, we determined the ontogeny of endothelial NO production and of oxygen modulation of that process in pulmonary arteries from fetal and newborn lambs. NO production was assessed by measuring endothelium-dependent arterial guanosine 3',5'-cyclic monophosphate synthesis. Basal NO rose two-fold from late gestation to 1 wk of age and another 1.6-fold from 1 to 4 wk. Acetylcholine-stimulated NO also increased 1.6-fold from 1 to 4 wk. The maturational rise in NO was evident at high Po2 in vitro, and it was not modified by L-arginine. This suggests that the developmental increase may alternatively involve enhanced calcium-calmodulin-mediated mechanisms, increased expression of NO synthase, or greater availability of required cofactor(s). With an acute decline in Po2 in vitro from 680 to 150 or 40 mmHg, there was 50-88% attenuation of basal and acetylcholine-stimulated NO late in the third trimester and in the newborn but not early in the third trimester. Parallel studies of mesenteric endothelium revealed postnatal increases in basal and stimulated NO but no decline in NO at lower Po2. Ontogenic changes in endothelial NO production and in oxygen modulation of that process may be involved in the maturational decrease in vascular resistance and the development of oxygen responsiveness in the pulmonary circulation.
Exhaustion of Frank-Starling mechanism in conscious dogs with heart failure
Authors: Komamura K. , Shannon R. P. , Ihara T. , Shen Y. T. , Mirsky I. , Bishop S. P. , Vatner S. F.
Published: December 2017

The goal of this study was to elucidate the ability of the left ventricle to accommodate an increase in preload (Frank-Starling mechanism) in the presence of congestive heart failure (CHF) but in the absence of the complicating effects of hypertrophy and fibrosis. To accomplish this, the effects of volume loading were examined in eight conscious dogs during the control state and after 3 wk of right ventricular pacing (240 beats/min). CHF increased heart rate (by 16 +/- 5 from 92 +/- 5 beats/min), left ventricular (LV) end-diastolic pressure (by 17 +/- 2 from 10 +/- 1 mmHg), and LV end-diastolic volume (EDV; by 23 +/- 4 from 57 +/- 3 ml). Despite reduced LV ejection fraction (from 54 +/- 3 to 31 +/- 3%), there was no significant change in cardiac output (2.5 +/- 0.3 l/min) compared with control (2.7 +/- 0.2 l/min). Stroke volume was preserved (control 19 +/- 2 ml; CHF 18 +/- 2 ml) at a constant heart rate by a shift to the right in the relationship between LV stroke volume and EDV, indicating the importance of chronic ventricular dilatation in maintaining pump performance. In the control state, acute volume load increased LV EDV (by 17 +/- 2 ml) and stroke volume (by 11 +/- 2 ml), whereas in CHF it did not increase LV EDV or stroke volume. Scanning electron microscopy revealed areas of reduced collagen weave pattern surrounding myofibers. Myocyte cross-sectional area by transmission electron microscopy was significantly reduced, and there were multiple electron-dense expansions of the Z lines with disruption of the normal lateral sarcomere alignment. These morphological findings suggest that chronic ventricular dilatation utilized in CHF results from myocyte stretch and morphological intracellular rearrangement. Furthermore, the failing heart cannot further augment stroke volume by acutely increasing EDV in CHF, suggesting that the Frank-Starling reserve is essentially exhausted.
Pressure-independent baroreflex resetting produced by chronic infusion of angiotensin II in rabbits
Authors: Brooks V. L. , Ell K. R. , Wright R. M.
Published: December 2017

The purpose of this study was to test the hypothesis that chronic infusion of angiotensin II (ANG II) in rabbits shifts or resets baroreflex control of heart rate to a higher pressure level via a mechanism that is independent of the hypertension that is produced. The baroreflex relationship between arterial pressure and heart rate was assessed by first infusing progressively increasing doses of nitroprusside (3, 6, 12, 24, and 48 micrograms.kg-1 x min-1) to lower pressure and then increasing doses of phenylephrine (0.5, 1, 2, 4, and 8 micrograms.kg-1 x min-1) to raise pressure. Two weeks of intravenous ANG II infusion (20 ng.kg-1 x min-1) increased plasma ANG II levels from 9 +/- 1 to 146 +/- 24 pg/ml (P < 0.05), increased arterial pressure from 62 +/- 2 to 95 +/- 2 mmHg (P < 0.05), and transiently increased heart rate. The baroreflex was shifted to a higher pressure level after 30 min and 1, 3, 7, 9, and 14 days of ANG II infusion. Thirty minutes after the ANG II infusion on days 1, 7, and 14 was stopped, arterial pressure decreased, and the baroreflex shifted back to control, indicating that ANG II was required for the resetting that was produced. However, when the ANG II infusion was continued and arterial pressure was instead reduced for 30 min by infusing nitroprusside on days 3 and 9, the baroreflex relationship between arterial pressure and heart rate remained positioned at a higher pressure level.(ABSTRACT TRUNCATED AT 250 WORDS)