bluuebunny/crossref_metadata_2025 huggingface dataset:
Transfer function analysis of the circulation: unique insights into cardiovascular regulation
Authors: Saul J. P. , Berger R. D. , Albrecht P. , Stein S. P. , Chen M. H. , Cohen R. J.
Published: December 2017

We have demonstrated previously that transfer function analysis can be used to precisely characterize the respiratory sinus arrhythmia (RSA) in normal humans. To further investigate the role of the autonomic nervous system in RSA and to understand the complex links between respiratory activity and arterial pressure, we determined the transfer functions between respiration, heart rate (HR), and phasic, systolic, diastolic, and pulse arterial pressures in 14 healthy subjects during 6-min periods in which the respiratory rate was controlled in a predetermined but erratic fashion. Pharmacological autonomic blockade with atropine, propranolol, and both, in combination with changes in posture, was used to characterize the sympathetic and vagal contributions to these relationships, as well as to dissect the direct mechanical links between respiration and arterial pressure from the effects of the RSA on arterial pressure. We found that 1) the pure sympathetic (standing + atropine) HR response is characterized by markedly reduced magnitude at frequencies greater than 0.1 Hz and a phase delay, whereas pure vagal (supine + propranolol) modulation of HR is characterized by higher magnitude at all frequencies and no phase delay; 2) both the mechanical links between respiration and arterial pressure and the RSA contribute significantly to the effects of respiration on arterial pressure; 3) the RSA contribution to arterial pressure fluctuations is significant for vagal but not for sympathetic modulation of HR; 4) the mechanical effects of respiration on arterial pressure are related to the negative rate of change of instantaneous lung volume; 5) the mechanical effects have a higher magnitude during systole than during diastole; and 6) the mechanical effects are larger in teh standing than the supine position. Most of these findings can be explained by a simple model of circulatory control based on previously published experimental transfer functions from our laboratory.
Effect of graded umbilical cord compression in fetal sheep at 0.6-0.7 gestation
Authors: Iwamoto H. S. , Stucky E. , Roman C. M.
Published: December 2017

To define responses of immature fetuses to asphyxia, we occluded the umbilical cord of 11 chronically instrumented fetal sheep at 82-94 days gestation and measured hemodynamic and catecholamine responses. The fetuses became acidemic, hypoxemic, and hypercarbic: arterial pH and PO2 decreased from 7.36 +/- 0.04 and 22 +/- 3 Torr to 7.10 +/- 0.04 (mean +/- SD, P less than 0.01) and 15 +/- 4 Torr (P less than 0.01), respectively, and PCO2 increased from 56 +/- 5 to 86 +/- 8 Torr (P less than 0.01) when umbilical blood flow was reduced by 75-88%. This degree of reduction in umbilical blood flow decreased cardiac output from 606 +/- 101 to 247 +/- 67 ml.min-1.kg-1 (P less than 0.01) and blood flow to hepatic, renal, musculoskeletal, and pulmonary vascular beds. Plasma norepinephrine concentrations increased from 1,557 +/- 975 to 16,718 +/- 14,672 pg/ml (P less than 0.05) with a 75-88% reduction, but mean arterial blood pressure did not increase. The absence of a hypertensive response probably relates to the decrease in cardiac output. These data indicate that asphyxia severely compromises cardiac output and organ perfusion in the midgestation fetus.
Effect of pregnancy on endothelium and smooth muscle: their role in reduced adrenergic sensitivity
Authors: Weiner C. , Liu K. Z. , Thompson L. , Herrig J. , Chestnut D.
Published: December 2017

During pregnancy, vascular reactivity of the uterine artery is characterized by decreased contraction to norepinephrine and increased relaxation to acetylcholine. We investigated whether 1) relaxation to A23187 is increased during pregnancy and 2) endothelium-derived relaxing factor (EDRF) and/or prostaglandins are responsible for the decreased uterine artery sensitivity to norepinephrine during pregnancy. Isolated rings of uterine and carotid arteries were obtained from pregnant and nonpregnant guinea pigs. Relaxation to sodium nitroprusside in uterine but not carotid artery was reduced during pregnancy. Relaxation of both uterine and carotid arteries to the calcium ionophore A23187 was unaffected by pregnancy. During pregnancy, contractions to norepinephrine were reduced in the uterine artery compared with arteries from nonpregnant animals. Indomethacin slightly enhanced the contractions of uterine artery to norepinephrine during pregnancy. However, indomethacin-treated uterine arteries from pregnant animals were still less responsive to norepinephrine than control uterine arteries from nonpregnant animals. Methylene blue enhanced the efficacy of norepinephrine in uterine arteries of nonpregnant animals as well as carotid arteries of pregnant and nonpregnant animals but not in uterine arteries of pregnant animals. In contrast, N-monomethyl-L-arginine, a specific inhibitor of EDRF synthesis, not only enhanced uterine and carotid artery responses to norepinephrine in both pregnant and nonpregnant animals but fully reversed the blunted potency of norepinephrine on uterine arteries of pregnant to that of nonpregnant animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Peripheral lymphatic cannulation for physiological analysis of interstitial fluid compartment in humans
Authors: Castillo C. E. , Lillioja S.
Published: December 2017

Analysis of peripheral interstitial concentrations of hormones or substrates in humans has undoubtedly been hampered by the difficulty in performing retrograde peripheral lymphatic cannulation and obtaining adequate flow rates of lymph. We now describe a technique for direct continuous sampling of peripheral lymph. A lymphatic vessel was cannulated in the lower legs of 14 males, and lymph was collected for 24-48 h. Adequate quantities of lymph were obtained basally and during physiological manipulations to make collections at 15-min intervals. Flow rates averaged 1.84 ml/h and ranged from 0.34 to 4.96 ml/h. We conclude that peripheral lymphatic vessels can be cannulated and flow rates are sufficient to measure interstitial concentration of hormones or substrates both at steady state and dynamically in adult humans.
Nocturnal variations in peripheral blood flow, systemic blood pressure, and heart rate in humans
Authors: Sindrup J. H. , Kastrup J. , Christensen H. , Jorgensen B.
Published: December 2017

Subcutaneous adipose tissue blood flow rate, together with systemic arterial blood pressure and heart rate under ambulatory conditions, was measured in the lower legs of 15 normal human subjects for 12-20 h. The 133Xe-washout technique, portable CdTe(Cl) detectors, and a portable data storage unit were used for measurement of blood flow rates. An automatic portable blood pressure recorder and processor unit was used for measurement of systolic blood pressure, diastolic blood pressure, and heart rate every 15 min. The change from upright to supine position at the beginning of the night period was associated with a 30-40% increase in blood flow rate and a highly significant decrease in mean arterial blood pressure and heart rate (P less than 0.001 for all). Approximately 100 min after the subjects went to sleep an additional blood flow rate increment (mean 56%) and a simultaneous significant decrease in mean arterial blood pressure (P less than 0.001) were observed. The duration of this hyperemic phase was 116 min. A highly significant reduction of the subcutaneous vascular resistance (50%) was demonstrated during the hyperemic blood flow rate phase compared with the surrounding phases (P less than 0.0001). The synchronism of the nocturnal subcutaneous hyperemia and the decrease in systemic mean arterial blood pressure point to a common, possibly central nervous or humoral, eliciting mechanism.
Cardiac contraction affects deep myocardial vessels predominantly
Authors: Goto M. , Flynn A. E. , Doucette J. W. , Jansen C. M. , Stork M. M. , Coggins D. L. , Muehrcke D. D. , Husseini W. K. , Hoffman J. I.
Published: December 2017

To evaluate the roles of intramyocardial forces and systolic ventricular pressure in myocardial flow in the different layers separately, we measured myocardial flow in rabbit hearts during stable systolic contracture with left ventricular pressures of 60 (n = 5) and 0 mmHg (n = 5) and during stable diastolic arrest (n = 5). We also measured the number and size of the intramyocardial vessels after perfusion fixation (systolic arrest, n = 5; diastolic arrest, n = 5). In 25 rabbits, hearts were excised and perfused from the aortic root. Systolic arrest was achieved by perfusion of a low-Ca2+ Tyrode solution containing 2.0 mM Ba2+. Diastolic arrest was achieved by intraventricular injection of 700-1,000 mg pentobarbital sodium and was maintained by perfusion with St. Thomas cardioplegic solution. At perfusion pressure of 100 mmHg, subendocardial flow was lower than subepicardial flow during systolic arrest regardless of left ventricular pressure, whereas during diastolic arrest, subendocardial flow was higher than subepicardial flow. Subendocardial-to-subepicardial flow ratios for a physiological range of perfusion pressures were lower during systolic arrest with low rather than with high left ventricular pressure. Small arteriolar and capillary densities showed no difference between subendocardium and subepicardium. During systolic arrest, diameters of subendocardial terminal arterioles (4.6 +/- 1.3 microns) and capillaries (4.0 +/- 1.3 microns) were smaller than those in the subepicardium (8.8 +/- 1.7 and 7.1 +/- 1.6 microns, respectively; P less than 0.0001), whereas during diastolic arrest, diameters of subendocardial terminal arterioles (10.1 +/- 2.0 microns) and capillaries (7.6 +/- 1.8 microns) were slightly larger than those in the subepicardium (9.5 +/- 1.5 and 6.7 +/- 1.0 microns, respectively; P less than 0.01). We conclude that cardiac contraction predominantly affects subendocardial vessels and impedes subendocardial flow more than subepicardial flow regardless of left ventricular pressure.
gamma-Aminobutyric acid is a neuromodulator in sinus node of guinea pig heart
Authors: Matsuyama S. , Saito N. , Taniyama K. , Tanaka C.
Published: December 2017

A possible neurotransmitter role for gamma-aminobutyric acid (GABA) in the sinus node of guinea pig heart was examined. Among right atrium, left atrium, right ventricle, left ventricle, and sinus node, the highest amount of the endogenous GABA was found in the sinus node (1,240.6 +/- 120.8 nmol/g protein). The neuronal uptake of [3H]GABA was also the highest in the sinus node and kinetic analysis of the [3H]GABA uptake system in the sinus node showed one saturable component (Km = 17.3 microM, Vmax = 2.18 nmol.g protein-1.10 min-1). Autoradiography of [3H]GABA demonstrated heavy labeling of [3H]GABA in the nonmyelinated nerve fibers within the sinus node compared with findings in the atrial muscle. Electrical transmural stimulation evoked a Ca(2+)-dependent tetrodotoxin-sensitive release of [3H]GABA from the isolated sinus node preloaded with [3H]GABA in the presence of beta-alanine, thereby indicating that the [3H]GABA in the nerve is released from nerve terminals following electrical stimulation. These results provide evidence for the neuromodulator role of GABA in the sinus node of the guinea pig.
Direct observation of platelet adhesion to fibrinogen- and fibrin-coated surfaces
Authors: Jen C. J. , Lin J. S.
Published: December 2017

A flow system consisting of a parallel-plate flow chamber mounted on the epifluorescence video microscope was constructed to allow direct visualization of the entire platelet adhesion process under flow conditions. Digital image-processing techniques were applied to analyze the fluorescence images from video tapes. In this study we used cover glasses coated with either fibrinogen or fibrin as the testing surface of our flow chamber to compare platelet adhesion to both types of surfaces. We found that 1) platelets adhered to both types of protein-coated surfaces but not to uncoated glass; 2) platelets that adhered to fibrinogen were nonoverlapping, clustering, and saturated at approximately 40 cells/1,000 microns 2 at 445 s-1 surface shear rate and at approximately 60 cells/1,000 microns 2 at 70 s-1 surface shear rate; 3) platelets that adhered to fibrin were nonoverlapping, random, and saturated at approximately 55 cells/1,000 microns 2 at 445 s-1 surface shear rate and at approximately 65 cells/1,000 microns 2 at 70 s-1 surface shear rate; 4) ethyleneglycol- bis(beta-aminoethylether)-N,N'-tetraacetic acid, the snake venom halysin (against glycoprotein IIb-IIIa complex), and monoclonal antibody Ab-15 (against glycoprotein IIIa) blocked platelet adhesion to both surfaces; 5) Arg-Gly-Asp-Ser and monoclonal antibody LIBS-1 (against glycoprotein IIIa) partially inhibited platelet adhesion to fibrinogen-coated surface but were almost ineffective in preventing platelet adhesion to fibrin-coated surface; and 6) monoclonal antibody Ab-144 (against glycoprotein Ib) was ineffective for platelet adhesion on both surfaces. These observations provide basic characteristics of platelet adhesion to fibrinogen- and fibrin-coated surfaces under controlled flow conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
Endothelium-dependent vasodilation of canine coronary collateral vessels
Authors: Flynn N. M. , Kenny D. , Pelc L. R. , Warltier D. C. , Bosnjak Z. J. , Kampine J. P.
Published: December 2017

The objective of this study was to determine whether endothelium-mediated relaxation occurs in canine coronary collateral vessels. Responses to endothelium-dependent vasodilators in coronary collateral vessels (250-350 microns) were compared with those obtained in normal native coronary arteries of similar size. Rings of small arteries and collateral vessels were suspended in baths, and tension was recorded. All rings were constricted with prostaglandin F2 alpha (3 microM) and subsequently exposed to cumulative concentrations of acetylcholine or bradykinin. In separate experiments, the procedure was repeated in the presence of 300 microM NG-monomethyl-L-arginine (L-NMMA) to inhibit endothelium-mediated vasodilation. Endothelium-dependent relaxation was further studied in the presence of indomethacin, and endothelium-independent relaxation was examined with sodium nitroprusside. Acetylcholine and bradykinin relaxed both normal native and collateral rings. In preconstricted small arteries and collateral vessels the concentration at 50% of maximal response of acetylcholine was 85.5 +/- 19.5 and 61.0 +/- 14.0 microns, and bradykinin was 11.9 +/- 7.4 and 10.7 +/- 2.1 microns, respectively. L-NMMA attenuated the response to acetylcholine and bradykinin in both groups. The results indicate that endothelium is present and functional in canine coronary collateral vessels. Both small coronary arteries and collateral vessels are equally responsive to endothelium-dependent vasodilators and inhibition of endothelium-dependent relaxing factor.
Regulation of glycolytic flux by coronary flow in guinea pig heart. Role of vascular endothelial cell glycocalyx
Authors: Suarez J. , Rubio R.
Published: December 2017

Hemodynamic forces continuously act on endothelial cell lining of blood vessels. Blood flow, perfusing pressure, and shear stress are known to induce the release of bioactive substances from the endothelium. Furthermore, coronary flow (CF) is a well-known stimulant of myocardial contraction. Our concern was whether other Ca(2+)-dependent responses like glycolytic flux (Gf) were also CF dependent. For this purpose, isolated guinea pig hearts were perfused with a medium containing 5 mM 3-[3H]glucose, and the 3H2O released during perfusion was measured as an index of Gf. Changes in CF within the 3- to 25-ml/min range resulted in linear increase of Gf. This stimulatory effect of CF was also observed in K(+)-arrested hearts. In addition, increasing shear stress on addition of dextran to the perfusing solution (5% and 10% wt/vol), while keeping CF constant, also stimulated Gf. We hypothesized that endothelial cell membrane glycocalyx may act as sensor to this stimuli. Thus one would expect that substances acting on these structures (enzymes heparinase, hyaluronidase, or chondroitinase or the lectin concanavalin A) when added to the perfusate might inhibit the CF-induced Gf. The results showed that concanavalin A and heparinase inhibited the Gf-CF-induced response, whereas chondroitinase and hyaluronidase had no effect. These findings suggest that there may be a selective effect of these agents affecting the Gf response to CF. Our data suggest that CF stimulates Gf through shearing forces acting on specific endothelial glycocalyx component(s). Therefore, deformation of these components could result in the transduction of physical signals into release of chemical messengers that act on the biochemical machinery of underlining parenchymal cells.
Arteriovenous oxygen diffusion shunt is negligible in resting and working gracilis muscles
Authors: Honig C. R. , Gayeski T. E. , Clark A. , Clark P. A.
Published: December 2017

Distribution of O2 within and among arterioles and venules was determined in dog and rat gracilis muscles with a cryospectrophotometric method. Saturation in 40-microns arterioles was not demonstrably different from saturation in the aorta even when flow was abnormally low. Arterioles greater than 40 microns ran parallel to venules. Measurements and a mathematical model indicate that diffusive shunting is negligible for typical separation distances between arterioles and venules. Most separation distances were greater than 30 microns. In some venule segments less than 15 microns from an arteriole, saturation within 10 microns of the wall facing the arteriole was higher than at other locations within the venule. However, saturation in the population of venules did not increase with venule diameter, and mean venular saturation was not different from saturation in effluent blood. We make the following conclusions: 1) a small arteriovenous diffusive O2 flux exists in postural muscles; 2) contribution of this flux to O2 mass balance is negligible; 3) O2 diffusivity of the arteriolar wall and surrounding tissue in vivo cannot be much higher than O2 diffusivity determined in vitro; and 4) effluent PO2 closely approximates mean end-capillary PO2.
Favorable effects of hyperosmotic reperfusion on myocardial edema and infarct size
Authors: Garcia-Dorado D. , Theroux P. , Munoz R. , Alonso J. , Elizaga J. , Fernandez-Aviles F. , Botas J. , Solares J. , Soriano J. , Duran J. M.
Published: December 2017

Myocardial water content and infarct size were studied in 39 pigs randomly assigned to a nonintervention group, a group with an intracoronary infusion of a control solution, and a group with a hyperosmotic infusion to 450 mosM by the addition of D-mannitol. The intracoronary solutions were selectively infused into the left anterior descending coronary artery just distal to the occlusion site starting 48 min after occlusion. Reperfusion was performed 3 min later and the infusion rate progressively tapered off over the following 33 min. Multiple myocardial fragments were then obtained in nine pigs, from endocardial, mesocardial, and epicardial regions of the ischemic and control myocardium. Water content measured after 48 h of dessication was significantly greater in the reperfused [530 +/- 7 ml/100 (mean +/- SE) g dry wt] compared with control myocardium (374 +/- 3; P less than 0.0001) and similar in reperfused control and isotonic infusion groups (556 +/- 7 and 543 +/- 8 ml/100 g dry wt); it was 491 +/- 11 with intracoronary D-mannitol infusion, representing 35% less increase (P less than 0.001). In the 30 remaining pigs, area at risk and infarct size were measured 24 h later by in vivo fluorescein and in vitro triphenyltetrazolium chloride. Infarct size was similar in control and in the isotonic reperfused hearts, 6.80 +/- 1.05 and 6.22 +/- 0.76% of ventricular weight, and smaller with D-mannitol, 4.46 +/- 0.46 (P less than 0.05). The ratio of infarct size to area at risk was also smaller [0.415 +/- 0.029 vs. 0.543 +/- 0.052 and 0.547 +/- 0.045 (P less than 0.02)].(ABSTRACT TRUNCATED AT 250 WORDS)
gp60 is an albumin-binding glycoprotein expressed by continuous endothelium involved in albumin transcytosis
Authors: Schnitzer J. E.
Published: December 2017

Albumin reduces capillary permeability and acts as a carrier for various small molecules. Recently, we identified a 60-kDa sialoglycoprotein (gp60) on the surface of cultured rat microvascular endothelial cells (MEC) that binds albumin and antiglycophorin serum (alpha-gp). We verified that alpha-gp recognizes the albumin-binding gp60 by affinity, purifying proteins from MEC extracts using immobilized albumin. gp60 was immunoblotted with alpha-gp only when the MEC extract was reacted with albumin and not in controls. We immunoprecipitated gp60 from biosynthetically radiolabeled MEC lysates and from extracts containing endothelial surface proteins of isolated rat hearts that were radioiodinated in situ. gp60 was immunoblotted selectively in rat tissue microvascular beds lined with continuous endothelium (heart, lung, diaphragm, fat, skeletal muscle, mesentery, and duodenal muscularis but not cortical brain) and not those exclusively lined with fenestrated or sinusoidal endothelium (adrenal, pancreas, liver, and small intestinal mucosa). MEC isolated from rat heart, lung, and epididymal fat pad expressed gp60 and bound albumin, whereas various nonendothelial cells and brain-derived MEC did not. gp60 is an albumin-binding glycoprotein expressed specifically on the surface of continuous endothelium that binds albumin apparently not only to initiate its transcytosis via plasmalemmal vesicles but also to increase capillary permselectivity.
Bromcresol green assay is nonspecific for rat plasma albumin
Authors: Barber B. J. , Stanhope V. L.
Published: December 2017

Bromcresol green (BCG) assay has been used in microvascular studies to determine albumin in rat plasma. The purpose of this study was to demonstrate that BCG overestimates rat plasma albumin partly because BCG binds to transferrin, a beta-globulin. The light absorbance of a transferrin-BCG reagent solution is shown to increase with time; appreciable binding occurs within a few seconds. Pure transferrin produced BCG assay results (P less than 0.001) that could be expressed as pseudoalbumin concentrations. Albumin and transferrin solutions of equal concentrations were mixed in equal parts; a plot of albumin concentration determined by BCG vs. actual albumin concentration had a slope greater than the expected value of 1.0 (P less than 0.001). Plasma samples were obtained from six rats and assayed for albumin. Electrophoresis yielded a plasma albumin of 2.97 +/- 0.11 g/dl, whereas BCG assay yielded a significantly (P less than 0.01) greater value of 3.58 +/- 0.07 g/dl. We conclude that BCG assay estimates of albumin-to-globulin ratio (A/G), in which G is determined from the difference between total protein and albumin, are especially subject to error.
Vulnerability of rabbit atrium to reentry by hypoxia. Role of inhomogeneity in conduction and wavelength
Authors: Lammers W. J. , Kirchhof C. , Bonke F. I. , Allessie M. A.
Published: December 2017

In isolated superfused left atria of the rabbit, the inducibility of tachyarrhythmias by single early premature stimuli was highly increased by hypoxia. High-resolution mapping showed that these arrhythmias were caused by circus movement around a functional arc of conduction block (leading circle reentry). To determine the electrophysiological changes by hypoxia responsible for the higher vulnerability to intra-atrial reentry, the wavelength of the atrial impulse and spatial inhomogeneities in refractory periods and local conduction delays were measured. Hypoxia caused a transient increase in refractory periods during the first 10-15 min of hypoxia. After this period, refractory periods shortened again to values slightly lower than during control. During the whole period of hypoxia, local differences in refractory periods were enlarged. Conduction velocity was significantly depressed by hypoxia. As a result, the wavelength of the atrial impulse gradually shortened during hypoxia to approximately 80% of control. Inhomogeneity in conduction was quantified by phase maps in which the maximal local delays in conduction are plotted. Hypoxia caused a marked increase in inhomogeneity in conduction both during slow rhythm (inhomogeneity index increased from 2.3 to 3.4) and premature activation (from 3.1 to 4.7). We conclude that the higher vulnerability of the atrium for reentrant arrhythmias by hypoxia is based on a combination of a moderate shortening of the wavelength and an increase in inhomogeneity in conduction of premature wavefronts.
Mechanical properties of the canine mitral valve: effects of autonomic stimulation
Authors: Curtis M. B. , Priola D. V.
Published: December 2017

Experiments were designed to determine whether the canine mitral valve actively contracts and, if so, if its mechanical activity can be modulated by the autonomic nervous system. A miniature displacement gauge was sutured to the atrial (muscular) surface of the septal leaflet in 65 dogs under pentothal sodium anesthesia during total cardiopulmonary bypass. During bypass, with blood constantly drained from the left ventricle (LV), the leaflet deflected into the LV during ventricular systole as would be expected with active contraction. With blood present in the LV, leaflet deflection was reversed, indicating a passive displacement. After application of 85% phenol to the atrial surface, ventricular displacement of the leaflet was abolished, whereas the atrial displacement was significantly augmented. There was a positive inotropic effect during sympathetic stimulation and a negative inotropic effect with parasympathetic stimulation, i.e., increased and decreased ventricular deflection, respectively. These effects of autonomic stimulation were abolished by application of phenol to the leaflet muscle. During simultaneous electrical and mechanical recordings from the valve, activation appeared to originate from the atrium, before ventricular depolarization. It was concluded that the valvular muscle actively contracts to assist in bringing the valve leaflets into early apposition. This contraction imparts a measurable level of active “stiffness” to the valve, reducing atrial displacement during ventricular systole. This “stiffness” can be modified by autonomic input and may contribute to dysfunction of morphologically normal mitral valves.
Chronic elevation of norepinephrine in conscious dogs produces hypertrophy with no loss of LV reserve
Authors: Stewart J. M. , Patel M. B. , Wang J. , Ochoa M. , Gewitz M. , Loud A. V. , Anversa P. , Hintze T. H.
Published: December 2017

Elevated plasma catecholamine levels may cause both myocardial hypertrophy and tissue damage. To determine whether the left ventricle from dogs with chronic norepinephrine infusion can sustain additional functional loads, we altered ventricular preload or afterload and determined both global and left ventricular (LV) wall function. Dogs were instrumented to measure LV wall function, LV internal base diameter, and LV pressures and were allowed to fully recover. Preload was altered by volume loading and afterload by injection of phenylephrine. Osmotic infusion pumps were implanted to continuously release norepinephrine at 0.5 micrograms.kg-1.min-1 for 28 days, and the volume loading and phenylephrine were repeated on days 14 and 28. Heart rate decreased, whereas there were no differences in mean arterial pressure, maximum first derivative of LV pressure (dP/dt), LV dP/dt/developed pressure of 40 mmHg, LV dP/dt/end-diastolic circumference, slope of the pressure-diameter relation, peak systolic wall stress, LV/end-diastolic diameter, or LV/end-systolic diameter during norepinephrine infusion. Diastolic and systolic wall thickness and chamber weights were increased (P less than 0.05). Indexes of diastolic function, including end-diastolic pressure, end-diastolic pressure-end-diastolic diameter relationship, maximum negative dP/dt, and the time constant (tau) were unchanged after chronic norepinephrine infusion, although maximum end-diastolic pressure during volume loading was increased from 17.7 +/- 2.0 to 21.7 +/- 1.0 mmHg. Chronic norepinephrine infusion did not alter tau, and tau increased equivalently with phenylephrine injection in both normal (36 +/- 1 to 62 +/- 5 ms) dogs and in those chronically infused with norepinephrine (36 +/- 1 to 56 +/- 5 ms).(ABSTRACT TRUNCATED AT 250 WORDS)
Does basal production of nitric oxide contribute to regulation of brain-fluid balance?
Authors: Faraci F. M. , Heistad D. D.
Published: December 2017

Nitric oxide (NO), or a NO-containing compound, appears to mediate endothelium-dependent relaxation and may influence resting vascular tone. The goal of the present study was to examine the hypothesis that formation of NO has an important influence on blood flow to the brain and the choroid plexus. We measured blood flow with microspheres in anesthetized rabbits. Intravenous injection of NG-nitro-L-arginine (L-NNA, 3 and 30 mg/kg), an analogue of arginine that inhibits the enzymatic formation of NO, had no significant effect on cerebral blood flow. Arterial pressure was maintained at control levels after injection of L-NNA. In contrast, L-NNA decreased blood flow to the choroid plexus by 36 +/- 4 (mean +/- SE) and 51 +/- 8% (P less than 0.05 for both doses), respectively, from a control value of 563 +/- 77 ml.min-1.100 g-1. L-NNA also reduced blood flow to the kidney, but the effect tended to be less than that observed in the choroid plexus. Decreases in blood flow to the choroid plexus and kidney were inhibited by pretreatment with L-arginine (60 mg.kg-1.min-1). L-Arginine alone had little effect on blood flow to the choroid plexus, brain, or kidney. These findings suggest that NO, or a closely related compound, derived from L-arginine has important effects on basal perfusion of the choroid plexus, the major site of formation of cerebrospinal fluid.
Right and left ventricular function in fetal sheep exposed to long-term high-altitude hypoxemia
Authors: Kamitomo M. , Longo L. D. , Gilbert R. D.
Published: December 2017

To test the hypothesis that long-term hypoxemia affects fetal cardiac function, we measured right (RVO) and left (LVO) ventricular output by electromagnetic flow probes. We also determined their responses to increased preload (ventricular function curve, VFC) and afterload (arterial sensitivity curve, ASC). We exposed seven pregnant ewes to high altitude (3,820 m) from 30 to 120 days gestation, at which time surgery was performed. Thereafter, maternal arterial PO2 was maintained at approximately 60 Torr by N2 administration. Fetal arterial PO2 was significantly reduced in the hypoxemic fetuses (Hyp, n = 7) compared with that of control (Con, n = 9) (19.3 +/- 0.8 vs. 23.3 +/- 0.5 Torr, P less than 0.01). Mean arterial pressures in the Hyp group were elevated (52.0 +/- 1.2 vs. 44.4 +/- 1.7 mmHg, P less than 0.01) and fetal heart rate showed minimal change. Catecholamine concentrations in the Hyp group tended to be higher than the Con group, but not significantly so. For Con and Hyp, RVO equaled 275.7 +/- 9.1 vs. 183.1 +/- 10.1 (P less than 0.01), LVO equaled 165.7 +/- 16.9 vs. 141.6 +/- 16.5 (NS), and combined ventricular output (CVO) equaled 441.1 +/- 22.9 vs. 334.9 +/- 28.3 ml.min-1.kg-1 (P less than 0.05). For the LV there were no significant differences of the VFC between the Con and Hyp groups. However, the right VFC in the Hyp was significantly shifted downward. Concerning afterload, in the RV the slope of the ASC of Con was steeper than that of Hyp (-3.00 +/- 0.05 vs. -0.84 +/- 0.11 ml.ml.min-1.g-1.mmHg-1, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Apamin, a highly potent fetal L-type Ca2+ current blocker in single heart cells
Authors: Bkaily G. , Sculptoreanu A. , Jacques D. , Economos D. , Menard D.
Published: December 2017

Apamin, a bee venom polypeptide, was reported to block the naturally occurring Ca2+ slow action potentials (APs) in cultured cell reaggregates from old chick hearts [Bkaily, G. et al. Am. J. Physiol. 248 (Heart Circ. Physiol. 17): H961-H965, 1985] as well as the tetrodotoxin (TTX)- and Mn(2+)-insensitive slow Na+ current in young embryonic chick heart cells (Bkaily, G. In Vitro Toxicology. Academic, In press; Bkaily et al. J. Mol. Cell. Cardiol. 23: 25-39, 1991). With the use of the whole cell voltage-clamp technique in single ventricular cells from 10-day-old chick embryos and 17- to 20-wk-old human fetuses, two types of Ca2+ currents (ICa), T and L, were found. These two types of slow inward current in both heart preparations were nearly similar in their voltage, kinetics, and pharmacology. Apamin, a slow Ca2+ action potential blocker in old embryonic chick heart, was found to block the L-type ICa (IL) in a dose-dependent manner without affecting the T-type ICa in both heart cell preparations. The blockade of the IL by apamin was completely reversible upon washout with apamin-free solution. Therefore, when compared with nifedipine or to PN 200-110, apamin seems to be a highly potent L-type Ca2+ channel blocker in heart cells.
Strain distribution in small blood vessels with zero-stress state taken into consideration
Authors: Fung Y. C. , Liu S. Q.
Published: December 2017

The active and passive deformation of a blood vessel is related to the stress in it. Any analysis of stress and strain must begin with the zero-stress state. Recent reports on large blood vessels such as the aorta, pulmonary arteries, and vena cava have shown that, at zero-stress state, blood vessels are not tubes, but opens sectors. This report presents data on the zero-stress state of small blood vessels with lumen diameters down to approximately 50 microns. Zero-stress state of a vessel was obtained by cutting the vessel into rings and then the rings into sectors; each sector is characterized by an opening angle, alpha. In rat ileal and plantar arterioles, the opening angles are in the order of 100-250 degrees; those in the venules are in the order of 50-100 degrees. The effect of norepinephrine on the opening angle alpha is minor; it decreases alpha of the superior mesenteric artery, and increases alpha of the ileocecocolic and ileal arteries. EDTA has little effect on alpha of arteries greater than 100 microns in diameter, but decreases alpha of arteries less than 100 microns. The physiological meaning of the opening angle is demonstrated in terms of the residual strains in a vessel at the no-load state and homeostatic strains at normal blood pressure. The strains in real vessels are compared with those in hypothetical vessels having an opening angle of zero. It is shown that ignoring the opening angle will cause a large error in strain evaluation.(ABSTRACT TRUNCATED AT 250 WORDS)
C-myc protooncogene modulates cardiac hypertrophic growth in transgenic mice
Authors: Robbins R. J. , Swain J. L.
Published: December 2017

Protooncogenes such as c-myc have been implicated in the transduction of growth signals in the cardiac myocyte. We examined whether increases in c-myc expression occur in murine heart in vivo as a generalized response to the pharmacological stimulation of myocyte growth. Both triiodothyronine (T3) and the beta-adrenergic agonist isoproterenol were demonstrated to induce a rapid and transient increase in cardiac c-myc mRNA abundance, which preceded an increase in cardiac mass. We then examined whether myocyte growth could be modulated by selectively altering cardiac c-myc expression. The model system used was a strain of transgenic mice exhibiting a 20-fold increase in cardiac c-myc expression. Although in nontransgenic mice the administration of T3 and isoproterenol resulted in similar increases in cardiac mass, in transgenic mice the degree of myocardial growth induced with T3 was significantly greater than that induced with isoproterenol (P less than 0.001). This study demonstrates that increasing the basal expression of c-myc in cardiac myocytes alters the growth response of the heart in vivo to certain hypertrophic stimuli and implicates the c-myc protooncogene in the transduction of selective hypertrophic growth signals in differentiated cardiac myocytes.
Role of L-arginine-nitric oxide pathway in myocardial reoxygenation injury
Authors: Matheis G. , Sherman M. P. , Buckberg G. D. , Haybron D. M. , Young H. H. , Ignarro L. J.
Published: December 2017

In view of the recent findings that NO reacts with superoxide anion to generate hydroxyl radical, the present study was conducted to ascertain the role of endogenous NO in mediating myocardial reoxygenation injury in the hypoxic piglet on cardiopulmonary bypass. Anesthetized piglets were made hypoxic (PaO2 = 20-30 mmHg) for up to 120 min, followed by reoxygenation on cardiopulmonary bypass for 30 min. Reoxygenation caused rapidly developing myocardial injury characterized by decreased contractility (expressed as end-systolic elastance) and increased lipid peroxidation (measured as conjugated dienes). Systemic venous and coronary sinus blood content of NO decreased significantly during hypoxia and increased substantially above prehypoxic levels during reoxygenation on cardiopulmonary bypass. Administration of either the antioxidants mercaptopropionyl glycine and catalase or the NO synthase inhibitor, NG-nitro-L-arginine methyl ester, to the extracorporeal circuit afforded similar and nearly complete protection against myocardial reoxygenation injury. The protective effects of NG-nitro-L-arginine methyl ester were nullified by adding an excess of L-arginine to the pump circuit, suggesting that the L-arginine-NO pathway is involved in myocardial reoxygenation injury.
Effect of reduction in myocardial edema on myocardial blood flow and ventricular function after coronary reperfusion
Authors: Carlson R. E. , Aisen A. M. , Buda A. J.
Published: December 2017

The contribution of myocardial edema to the no-reflow phenomenon, left ventricular functional recovery, and infarct size after coronary occlusion and reperfusion is uncertain. To examine this, we studied 26 open-chest dogs after coronary occlusion and reperfusion. Twelve dogs received hypertonic mannitol 30 min before reperfusion, which increased serum osmolality (P less than 0.01 vs. control). Fourteen control dogs received a similar volume of saline that had no effect on serum osmolality. Tissue biopsies of central ischemic and normal myocardial areas were analyzed by proton nuclear magnetic resonance relaxation spectroscopy to assess edema content. Hypertonic mannitol resulted in a significant decrease in ischemic tissue T1 (767.0 +/- 16.3 vs. 818.6 +/- 19.0 ms, P less than 0.05) compared with the control group. Despite this, no significant differences were found between the mannitol and control groups in 4-h reperfusion subendocardial blood flow or left ventricular wall thickening. In addition, mannitol administered before reperfusion did not modify infarct size compared with the control group (infarct/risk area, 41.0 +/- 1.4 vs. 37.9 +/- 1.9%, P not significant). In conclusion, no benefit is produced in reperfusion blood flow or functional recovery by reducing edema in postischemic myocardial tissue. This suggests that mechanisms other than myocardial edema are responsible for myocardial no reflow and contractile dysfunction after coronary reperfusion. Furthermore, hypertonic mannitol administered before reperfusion does not reduce infarct size.
Evidence of spare A1-adenosine receptors in guinea pig atrioventricular node
Authors: Dennis D. , Jacobson K. , Belardinelli L.
Published: December 2017

In normoxic, isolated perfused guinea pig hearts instrumented for measurement of atrioventricular nodal conduction time (AVCT), an analysis utilizing the irreversible A1-adenosine (Ado) antagonist, meta-1,3-phenylene diisothiocyanate xanthine amine cogener (m-DITC-XAC), a novel isothiocyanate derivative of 1,3-dialkylxanthine, was used to investigate whether spare A1-Ado receptors exist in the guinea pig atrioventricular (AV) node and the degree of amplification (reserve) between A1-Ado receptor occupancy and dromotropic response (e.g., AVCT slowing). The potency, dose dependency, and kinetic profile (time dependence of washout and washin) of m-DITC-XAC was determined and compared with those of known competitive (reversible) A1-Ado receptor antagonists. In the presence of m-DITC-XAC, Ado and N6-cyclopentyladenosine (CPA) produced submaximal dromotropic responses. In a series of 19 hearts, m-DITC-XAC caused 100% apparent antagonism of the effect of Ado on AVCT even after 60 min of washout. In contrast, greater than 90% of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and XAC-induced antagonism of the effect of Ado on AVCT dissipated within 35 min. Unlike XAC, which caused maximal attenuation of Ado's AVCT effect within 5 min and remained constant thereafter, m-DITC-XAC showed marked time- and concentration-dependent behavior. It was found that 5 min of 0.5 microM m-DITC-XAC pretreatment irreversibly inactivated 72% of the A1-Ado receptors mediating the dromotropic effect, and the estimated agonist equilibrium dissociation constant for CPA was 84 +/- 4 nM. The percent of spare A1-Ado receptors at the EC50 and extrapolated maximal S-H interval prolongation levels was 20 and 54%, respectively, and the reserve (coupling amplification) varied from 1 to 2.3 within the 0-50% maximal response range. In summary, m-DITC-XAC appears to specifically and irreversibly antagonize the negative dromotropic effect of Ado and CPA, and guinea pig AV nodal tissue possesses spare A1-Ado receptors.
Superior and inferior vena caval flows during respiration: pathogenesis of Kussmaul's sign
Authors: Takata M. , Beloucif S. , Shimada M. , Robotham J. L.
Published: December 2017

Respiratory induced changes in superior (QSVC) and inferior (QIVC) vena caval flows and abdominal pressures were evaluated in anesthetized closed-chest dogs. QSVC and QIVC were measured with ultrasound transit time flow probes (n = 5), and general (Pab) and regional subdiaphragmatic (Pd) abdominal pressures were measured by air-filled balloons (n = 5), during two respiratory maneuvers produced by phrenic nerve stimulation, i.e., simulated spontaneous inspiration (SSI), and Mueller maneuver (MM), with the airway occluded to minimize diaphragmatic descent. With hypervolemia: during SSI, QSVC decreased, QIVC increased, and right atrial pressure increased (P less than 0.05) despite a decrease in esophageal pressure (Pes), i.e., Kussmaul's sign; during MM, both QSVC and QIVC increased (P less than 0.05) without Kussmaul's sign. The ratios delta Pab/delta Pes and delta Pd/Pes were larger during SSI than MM (P less than 0.01). With hypovolemia: during SSI and MM, QSVC increased and QIVC decreased with a venous pressure gradient across the diaphragm (P less than 0.05), consistent with development of a vascular waterfall. These results suggest that 1) changes in abdominal pressure may affect the patterns of QSVC and QIVC during respiration, depending on blood volume status; 2) a prolonged inspiration with hypovolemia may decrease QIVC because of the development of a vascular waterfall; 3) QSVC and QIVC may be interdependent during respiration; and 4) the essential mechanism of Kussmaul's sign is a substantially larger inspiratory increase in abdominal pressures produced by diaphragmatic descent compared with the decrease in intrathoracic pressure under hypervolemic conditions, rather than the presence of pericardial pathology or right heart dysfunction.
Hemodynamic changes in rats after opening an arteriovenous fistula
Authors: Huang M. , Hester R. L. , Guyton A. C.
Published: December 2017

Time course of multiple hemodynamic changes in rats after opening an AV fistula was assessed. The fistula was made in male Sprague-Dawley rats by anastomosing the aorta and vena cava below the renal arteries. At 1 h (1H), 1 day (1D), 1 wk (1W) and 5 wk (5W) in sham controls or after opening an AV fistula, we measured cardiac output (CO) and tissue flows by using radioactive microspheres. The flow of microspheres to the lungs was used as a measure of shunt flow. In the fistula animals this lung flow (fistula flow) was 50-77% of the CO compared with 1-3% in the control animals. Cardiac index in the fistula animals increased by 40, 107, 129, and 307% compared with the respective control animals in the consecutive time groups. Systemic flow, tissue flows, and mean arterial blood pressure (MAP) in the fistula animals in the 1H and 1W groups were significantly decreased below control values, but each of these variables returned to control levels after 5W. Hematocrit (Hct) significantly decreased, whereas right atrial pressure (RAP) gradually increased over the experimental period. These two observations suggest retention of fluid. Plasma renin activity increased in the 1H animals but returned to control in the 1D animals. Atrial natriuretic peptide (ANP) gradually increased throughout the 5 wk from 86 +/- 22 (1H) to 709 +/- 217 pg/ml (5W). The increase in ANP correlated with the increase in RAP. Calculated total peripheral resistance in fistula animals was significantly decreased throughout the experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
Compensatory recovery of parasympathetic control of heart rate after unilateral vagotomy in rabbits
Authors: Lund D. D. , Davey G. A. , Subieta A. R. , Pardini B. J.
Published: December 2017

Compensatory recovery by the intact vagal innervation after unilateral vagotomy was investigated by measuring parasympathetic-mediated control of heart rate in beta-adrenergic-blocked rabbits. Direct contralateral vagal nerve stimulation produced greater bradycardia in anesthetized rabbits with chronic vagotomy compared with acutely vagotomized controls. Vagal stimulation during acetylcholinesterase inhibition by physostigmine and direct neuroeffector stimulation by methacholine indicated that a change in metabolism of the neurotransmitter or an increased sensitivity of the tissue to acetylcholine were not responsible for augmentation of vagal responses. Baroreflex control of heart rate in response to an increase in arterial pressure was also tested in urethan-anesthetized rabbits. There was a significant reduction in the prolongation of the R-R interval during baroreflex activation acutely after midcervical vagotomy. These values were subsequently above control levels in rabbits 28 days after vagotomy. In conscious rabbits, the decrease in baroreflex control of heart rate progressively recovered to control levels within 6 days. These results suggest that the recovery mechanism after unilateral vagotomy may be related to peripheral and central compensatory changes in the intact contralateral vagus nerve.
Leukocyte plugging in vivo in skeletal muscle arteriolar trees
Authors: Warnke K. C. , Skalak T. C.
Published: December 2017

To provide quantitative data on leukocyte plugging and to estimate its effects on blood flow resistance in the microcirculation, in vivo observations of leukocyte plugging of capillaries were made in all branches of 27 terminal arteriolar trees in spinotrapezius muscles of anesthetized Sprague-Dawley rats. The durations of 1,257 observed plugs had a lognormal distribution with a median of 0.12 s. Of 596 branches, 211 experienced at least one plug; this subpopulation had a median plugging frequency of 0.016/s and a median plugging fraction (plugging frequency times average duration) of 0.28%. A new variable, the network occlusion fraction, was defined to quantify plugging in a whole arteriolar tree. Applying in vivo data to a model relating plugging to resistance increases resulted in a lognormal distribution of resistance increases with a median of 1.6%. Each of the resistance increases that were greater than 3% was due to one or two individual leukocytes that plugged a capillary for greater than 30 s. The results suggest that, under physiological conditions, leukocyte plugging has little effect on blood flow resistance.