bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrinsic cardiac enkephalins inhibit vagal bradycardia in the dog
Authors: Caffrey J. L. , Mateo Z. , Napier L. D. , Gaugl J. F. , Barron B. A.
Published: December 2017

Met-enkephalin-Arg-Phe (MEAP) has been identified in acid extracts of canine heart tissue. The effects of synthetic MEAP on the vagal control of heart rate were investigated in anesthetized dogs. The arterial infusion of MEAP (3 nmol.min-1.kg-1) inhibited the bradycardia observed during electrical stimulation of the right vagus nerve by 72%. After the infusion was stopped, the responsiveness to vagal stimulation returned to normal, with a half-time between 2 and 3 min. The inhibition by MEAP was reversed by the high-affinity opiate antagonist diprenorphine (100 micrograms/kg). MEAP did not alter the negative chronotropic effect of the direct-acting muscarinic agonist methacholine. This observation suggested that MEAP exerted its effect at a site in the efferent vagal tract proximal to nodal muscarinic receptors. Increasing MEAP infusions (0.09-3.00 nmol.min-1.kg-1) produced a graded suppression of vagal bradycardia, with a half-maximal effect near 0.3 nmol.min-1.kg-1. Met-enkephalin (ME) produced responses very similar to those obtained with MEAP. The effects of ME were also blocked by prior administration of diprenorphine. Dose responses to ME were shifted to the right of those for MEAP, and half-maximal responses for ME were obtained at two to four times the dose required for MEAP. The data suggest that the intrinsic cardiac enkephalin MEAP can regulate vagal control of heart rate at physiologically achievable concentrations and may serve as a local regulator of the parasympathetic-myocardial interface.
Acute compensation to abrupt occlusion of rat femoral artery is prevented by NO synthase inhibitors
Authors: Unthank J. L. , Nixon J. C. , Dalsing M. C.
Published: December 2017

Pages H5237–H2530: J. L. Unthank, J. C. Nixon, and M. C. Dalsing. “Acute compensation to abrupt occlusion of rat femoral artery is prevented by NO synthase inhibitors.” The volume number and year in the abstract line were incorrectly cited and should appear as the following.

Unthank, Joseph L., J. Craig Nixon, and Michael C. Dalsing. Acute compensation to abrupt occlusion of rat femoral artery is prevented by NO synthase inhibitors. Am. J. Physiol. 267 ( Heart Circ. Physiol. 36): H2523–H2530, 1994.
Critical role of endothelium in sustained arterial contraction during prolonged hypoxia
Authors: Yang B. C. , Mehta J. L.
Published: December 2017

Acute anoxia or severe hypoxia causes an initial transient contraction followed by marked relaxation of vascular tissues. We observed a spontaneous gradual sustained contraction of rat aortic rings following relaxation when hypoxia was prolonged. Deendothelialization as well as treatment of the endothelium-intact rings with nitric oxide synthase inhibitors or oxyhemoglobin abolished the late hypoxic contraction despite prolonged hypoxia. The prolonged hypoxia-induced sustained contraction was not affected by adenosine receptor blockade, cyclooxygenase inhibition, free radical scavengers, or the endothelin receptor antagonists. The ATP-sensitive K+ channel blocker glibenclamide abbreviated the duration of hypoxic relaxation and potentiated the magnitude of late hypoxic contraction. These data suggest that the late-sustained hypoxic contraction of arterial tissues is dependent on the presence of intact functional endothelium. Activation of ATP-sensitive K+ channels may participate in the genesis of hypoxic relaxation. However, cyclooxygenase products, free oxygen radicals, adenosine, and endothelin are not involved in the regulation of hypoxia-mediated events in rat aortic rings.
Role of nitric oxide and cAMP in beta-adrenoceptor-induced pial artery vasodilation
Authors: Rebich S. , Devine J. O. , Armstead W. M.
Published: December 2017

The present study was designed to investigate the role of nitric oxide (NO), guanosine 3',5'-cyclic monophosphate (cGMP), and adenosine 3',5'-cyclic monophosphate (cAMP) in the vasodilator response to beta-adrenoceptor agonists in newborn pigs equipped with a closed cranial window. Dobutamine (10(-8) and 10(-6) M), a beta 1-agonist, produced pial artery dilation that was blunted by NG-nitro-L-arginine (L-NNA; 10(-6) M), a NO synthase inhibitor (12 +/- 1 vs. 0 +/- 2% and 24 +/- 3 vs. 4 +/- 1% for 10(-8) and 10(-6) M dobutamine, respectively). Dobutamine-induced vasodilation was associated with increased cortical periarachnoid cerebrospinal fluid (CSF) cGMP, and these changes in CSF cGMP were blocked by L-NNA (391 +/- 10 and 675 +/- 36 fmol/ml vs. 307 +/- 3 and 346 +/- 37 fmol/ml for control and 10(-6) M dobutamine before and after L-NNA, respectively). In contrast, dobutamine-associated changes in CSF cAMP were unchanged by L-NNA (1,108 +/- 56 and 2,623 +/- 139 fmol/ml vs. 1,059 +/- 24 and 2,500 +/- 61 fmol/ml for control and 10(-6) M dobutamine before and after L-NNA, respectively). Salbutamol, a beta 2-agonist, and isoproterenol, a nonselective beta-agonist, elicited similar changes in pial diameter and cyclic nucleotides; vasodilation and changes in CSF cGMP also were similarly inhibited by L-NNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Inducible L-arginine/nitric oxide pathway in human internal mammary artery and saphenous vein
Authors: Thorin-Trescases N. , Hamilton C. A. , Reid J. L. , McPherson K. L. , Jardine E. , Berg G. , Bohr D. , Dominiczak A. F.
Published: December 2017

To characterize the L-arginine/nitric oxide (NO) pathway in human vascular smooth muscle (VSM), contractile responses of isolated internal mammary arteries (IMA) and saphenous veins (SV) were observed after induction of NO synthase by interleukin-1 beta (IL-1 beta) or by lipopolysaccharide (LPS). In IL-1 beta-treated endothelium-denuded rings, contractile responses to phenylephrine were reduced in SV rings only. Maximum phenylephrine-induced contraction was depressed by approximately 50%. This was not modified by the presence of indomethacin, NG-nitro-L-arginine methyl ester (L-NAME), or methylene blue (MeB). In LPS-treated vessels, contractile responses were depressed in both SV and IMA rings (40%), and this was not affected by indomethacin. In SV, L-NAME, NG-monomethyl-L-arginine, or MeB did not affect the inhibitory effect of LPS, whereas the effect was reversed in IMA by these inhibitors. In LPS-treated IMA, but not in SV, exogenous L-arginine evoked significant vasodilation (20%). We conclude that VSM of the human IMA possesses an L-arginine/NO pathway inducible by LPS. In SV, LPS or IL-1 beta treatment inhibits contraction by an unidentified system that is not dependent on NO synthase or on guanylate cyclase activities.
Vessel tone affects transmural distribution of coronary flow during hypoperfusion
Authors: Buffington C. W. , Watanabe S.
Published: December 2017

Subendocardial flow is selectively impaired during coronary hypoperfusion. Systolic compression of intramyocardial vessels not only stops capillary flow but empties vessels as well, leading to reversed flow in the arteries that penetrate the myocardium. The tone of these vessels influences the magnitude of flow oscillation during the cardiac cycle, but whether vessel tone is an independent determinant of subendocardial perfusion during coronary hypoperfusion has not been determined. The discovery of endothelin (ET-1) has made it possible to counteract metabolic vasodilation and increase vessel tone during hypoperfusion. A shunt from a carotid artery to the left anterior descending coronary artery was installed in open-chest pigs anesthetized with halothane. Arterial pressure and heart rate were held constant, and coronary pressure was reduced in stages by restricting shunt flow during intracoronary infusion of ET-1 (n = 7) or adenosine (n = 5). Microspheres were injected at each stage to determine layer flow. Coronary resistance was two- to three-fold higher and subendocardial flow was lower at similar coronary pressures in the animals receiving ET-1 than in those receiving adenosine. In contrast, flow distribution across the left ventricular wall was more homogeneous with ET-1 than with adenosine, even at coronary pressures low enough to cause lactate production and regional hypokinesis. These results demonstrate that vessel tone has an independent effect on absolute subendocardial flow as well as transmural flow distribution during coronary hypoperfusion.
Segmental motion and deformation of transmurally infarcted myocardium in acute postinfarct period
Authors: Lima J. A. , Ferrari V. A. , Reichek N. , Kramer C. M. , Palmon L. , Llaneras M. R. , Tallant B. , Young A. A. , Axel L.
Published: December 2017

Mechanical behavior of infarcted myocardium in the first week following coronary occlusion has not been well characterized. Prior unidimensional studies failed to account for perpendicular deformation or shearing. This study characterizes three-dimensional motion and deformation of transmural infarcts 1 wk after coronary ligation in seven sheep. Principal strains and systolic in-plane translation and rotation were calculated for triangular elements defined by tissue tagging in short- and long-axis magnetic resonance images. The magnitudes of the first and second principal strains were reduced in both the short- and long-axis planes 1 wk after infarction. In addition, the absolute angular difference between the direction of the first principal strain and the radial direction increased from 14.7 +/- 1.9 to 43.5 +/- 2.7 degrees in the short-axis plane and from 19.6 +/- 7.3 to 43.9 +/- 10.0 degrees (P < 0.05) in the long-axis plane. In-plane rigid-body translation and rotation were also reduced in both planes. In conclusion, marked reduction and reorientation of principal strains and reduction in segmental rigid-body motion characterize nonreperfused transmural myocardial infarctions 1 wk after coronary occlusion.
Impairment of cardiopulmonary baroreflexes during the newborn period
Authors: Merrill D. C. , McWeeny O. J. , Segar J. L. , Robillard J. E.
Published: December 2017

The present study was designed to characterize the maturation of cardiopulmonary reflex control of renal sympathetic nerve activity (RSNA) independent of influences from the arterial baroreflex. Studies were conducted in conscious newborn lambs (3- to 7-days-old) (n = 16) and older lambs (6- to 8-wk-old) (n = 18). All animals underwent either sinoaortic denervation (SAD) or a sham procedure. Hemodynamic, humoral, neural, and renal responses to volume expansion (6% Dextran 70, 0.7 ml.kg-1.min-1 x 60 min) were recorded. Volume expansion resulted in a significant decrease (P < 0.05) in RSNA in intact newborn (-28.1 +/- 5.3% change from control) and older lambs (-19.4 +/- 10.1%). SAD totally abolished the sympathetic inhibition seen with volume expansion in newborn lambs (-3.6 +/- 5.7%) but not in older lambs (-25.6 +/- 8.4%). Right atrial pressure increased in a similar fashion in both newborn (intact: 5.6 +/- 0.5 mmHg; SAD: 6.1 +/- 0.8 mmHg) and older lambs (intact: 5.2 +/- 0.9 mmHg; SAD: 5.3 +/- 0.9 mmHg) and was not altered by SAD. The reflex bradycardia seen with volume expansion in newborn lambs was blocked by SAD. The present study demonstrates that, during the newborn period, the RSNA and heart rate responses to volume expansion are dependent mainly on the integrity of the arterial baroreflex. Furthermore, these studies suggest that cardiopulmonary reflex control of RSNA in response to volume expansion is impaired early in life and increases with maturation.
Selective kallikrein inhibitors alter human neutrophil elastase release during extracorporeal circulation
Authors: Wachtfogel Y. T. , Hack C. E. , Nuijens J. H. , Kettner C. , Reilly T. M. , Knabb R. M. , Bischoff R. , Tschesche H. , Wenzel H. , Kucich U. , et al.
Published: December 2017

Cardiopulmonary bypass causes hemorrhagic complications and initiates a biochemical and cellular “whole body inflammatory response.” This study investigates whether a variety of selective inhibitors of the contact pathway of intrinsic coagulation modulate complement and neutrophil activation during simulated extracorporeal circulation. After 60 min of recirculation in the presence of the slow tight-binding boronic acid inhibitor, Bz-Pro-Phe-boroArg-OH (10.7 microM), complete inhibition of kallikrein-C1-inhibitor complex formation and marked inhibition of C1-C1-inhibitor complex formation and the release of human neutrophil elastase were observed. Arg15-aprotinin (3.1 microM), Ala357,Arg358 alpha 1-antitrypsin (2.6 microM), and soybean trypsin inhibitor (48.0 microM) either completely or partially inhibited the generation of kallikrein-C1-inhibitor complexes but were less effective inhibitors of human neutrophil elastase release. The second-order rate constants for the inhibition of kallikrein in purified systems are consistent with the order of effectiveness of the inhibitors in blocking human neutrophil elastase release in heparinized blood. Our results suggest that low-molecular-weight selective inhibitors of kallikrein may be effective agents in the attenuation of the contact-mediated inflammatory response in cardiopulmonary bypass.
Calcium currents in ventricular myocytes of prehypertrophic cardiomyopathic hamsters
Authors: Li G. R. , Ferrier G. R. , Howlett S. E.
Published: December 2017

Possible changes in Ca2+ currents (ICa), which might contribute to Ca2+ overload in young (70- to 100-day-old) cardiomyopathic (CM) hamster hearts, were determined in isolated ventricular myocytes with conventional recording and discontinuous single-electrode voltage-clamp techniques. Action potential duration at 90% repolarization (APD90) was significantly longer in CM myocytes compared with normal cells (APD90 = 120.3 +/- 4.5 vs. 98.2 +/- 5.9 ms, P < 0.01). Input resistance, membrane time constant, and membrane capacitance were similar in normal and CM myocytes. Current-voltage (I-V) relations for peak ICa were depressed in CM cells compared with normal cells; this difference was statistically significant at the peak of the I-V curve. Activation and inactivation relations for ICa and recovery from inactivation were similar in myocytes from normal and CM hearts. These changes occurred in myocytes from young CM animals before development of heart failure. Results indicate that increased Ca2+ influx through L-type Ca2+ channels does not account for the longer APD in cardiomyopathy and is not involved in the development of Ca2+ overload in cardiomyopathy.
Synergistic regulation of ANF in isolated rat hearts
Authors: Jiao J. H. , Baertschi A. J.
Published: December 2017

The interaction between cardiac sympathetic stimulation of atrial natriuretic factors (ANF) release and left atrial stretch was examined in groups (n = 5 or 6) of isolated, perfused (10 ml/min), paced rat hearts. Left atrial stretch, produced by an increase in atrial pressure of 1.1 +/- 0.2 mmHg over 8 min, transiently (4 min) increased ANF release by 46 +/- 4% over baseline (220 pg/ml buffer; P < 0.05). Infusion of 1 microM norepinephrine (NE) over 28 min caused a sustained increase in ANF release of 76 +/- 10% (P < 0.05). Atrial stretch plus NE caused additive effects on ANF release during stretch but 2.4 times the additive effects after stretch (P < 0.05). To examine whether resting tension modulates the ANF response to sympathetic stimulation, the left atrium was stretched throughout the experiment by increasing the atrial pressure by 1–1.5 mmHg. Infusion of 1 microM NE over 28 min increased ANF release by 216 +/- 46% (P < 0.01) in the prestretched heart, compared with a calculated summed increase of 85% due to NE alone plus prestretch alone. Infusion of 0.5 microM veratridine, known to stimulate ANF via mechanical effects on the heart, increased ANF release by 88 +/- 3% (P < 0.01). Scorpion venom, known to dose dependently stimulate ANF secretion via activation of neuronal sodium channels, elicits a negligible increase in ANF release at the threshold concentration of 0.1 microM. The combined infusion of 0.5 microM veratridine plus 0.1 microM venom increased ANF release by 239 +/- 53% (n = 6, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Human endothelial cell morphology and autacoid expression
Authors: de Groot C. J. , Chao V. A. , Roberts J. M. , Taylor R. N.
Published: December 2017

Human umbilical vein endothelial (HUVE) cells plated on plastic or gelatin-coated dishes grow as a “cobblestone” monolayer. By contrast, endothelial cells cultured on a complex matrix (e.g., Matrigel) form three-dimensional, capillary-like structures. In the current study, we verified the capillary phenotype of the latter structures and asked whether the morphological changes induced by extracellular matrix also affect human endothelial gene expression and function in vitro. Concentrations of cellular fibronectin, prostacyclin, and endothelin-1 were measured in the conditioned media by enzyme-linked immunosorbent and radioimmunoassays. Steady-state concentrations of HUVE mRNA were estimated by reverse transcription-polymerase chain reaction and quantified by Northern analyses to assess fibronectin and endothelin-1 gene expression. We found that the subjacent extracellular matrix affects the morphology, proliferation, and differentiation of HUVE cells in vitro. Cells cultured on gelatin were more mitotically active, expressed significantly less cellular fibronectin, made similar amounts of prostacyclin, and secreted significantly more endothelin-1 compared with the same cells grown on a Matrigel substrate.
Palmitate uptake by cardiac myocytes and endothelial cells
Authors: Burczynski F. J. , Cai Z. S. , Moran J. B. , Geisbuhler T. , Rovetto M.
Published: December 2017

The mechanisms regulating the cellular uptake of long-chain fatty acids are poorly understood. Although there is evidence that hepatocytes facilitate the uptake of ligands from the protein-bound fraction, it is not known whether cardiac myocytes also facilitate the uptake process. The present studies were designed to address the role of albumin in the uptake of long-chain fatty acids by cardiac myocytes isolated from adult male rats. At low albumin concentrations (1 microM), the myocyte palmitate clearance rate did not exceed that predicted by the diffusion-reaction model. At high albumin concentrations (300 and 600 microM), the clearance ratio test was used to determine whether myocytes facilitate the uptake of palmitate. As with the low albumin concentrations, the diffusion-reaction model accounted for the overall clearance rates. Because endothelial cells might be involved in enhancing fatty acid transport into myocytes, we also determined the effects of endothelial cells on palmitate uptake by cardiac myocytes. Based on cell number, the palmitate clearance rate by endothelial cells in the presence of albumin was only 7% of the cardiac myocyte clearance rate. Combining the endothelial cells with the myocytes did not result in any synergistic effect on the palmitate clearance rate.
Methodology of spontaneous baroreflex relationship assessed by surrogate data analysis
Authors: Blaber A. P. , Yamamoto Y. , Hughson R. L.
Published: December 2017

We tested the hypothesis that the spontaneous beat-by-beat interactions of systolic blood pressure (SBP) and R-R interval reflected true baroreflex events rather than chance interactions. Original data sets of 1,024 heartbeats obtained in seated rest from six healthy subjects [R-R interval = 953 +/- 94 (+/- SE) ms] were compared with isospectral [generated by a windowed (inverse) Fourier transform with phase randomization] and isodistribution (data points randomly shuffled) surrogate data sets. The isospectral data set was used to test for random phase relationships, and the isodistribution data set was used for effects of white noise between SBP and R-R interval. Spontaneous baroreflex sequences were defined as three or more beats in which SBP and the R-R interval of the same (lag 0), next (lag 1), or next following (lag 2) beat changed in the same direction. The total number of baroreflex sequences in the original data was significantly greater than the surrogates (P < 0.001). In the original data, there were significantly (P < 0.001) more lag 0 than lag 1 or lag 2 baroreflex sequences. Therefore, these results indicated that spontaneous baroreflex sequences represented physiological rather than chance interactions and that baroreflex responses can occur within the same beat.
Influence of sleep and myometrial activity on systemic and uteroplacental hemodynamics in pregnant ewes
Authors: Fewell J. E.
Published: December 2017

Little is known about the influence of sleep on systemic and uteroplacental hemodynamics during pregnancy. Experiments were therefore carried out on six chronically instrumented pregnant ewes (125–133 days of gestation) to investigate the influence of sleep on systemic and uteroplacental hemodynamics. Because nonlabor myometrial activity influences uteroplacental hemodynamics, we made measurements during quiet wakefulness, quiet sleep, and active sleep in the presence and absence of myometrial activity. Cardiac output, heart rate, and systemic arterial pressure were decreased in active sleep compared with quiet wakefulness; these variables were not significantly altered by myometrial activity. The interaction between sleep and myometrial activity was such that the lowest values of uteroplacental blood flow, as estimated from middle uterine artery blood flow to the pregnant uterine horn and, hence, uteroplacental oxygen delivery occurred during active sleep in the presence of myometrial activity (i.e., decreased approximately 19% compared with quiet wakefulness and the absence of myometrial activity). Further investigation is required to determine the possible fetal consequences of a reduced uteroplacental perfusion in the presence of myometrial activity during sleep.
Impaired subendocardial function in tachycardia-induced cardiac failure
Authors: LeGrice I. J. , Takayama Y. , Holmes J. W. , Covell J. W.
Published: December 2017

Chronic rapid ventricular pacing (CRVP) in many experimental models induces ventricular dilatation, reduced ejection fraction, and symptomatic congestive heart failure. We have investigated transmural mechanical function in the left ventricular (LV) wall of five Hanford miniature swine before and after CRVP-induced failure. Three columns of radiopaque markers 1 mm in diameter were implanted in the anterior LV wall through a median sternotomy. A pair of LV pacing wires were sutured into the myocardium, a pneumatic cuff was placed around the inferior vena cava (IVC), and two fluid-filled Silastic catheters were implanted into the LV apex. Two weeks after surgery, the pigs were suspended awake in a sling, and markers were tracked with biplane cineradiography. The hearts were paced for 3 wk (225-240 beats/min), and the study was repeated with the pacemaker off. Saline infusion and IVC occlusion were used to vary LV end-diastolic pressure (EDP) so control-to-failure comparisons could be made at matched LV EDPs. End-systolic strains in the circumferential (E11), longitudinal (E22), and transmural (E33) directions were quantified using finite element methods. There was a significant reduction in E11 and E33 for the subendocardium: in E11, from -0.27 to -0.18; in E33, from 0.83 to 0.46. There were no significant changes in subendocardial E22 or in any of the outer wall normal strains. These results indicate that CRVP causes substantial reduction of subendocardial, but not subepicardial, function; taken together with previous data indicating subendocardial hypoperfusion, these results support the contention that an imbalance between blood flow and oxygen demand plays a role in the etiology of heart failure in this model.
Effects of inotropic stimulation on energy metabolism and systolic function of ischemic right ventricle
Authors: Greyson C. , Garcia J. , Mayr M. , Schwartz G. G.
Published: December 2017

This study determined whether dobutamine enhances regional systolic function in the ischemic right ventricle (RV) at the cost of adverse effects on regional energy metabolism. Seventeen alpha-chloralose-anesthetized, open-chest pigs were studied under four conditions: 1) control; 2) dobutamine infusion (mean dose 9 micrograms.kg-1.min-1); 3) RV ischemia (45 +/- 5% reduction in RV free wall blood flow for 100 min); and 4) continued ischemia with dobutamine. Regional RV free wall high-energy phosphate metabolites were measured by 31P nuclear magnetic resonance (NMR) spectroscopy or by high-speed drill biopsies of the RV free wall. Regional RV free wall substrate and O2 consumption were measured using coronary venous blood sampling. Global RV systolic function was assessed by the maximal first derivative of RV pressure (dP/dtmax), and regional RV free wall systolic function was assessed by systolic segment shortening in the ischemic zone. Right coronary artery constriction caused markedly depressed regional RV systolic function, net lactate production, and coronary venous acidosis. Surprisingly, high-energy phosphates were unchanged compared with control. Addition of dobutamine caused a further decline in coronary venous pH and continued lactate production but did not reduce high-energy phosphates. While dobutamine markedly enhanced global RV systolic function (RV dP/dtmax 201 +/- 19% of control), systolic shortening in the ischemic RV free wall remained severely depressed (47 +/- 18% of control) despite dobutamine. The mechanism of high-energy phosphate preservation is likely due to diminished consumption of ATP in the hypocontractile ischemic region.
Platelet-activating factor increases vascular resistance in rat hindquarters by thromboxane A2
Authors: Rizzo A. , Taylor A. E. , Townsley M. I. , Logsdon P. , Khimenko P. L. , Fletcher J. R.
Published: December 2017

The effects of platelet-activating factor (PAF) on vascular resistance and capillary permeability were studied in the isolated rat hindquarter. Six groups were studied (n = 30): control; PAF alone (1.4 microM); and PAF (1.4 microM) pretreated with ibuprofen (30 mg/kg), thromboxane A2 (TxA2)-receptor antagonist (BM-13505, 2 mg/kg), PAF-receptor antagonist (WEB-2086, 5 mg/kg), or dexamethasone (5 mg/kg). The vascular resistance was calculated, and the reflection coefficient (sigma) was determined as an index of capillary permeability. Exogenous PAF caused a threefold increase in vascular resistance peaking at 5 min and a 2.5-fold increase in capillary permeability. The increased vascular resistance caused by PAF alone was significantly attenuated by ibuprofen, BM-13505, and dexamethasone. The PAF-induced permeability was neither attenuated by ibuprofen nor BM-13505. However, both the increased vascular resistance and permeability were blocked and attenuated by WEB-2086 and dexamethasone, respectively. We conclude that TxA2 mediates the PAF-induced increased vascular resistance; however, the increased vascular permeability is independent of the formation of TxA2 in the isolated hindquarter.
Role of chloride currents in repolarizing rabbit atrial myocytes
Authors: Wang Z. , Fermini B. , Feng J. , Nattel S.
Published: December 2017

Rabbit atrial cells manifest a prominent transient outward K+ current (Ito1), but this current recovers slowly from inactivation and is unlikely to be important at physiological rates (3-5 Hz). Depolarization of rabbit atrial cells also elicits a transient Ca(2+)-dependent outward Cl- current (Ito2). To compare the relative magnitude of these transient outward currents at various rates, we applied whole cell voltage-clamp techniques to isolated rabbit atrial myocytes. Whereas peak Ito1 exceeded Ito2 at slow rates (0.1 Hz), Ito1 was strongly reduced as rate was increased (by 97 +/- 2%, mean +/- SE, at 4 Hz), while Ito2 was slightly reduced (by 28 +/- 4%, 4 Hz). The reversal potential of transient outward tail currents at 0.07 Hz was -49 +/- 9 mV, while at 2.5 Hz the reversal potential became -18 +/- 7 mV (calculated Cl- reversal potential -18 mV). The addition of the Cl- transport blocker 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS; 150 microM) or the replacement of external Cl- with methanesulfonate inhibited a large part of the transient outward current elicited by depolarization at 4 Hz. DIDS and Cl- replacement increased action potential duration in both single rabbit atrial cells and multicellular rabbit atrial preparations. We conclude that the Ca(2+)-dependent Cl- current is substantially larger than the transient K+ current at physiological rates in the rabbit and is likely to play a more important role in action potential repolarization than the latter current in this tissue in vivo.
Contributions of sickle hemoglobin polymer and sickle cell membranes to impaired filterability
Authors: Hiruma H. , Noguchi C. T. , Uyesaka N. , Schechter A. N. , Rodgers G. P.
Published: December 2017

Sickle cell anemia is a disease of abnormal rheology caused by acute and reversible, as well as chronic and irreversible, changes in the properties and deformability of sickle erythrocytes. Deformability is determined by several factors, including intracellular sickle hemoglobin polymerization, the abnormal membrane properties of sickle cells, and the abnormal rheological properties of the soluble concentrated hemoglobin solution within dense sickle red blood cells. In this study, we used a 5-microns pore nickel mesh filter to evaluate quantitatively the effects of these factors on the filterability of erythrocytes containing sickle hemoglobin. We used sickle trait and sickle/beta(+)-thalassemia cells, because they have minimal membrane abnormalities or density heterogeneity, to investigate the effects of polymer formation on rheological properties. We found that filterability of these cells is sensitive to small amounts of intracellular polymer and that impaired filtration is linearly related to oxygen-dependent polymer formation, up to a polymer fraction of 0.3. By increasing the proportion of dense cells in populations of normal cells or cells from individuals with sickle syndromes and equilibrating these cells with gas ligands, we estimate that polymerization, even at 95% saturation, contributes twice as much to impaired filterability of sickle erythrocytes as the abnormal membranes in homozygous sickle cell disease. At lower saturation values, the effects of polymer are even greater. The viscosity of the concentrated hemoglobin in dense cells had the smallest effect, over physiologically relevant saturation values. These results emphasize the importance of sickle hemoglobin polymerization in the pathogenesis of sickle cell disease and should help define its pathophysiology and responses to therapy in quantitative terms.
Video microscopy of cerebrocortical capillary flow: response to hypotension and intracranial hypertension
Authors: Hudetz A. G. , Feher G. , Weigle C. G. , Knuese D. E. , Kampine J. P.
Published: December 2017

Although autoregulation of cerebral blood flow is well established, the response of cerebral capillary circulation to reduced cerebral perfusion pressure (CPP) is unclear. The objective of this study was to determine whether red cell flow velocity in individual capillaries of the cerebral cortex is maintained during acute decreases in CPP. Microcirculation of the superficial parietal cerebral cortex of adult barbiturate-anesthetized artificially ventilated rats was visualized using a new design of closed-perfused cranial window and epifluorescent-intensified video microscopy. Fluorescein-isothiocyanate-labeled red blood cells (FRBC) injected intravenously were used as markers of capillary flow. CPP, defined as mean arterial pressure minus intracranial pressure, was reduced by controlled hemorrhage or by stepwise elevation of local intracranial pressure. The movement of FRBC in the parenchymal capillary network was video recorded at each pressure level, and FRBC velocity in each capillary was measured off-line with use of the dual-window digital cross-correlation technique. FRBC flux in the capillaries was measured by automated cell counting. FRBC velocity at normal perfusion pressure was 1.47 +/- 0.58 (SD) mm/s and changed little in the perfusion pressure range of 70-120 mmHg. The autoregulatory index in this pressure range was 0.0049 mm.s-1.mmHg-1. Opening of previously unperfused capillaries was not observed. FRBC flux correlated with FRBC velocity, but the latter was maintained in a narrower range than FRBC flux, suggesting a decrease in capillary diameter or hematocrit with decreasing perfusion pressure. The results suggest that flow autoregulation is associated with the maintenance of capillary flow velocity and that capillary recruitment does not contribute to flow autoregulation in the rat cerebral cortex.
Continuous, on-line, real-time spectral analysis of SAP signals during cardiopulmonary bypass
Authors: Yang M. W. , Kuo T. B. , Lin S. M. , Chan K. H. , Chan S. H.
Published: December 2017

We communicated the application of continuous, on-line, real-time power spectral analysis of systemic arterial pressure (SAP) signals during cardiopulmonary bypass when the heart was functionally but reversibly disconnected from the blood vessels. Based on observations from 15 cases of successfully completed coronary artery bypass grafting procedures, we found that the very low (0.00-0.08 Hz), low (0.08-0.15 Hz)-, high (0.15-0.25 Hz)-, and very high (0.80-1.60 Hz) frequency components of SAP signals exhibited differential changes before, during, and after cardiopulmonary bypass. In particular, the very low-frequency component, which purportedly represents the contribution of vasomotor activity to SAP, presented only a mild decrease in power during hypothermic cardioplegia. Interestingly, the total peripheral resistance also manifested only a slight reduction during the same period. On the other hand, the low-, high-, and very high frequency components were essentially eliminated. These results unveiled an active role for the blood vessels in the maintenance of SAP during cardiopulmonary bypass, possibly as a result of a maintained vasomotor tone as reflected by the sustained very low frequency component of the SAP signals.
Analysis of responses to angiotensin peptides in the hindquarters vascular bed of the cat
Authors: Garrison E. A. , Santiago J. A. , Osei S. Y. , Kadowitz P. J.
Published: December 2017

Responses to angiotensin I, II, III, and IV, des-Asp1-angiotensin I, and (p-amino-Phe6)-angiotensin II were compared in the hindquarters vascular bed of the cat. The peptides produced dose-related increases in perfusion pressure, and dose-response curves to all six peptides were parallel. Des-Asp1-angiotensin I, angiotensin I, II, and III produced similar increases in perfusion pressure and were approximately 300-fold more potent than (p-amino-Phe6)-angiotensin II, 100-fold more potent than angiotensin IV, 30-fold more potent than norepinephrine, and 10-fold more potent than U-46619. The time courses of the response to des-Asp1-angiotensin I, angiotensin I, II, and III were similar, and responses were not altered by a time-delay coil. DuP-532, an AT1 receptor antagonist, reduced responses to the six angiotensin peptides. PD-123,319 did not alter responses to the angiotensin peptides. The angiotensin-converting enzyme inhibitor captopril reduced responses to angiotensin I and des-Asp1-angiotensin I. These results show that des-Asp1-angiotensin I as well as angiotensin I, II, III, and IV have similar efficacy and that responses to the peptides and (p-amino-Phe6)-angiotensin II are mediated by AT1 receptors. These results suggest that AT2 receptors have little role in modulating responses and that angiotensin IV has a lower affinity for the AT1 receptor than does angiotensin II or III. The results also indicate that complete rapid local conversion of the substrates into active peptides occurs near the site of action within the hindquarters vascular bed.
Acylcarnitine accumulation does not correlate with reperfusion recovery in palmitate-perfused rat hearts
Authors: Madden M. C. , Wolkowicz P. E. , Pohost G. M. , McMillin J. B. , Pike M. M.
Published: December 2017

Carnitine palmitoyltransferase-I (CPT-I) inhibitors improve postischemic myocardial function either by decreasing muscle long-chain acylcarnitines (LCAC) during ischemia or by increasing oxidation of alternate substrates such as glucose during reperfusion. These possibilities were evaluated using oxfenicine, a CPT-I inhibitor, and alternate substrates that bypass carnitine-dependent metabolism. Isolated rat hearts subjected to 20 min of ischemia followed by 40 min of reperfusion with 1.8 mM palmitate as exogenous substrate recovered little function during reperfusion. Hearts made ischemic and reperfused with palmitate and 2.4 mM hexanoate as exogenous substrates had significantly improved reperfusion function compared to palmitate-perfused hearts. Addition of 2 mM oxfenicine to palmitate-hexanoate-perfused hearts gave an additional small improvement in reperfusion function. At the end of ischemia, the LCAC content of hearts perfused with palmitate or hexanoate and palmitate was identical. Palmitate-, hexanoate, and oxfenicine-perfused hearts had significantly decreased LCAC content at the end of ischemia compared with hexanoate-palmitate-perfused hearts. Therefore, depressed reperfusion function in long-chain fatty acid-perfused hearts can be ameliorated by alternate substrates, including medium-chain fatty acids. LCAC accumulation during ischemia apparently plays only a minor role in the postischemic dysfunction of long-chain fatty acid-perfused hearts.
Ischemia- and reperfusion-induced ventricular arrhythmias in dogs: effects of estrogen
Authors: McHugh N. A. , Cook S. M. , Schairer J. L. , Bidgoli M. M. , Merrill G. F.
Published: December 2017

The purpose of this investigation was to determine if exogenous estrogen could attenuate the ventricular arrhythmias caused by myocardial ischemia and reperfusion. Conjugated equine estrogen, administered as an intravenous bolus injection (100 micrograms) to anesthetized, instrumented beagles of both genders, significantly attenuated the incidence of ventricular arrhythmias during a 20-min period of ischemia (2 +/- 1 vs. 19 +/- 16% ectopy) and in the first 5 min of reperfusion (15 +/- 9 vs. 69 +/- 20% ectopy). By 15-20 min of ischemia, ventricular salvos and nonsustained ventricular tachycardia were frequently observed in nontreated dogs. One dog in this group fibrillated during ischemia. In contrast, estrogen-treated dogs exhibited only an occasional ventricular premature beat during the same period of ischemia. When compared with baseline values, the percent ectopy during ischemia in estrogen-treated dogs was insignificant. During reperfusion, nontreated dogs displayed severe, life-threatening arrhythmias such as sustained ventricular tachycardia. In two of these dogs ventricular tachycardia deteriorated to ventricular fibrillation. In comparison, estrogen-treated dogs displayed only innocuous ventricular arrhythmias during reperfusion, i.e., ventricular premature beats, ventricular salvos, and ventricular bigeminy. In addition to the effect of estrogen on arrhythmias, there was a gradual increase in coronary blood flow on reperfusion in estrogen-treated dogs. This effect of estrogen was preceded by a significantly higher coronary perfusion pressure during ischemia (31 +/- 2 vs. 18 +/- 4 mmHg, P < 0.05). In conclusion, our findings suggest that antiarrhythmic effects of estrogen treatment might stabilize ventricular rhythmicity during ischemia and reperfusion.
Baseline arterial pressure affects sympathoexcitatory responses to ventricular premature beats
Authors: Smith M. L. , Ellenbogen K. A. , Eckberg D. L.
Published: December 2017

The seconds to minutes before sudden cardiac death are characterized by fluctuations of arterial pressure, cardiac rhythm, and probably sympathetic nerve activity. We explored the interrelations among these factors in seven patients undergoing clinical electrophysiological testing. We measured muscle sympathetic nerve activity (SNA) and arterial pressure responses to ventricular premature beats induced throughout the cardiac cycle under three conditions: 1) lowered arterial pressure and elevated SNA produced by intravenous nitroprusside, 2) baseline arterial pressure and SNA during saline infusion, and 3) elevated arterial pressure and decreased SNA activity produced by intravenous phenylephrine. Sympathetic responses to premature beats were inversely related to diastolic pressure. The magnitude of the sympathetic response was directly related to the prevailing arterial pressure and inversely related to baseline SNA. These data demonstrate that sympathoexcitation evoked by ventricular dysrhythmias is determined importantly by the prevailing arterial pressure and possibly by the background R-R interval and level of sympathetic activity. This effect may influence hemodynamic and electrophysiological stability during dysrhythmias.
Cardiac staircase and NMR-determined intracellular sodium in beating rat hearts
Authors: Lotan C. S. , Miller S. K. , Simor T. , Elgavish G. A.
Published: December 2017

Isolated, perfused rat hearts (30 degrees C, n = 13) were paced from 218 +/- 4 beats/min to 433 +/- 4 beats/min while systolic and diastolic pressure were recorded and intracellular Na+ concentration ([Na+]i) was monitored by 23Na nuclear magnetic resonance (NMR) spectroscopy. [Na+]i increased progressively with increasing stimulation frequency. In seven hearts (group I) an initial, progressive increase in systolic pressure was observed followed by a decrease in pressure with further increase in frequency. From the onset, a progressive decrease in systolic pressure was observed in group II (n = 6) in response to increased frequency. In group I an [Na+]i increase of up to 134 +/- 7% of control (P < 0.001) was observed, whereas in group II the gain in [Na+]i with increasing pacing rate was attenuated, reaching a maximum of 120 +/- 3% of control (P < 0.02). The differential pressure response between group I and group II hearts may reflect an enhanced sensitivity of rat hearts to the shortening of the restitution period of the sarcoplasmic reticulum, outweighing the positive inotropic effect induced by an increased [Na+]i. Only in rat hearts whose [Na+]i-induced increase in pressure outweights the restitution deficit would a complete positive inotropic effect be anticipated.
Postural vascular response vs. sympathetic vasoconstriction in human skin during orthostasis
Authors: Jepsen H. , Gaehtgens P.
Published: December 2017

Sympathetic activation and local vascular smooth muscle reactions to vessel distension contribute to the increase in vascular resistance in the skin during orthostasis. The relative contribution of these two mechanisms to the changes of skin blood flow along the body axis on standing was investigated in healthy male subjects by laser-Doppler (LD) fluxmetry. Compared with recumbency, LD flux (LDF) in the standing subjects was reduced by -19.6 +/- 7.2% at the forehead and by -69.6 +/- 9.6% in the leg. In the absence of hydrostatic pressure changes, the LDF changes on standing averaged -29 +/- 13%, independent of skin region, reflecting the effect of vasoconstriction due to sympathetic activation. The postural vascular response, elicited by lowering the arm or the leg from heart level, was significantly attenuated in orthostasis compared with recumbency. The vessel reaction to local alteration of transmural pressure was studied in the skin of the forehead and lower leg by application of external pressure in supine subjects. No difference in vessel responsiveness to changes of transmural pressure was found between these skin sites. The findings suggest that the changes of skin perfusion in orthostasis result from a nonadditive interaction of height-dependent and -independent mechanisms.
Cardiac energetics, cell volumes, sodium fluxes, and membrane permeability: NMR studies of cold ischemia
Authors: Askenasy N. , Vivi A. , Tassini M. , Navon G.
Published: December 2017

Intracellular sodium accumulation, cellular swelling, and energy deficiency are ischemia-associated processes that participate in the transition to irreversible ischemic injury. This study aims to determine the relationship among these parameters in intact rat hearts during global ischemia at 4 degrees C. High-energy phosphates were determined by 31P nuclear magnetic resonance, intracellular sodium accumulation was measured by 23Na spectroscopy with the shift reagent dysprosium triethyl tetraaminohexaacetic acid [Dy(TTHA)3(-)], and cell volumes were measured by 59Co and 1H spectroscopy with use of the extracellular marker Co(CN)3-(6). Intracellular sodium flux rates were 1.53 +/- 0.17, 0.17 +/- 0.05, and 0.30 +/- 0.06 mumol.g dry wt-1.min-1 at 0-1.5, 2-7, and 9-12 h, respectively. Sodium influx resulted in accumulation of the ion: 10% after 4 h, 16% after 10 h, and 29% after 12 h. Water followed sodium into the cells at two constant molar ratios (Na+/H2O): 3.80 +/- 0.15 x 10(-3) during the first 8 h of ischemia and 7.8 x 10(-3) at 8-12 h. Relative to initial intracellular volume, cells swelled by 38% after 8 h and 46% after 12 h; reperfusion reduced cellular swelling to 25 and 36%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Intracoronary nitric oxide improves postischemic coronary blood flow and myocardial contractile function
Authors: Pabla R. , Buda A. J. , Flynn D. M. , Salzberg D. B. , Lefer D. J.
Published: December 2017

In the present study a novel nitric oxide (NO) donor, CAS-1609, was utilized as a means of coronary NO replenishment in a canine model of myocardial ischemia-reperfusion. Administration of CAS-1609 (1.25 mg iv) 10 min before reperfusion, followed by a 1 mg/h intracoronary infusion throughout the 4.5-h reperfusion period, resulted in significant improvement in postischemic transmural myocardial blood flow (0.66 +/- 0.09 vs. 0.37 +/- 0.08 ml.min-1.g-1 for saline vehicle, P < 0.05). Dogs receiving NO supplementation also exhibited a significant recovery of myocardial contractility after 4.5 h of reperfusion (30 +/- 2% area ejection fraction vs. 22 +/- 2% for saline vehicle, P < 0.05). Moreover, myocardial necrosis as a percentage of the area at risk was reduced from 28.9 +/- 4.3% in the saline group to 8.5 +/- 2.6% in the CAS-1609 group (P < 0.01), while ischemic zone myeloperoxidase activity, indicative of neutrophil infiltration, was also attenuated by 70% with NO therapy. Injection of acetylcholine and nitroglycerin into the left circumflex coronary artery revealed a significant impairment of vasodilator responses in the saline vehicle dogs at 2 h of reperfusion. However, dogs treated with the NO donor demonstrated postischemic vasodilator responses which were similar to baseline (P = not significant vs. baseline). These studies demonstrate that intracoronary administration of NO significantly augments postischemic coronary blood flow and contractile function following ischemia and reperfusion. In addition, NO therapy reduces coronary vascular injury, attenuates myocardial necrosis, and reduces neutrophil infiltration. The cardioprotective actions of intracoronary NO administration may be related to the potent antineutrophil actions of NO.