bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of leukocytes in reperfusion injury of skeletal muscle after partial ischemia
Authors: Yokota J. , Minei J. P. , Fantini G. A. , Shires G. T.
Published: December 2017

These experiments evaluated the leukocyte as a potential source of oxygen free radical (OFR) generation during reperfusion injury in post-ischemic skeletal muscle. The infrarenal aorta of heparinized Sprague-Dawley rats was clamped for 90 min, declamped, and reperfused for 60 min. Hindlimb muscle resting transmembrane potential difference (Em) and high-energy phosphate content were determined at base line, during ischemia, and on reperfusion. Four groups were studied: a control group, a second group receiving superoxide dismutase and catalase (SOD + CAT) on declamping, a third group receiving dimethylmyleran (DMM) 7 days before the experiment to obtain a selective leukopenia (white blood cells = 1,210 +/- 144/mm3, neutrophils = 1.2%), and a fourth group pretreated with allopurinol (ALLO). During the ischemic period, resting Em was significantly depolarized (-78.6 +/- 0.5 mV from -90.3 +/- 0.3; P less than 0.05) in the control group, whereas creatine phosphate (CP) was depleted and ATP maintained. Data collected during the ischemic phase of the three other groups were similar to the control group (P = NS). On reperfusion, persistent depolarization of resting Em was observed despite restoration of muscle CP content in the control and ALLO groups (-75.4 and -77.0 mV, respectively). In contrast, significant repolarization of resting Em was noted after reperfusion in the SOD + CAT and DMM groups (-86.5 and -88.6 mV, respectively). These data implicate leukocyte-generated OFR as mediators of reperfusion-associated cellular membrane injury in postischemic skeletal muscle.
Nonuniform shortening of the anterior wall of feline left ventricles
Authors: Hexeberg E. , Matre K. , Birkeland S. , Lekven J.
Published: December 2017

Recorded performance of segments between implanted ultrasonic crystals placed at midwall position of the left ventricle reportedly depends almost exclusively on midwall function and alignment with fibers. Accordingly, one would expect the ratio between performance of a segment perpendicular to midwall fiber direction (transverse) and a parallel segment (longitudinal) to be constant and independent of changes in preload, afterload, and the inotropic state. We tested this hypothesis by implanting cross-oriented crystal pairs in nine open-chest cats and studied their performance during preload and afterload changes with and without isoproterenol infusion. Fiber orientation across the ventricular wall was determined by serial histological sectioning. The ratio between performance of transverse and longitudinal segments (trans/long) changed with interventions. Increased end-diastolic pressure leads to increased segment performances as well as trans/long. Inotropic stimulation produced increased sensitivity to preload changes both for individual segment performances and for trans/long. These results suggest that longitudinal segments represent the function of midwall fibers, whereas transverse segments may well represent the function of sub-endocardial fibers, which run closer to this orientation. Thus trans/long provides a way to quantify nonuniformity of local myocardial contraction.
Hemodynamics at low flow in resting vasodilated rat skeletal muscle
Authors: Sutton D. W. , Schmid-Schonbein G. W.
Published: December 2017

The low flow arterial pressure-flow relationship and zero-flow pressure (ZFP) are investigated in the hemodynamically isolated gracilis muscle using a high precision pump. The muscle is kept in situ with dilated vasculature. During steady-state perfusion, using a plasma-like medium, the pressure-flow curve is nonlinear with positive arterial ZFP of 3.5-12 mm Hg when normal central circulation pressure is present. When the central circulation is stopped the ZFP reduces to zero. Addition of nonaggregated red blood cells (RBCs) results in no significant increase in the ZFP; however, introduction of aggregated RBCs (with dextran, 77 kDa) causes a 9.4 +/- 1.2 mmHg elevation. The positive ZFPs observed using plasma-like and dispersed RBC perfusions are found to be caused by a back pressure from the central circulation via collateral arterioles. A single-step reduction of the arterial flow rate from a finite value to zero results in a ZFP, which decreases for more than a minute before steady state is reached. During harmonic flow inputs with oscillations down to zero flow, an increase in the ZFP is detected near 0.09 Hz and continues to rise up to the test limit of 10 Hz. Our results suggests that in vasodilated skeletal muscle three independent mechanisms exist, collateral flow, cell aggregation, and unsteady perfusion, which may cause a positive arterial ZFP.
Structure of canine Bachmann's bundle related to propagation of excitation
Authors: Dolber P. C. , Spach M. S.
Published: December 2017

Impulse propagation and histology were studied in adult and neonatal canine Bachmann's bundle. Both showed nonuniform electrical anisotropy: effective longitudinal conduction velocity (theta L) markedly exceeded effective transverse conduction velocity (theta T), and extracellular potential waveforms with transverse propagation were polyphasic. An age difference in theta L (0.80 m/s neonate, 1.31 m/s adult) was found; it could be largely accounted for by a difference in myocyte diameter (4.7 microns neonate, 17.1 microns adult). Close apposition of myocytes in the neonate and development of transverse tubules in the adult may have influenced theta L at each stage. Perimysial septa separated fascicles in both neonatal and adult bundles; however, endomysial septa between individual myocytes were completely developed only in adult bundles. Thus perimysial septa were much more responsible for nonuniform anisotropy and low theta T than endomysial septa. Fascicle diameter and length were greater in the adult, which may have affected transverse propagation. Specialized conduction system cells could not be identified.
Effects of dipyridamole on muscle blood flow in exercising miniature swine
Authors: Laughlin M. H. , Klabunde R. E. , Delp M. D. , Armstrong R. B.
Published: December 2017

The purpose of this study was to determine whether a vasodilator reserve exists in respiratory muscles and forelimb skeletal muscles in miniature swine during treadmill exercise. Blood flow (BF) was measured with radiolabeled microspheres during preexercise and before and after dipyridamole (DYP; 1 mg/kg iv) at 2 min of treadmill exercise at 11.2 (70% Vo2 max) and 17.6 km/h (Vo2 max). Muscle BFs were increased during exercise, and the relationship between exercise intensity and BF varied among the muscles. The high-oxidative extensor muscles and the flexor muscles attained peak BFs at 11.2 km/h, whereas the more superficial, lower oxidative extensor muscles showed increases in BF up to maximal exercise. During running at 11.2 km/h, DYP produced increases in BF only in cardiac muscle, respiratory muscle and the medial head of the triceps muscle (MHT), which is composed of 91% slow-twitch oxidative (SO) fibers. During maximal exercise (17.6 km/h), DYP produced a 31-mmHg decrease in mean arterial pressure (MAP) and increases in vascular conductance in all muscles studied. BF was only increased in MHT and cardiac muscle. We conclude that vasodilator reserve remains in skeletal muscle and respiratory muscle even during maximal exercise in swine. If it is assumed that DYP-induced vasodilation in a muscle sample is indicative of adenosine production, these results suggest that SO skeletal muscle (MHT) and respiratory muscle are similar to cardiac muscle in that they produce adenosine even when adequately perfused. Furthermore, during maximal exercise, all skeletal muscle appears to produce adenosine, suggesting that muscle BF is restricted under these conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
Microvascular responses in copper-deficient rats
Authors: Schuschke D. A. , Saari J. T. , Ackermann D. M. , Miller F. N.
Published: December 2017

In this study on copper deficiency, the rat crewmaster microcirculation was used as a model for endogenous histamine release and platelet thrombi formation. Male Sprague-Dawley rats were fed either a copper-supplemented diet (CuS, 5 ppm) or a copper-deficient diet (CuD, 0 ppm) for 5 wk before experimentation. The crewmasters of anesthetized rats were spread in a Krebs-filed tissue bath. In venules of CuS animals, photoactivation of intravascular fluorescein isothiocyanate tagged to bovine serum albumin caused significant platelet aggregation and reduction of red blood cell column diameter (RBCCD) by 40 min and stasis of flow by 60 min. In CuD animals there was only minor platelet aggregation and no reduction in RBCCD. Platelet aggregometry studies did not demonstrate reduced platelet aggregation in the CuD group, suggesting that copper deficiency alters the endothelium to inhibit adhesion. Compound 48/80 (1.0 and 10.0 microgram/ml) induced macromolecular leakage in both CuS and CuD groups, with the response in the CuD animals being significantly greater. The results demonstrate that copper deficiency results in alterations of the regulatory mechanisms governing inflammation and thrombosis.
Ethacizin blockade of calcium channels: a test of the guarded receptor hypothesis
Authors: Starmer C. F. , Undrovinas A. I. , Scamps F. , Vassort G. , Nesterenko V. V. , Rosenshtraukh L. V.
Published: December 2017

The effect on calcium channels of the sodium channel antagonist, ethacizin, was studied in isolated frog ventricular cells using the whole cell voltage-clamp methodology. Ethacizin was found to block inward calcium current in a frequency-, voltage-, and concentration-dependent manner. The frequency-dependent blocking properties were modeled by considering the drug interaction with a voltage-dependent mixture of calcium channels harboring either an accessible or an inaccessible binding site. With repetitive stimulation, the pulse-to-pulse reduction in peak current is shown to be exponential, with a rate linearly related to the interstimulus interval and the drug concentration. Observed frequency- and concentration-dependent blocks were consistent with the predictions of the model, and mixture-specific rate constants were estimated from these data. The negligible shift in channel inactivation and the reduction of apparent binding and unbinding rates with more polarized membrane potentials imply the active moiety of ethacizin blocks open channels and is trapped within the channel at resting membrane potentials. The binding rate at 0 mV is similar to that observed in studies of interactions of other open channel blocking agents with voltage- and ligand-gated channels.
Mechanism of contraction to endothelin in isolated porcine coronary artery
Authors: Kasuya Y. , Ishikawa T. , Yanagisawa M. , Kimura S. , Goto K. , Masaki T.
Published: December 2017

To elucidate the mechanisms of action of endothelin (ET) on vascular smooth muscles, the contractile responses of the isolated porcine coronary artery to ET were precisely investigated. ET produced concentration-dependent vasoconstrictions that were not mediated by biogenic amines, arachidonate metabolites, or endothelium-derived contractile factors. The maximum response to ET was identical to the response to K+ depolarization. The vasoconstrictor activity of ET was at least one or two orders of magnitude more potent than other vasoconstrictors (BAY K 8644, histamine, acetylcholine, and prostaglandin F2 alpha) examined. The action of ET was antagonized by a dihydropyridine Ca2+ antagonist, nicardipine, in a competitive fashion. ET-induced vasoconstriction was not mediated by membrane depolarization. A small amount of ET (2 x 10(-10) M) caused a leftward shift of the concentration-response relationship for K+. ET (5 x 10(-10), 5 x 10(-8) M) accelerated 45Ca2+ uptake to the smooth muscle cells, which were inhibited by nicardipine. However, ET did not affect the specific binding of [125I]iodipine to the smooth muscle cell membrane. These results suggest that ET produces vasoconstriction via ultimately accelerating Ca2+ influx through voltage-dependent Ca2+ channels but that the binding site is distinct from that of dihydropyridines.
Effects of a stabilized endothelium-derived relaxing factor on the coronary vasculature in awake dogs
Authors: Chu A. , Cobb F. R. , Hagen P. O. , Murray J. J.
Published: December 2017

The effects of a partially purified endothelium-derived relaxing factor (EDRF) stabilized by acidification from cultured bovine aortic endothelial cells stimulated with the calcium ionophore A23187 on coronary and peripheral vasculature were examined in five awake dogs. The dogs were chronically instrumented with miniature arterial dimension crystals and Doppler flow probes. Intracoronary or intra-arterial infusions of this EDRF induced a rapid (less than 15 s) significant increase in the proximal vessel diameter (P less than 0.02). The duration of proximal dilation response to this EDRF persisted up to 6 min, whereas the smaller changes in distal flow were more transient (less than 1 min). Similar but more pronounced changes in the proximal arterial dilation and distal flow occurred with infusion of nitroglycerin (0.4 mg). No vasoactive changes were observed during infusions of the control vehicle. The vasodilatory effects to this EDRF occurred in the absence of changes in aortic and left ventricular pressure, rate of pressure development (dP/dt), and heart rate. These data demonstrate that infusion of this partially purified relaxing factor from cultured endothelial cells causes vasodilation in vivo with a vasoactive profile similar to nitroglycerin. The biological effects of this EDRF persist significantly longer than the extreme lability of EDRF at neutral pH (approximately 6 s), consistent with its in vitro effects. Despite the demonstration of rapid inactivation of EDRF in vitro by hemoglobin, high oxygen tension, and plasma, the study shows that this EDRF can have significant in vivo vasoactive effects.
Adrenergic regulation of calcium-deficient hypertension in chick embryos
Authors: Koide M. , Tuan R. S.
Published: December 2017

Chick embryos rendered calcium deficient by long-term culture outside the eggshell develop hypertension and tachycardia (R. Tuan and H. Q. Nguyen, J. Exp. Med. 165: 1418-1423, 1987). To characterize the hypertension of cultured shell-less (SL) chick embryo, we have compared their cardiovascular response to adrenergic drugs with normal (NL) embryos at day 14 of incubation. Blood pressure and pulse rate were measured before and after administration of norepinephrine (NE), phentolamine (PA), isoproterenol (IP), and propranolol (PP). Base-line blood pressures (systolic and diastolic) were uniformly higher in SL than NL embryos. In both embryos, blood pressure was elevated by NE and PP but lowered by IP and PA; pulse rates were decreased by PP and PA and increased by NE and IP. Pharmacological sensitivity to NE and PA, based on their effective dosages and magnitude of response in blood pressure and pulse rate, was higher in SL embryos. On the other hand, the embryos did not differ significantly in their sensitivity to IP and PP. The plasma concentration of catecholamines was considerably higher in SL embryos. Although serum calcium was lower in SL embryos, myocardial calcium content was not significantly different. Thus the cardiovascular function of SL embryos is likely to be under more sensitive and potentiated alpha-adrenergic regulation, perhaps a result of different calcium handling by several tissues (e.g., myocardium). These properties of the SL chick embryo indicate that it is a novel and useful experimental system to study the relationship between calcium homeostasis and development of hypertension.
Effect of arteriovenous fistula size on arterialized and host livers in rats
Authors: D'Silva M. , Glassford E. , Bai S. , Moossa A. R. , Lee S.
Published: December 2017

In studying the hemodynamic relationship and behavior of peak blood flow indexes at different sizes of arteriovenous fistulas (AVF) using arterialized partial liver transplants (PLT), 96 male Wistar rats served as donors and recipients of heterotopic PLT in an acute phase study using ether anesthesia. AVF of 1, 2, and 3 mm were compared with a control group (0 mm) along the "index of peak perfusion rate" of blood flow, the dependent variable. We found that with increasing AVF sizes, a progressive fall in the peak blood flow in the host livers (P less than 0.01, r = -0.51) and a similar rise in the same index in the graft livers (P less than 0.01, r = +0.76) were documented. Also noted was a gradual fall in the cardiac pulsatility component of perfusion to both host and graft livers at AVF sizes of 2 and 3 mm. The same component of perfusion to host and graft livers was best at AVF size of 1 mm. It was concluded that a 1-mm AVF provided the best degree of arterialization to a PLT.
Effect of a lipoxygenase inhibitor on vasoconstriction in dog lung
Authors: el-Kashef H. A. , Hofman W. F. , Ehrhart I. C.
Published: December 2017

The effects of lipoxygenase inhibition and cyclooxygenase plus lipoxygenase inhibition on the pressor responses to serotonin (5-HT), acetylcholine (ACh), and norepinephrine (NE) were studied in the isolated, blood-perfused dog lung. Bolus doses of 50-250 micrograms 5-HT, 1-5 mumol ACh, and 10-50 micrograms NE were given before and after the lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), or the cyclooxygenase inhibitor, meclofenemate (Meclo), followed by NDGA. Lobar vascular resistance (LVR) was partitioned into upstream (Ra) and downstream (Rv) segments by venous occlusion. 50 microM NDGA did not change base-line LVR, Ra, or Rv; however, 100 microM NDGA increased base-line LVR (P less than 0.05) without increasing Ra or Rv (P greater than 0.05). Neither 50 or 100 microM NDGA affected the pressor response to 5-HT, ACh, or NE; however, the response to 50 micrograms 5-HT was slightly enhanced. Meclo increased base-line LVR (P less than 0.05) and subsequent addition of 50 microM NDGA did not change LVR (P greater than 0.05) from post-Meclo values. The LVR increase to both 5-HT and ACh was potentiated after Meclo (P less than 0.05) and 50 microM NDGA after Meclo did not change the LVR increase to either 5-HT or ACh. In contrast, Meclo did not enhance the pressor response to NE, and addition of 50 microM NDGA after Meclo diminished the increase to 20 and 50 micrograms NE (P less than 0.05). Our results suggest that unlike cyclooxygenase inhibition, lipoxygenase inhibition does not increase base-line LVR or the pressor response to either 5-HT or ACh.(ABSTRACT TRUNCATED AT 250 WORDS)
Endothelin is a potent long-lasting vasoconstrictor in men
Authors: Clarke J. G. , Benjamin N. , Larkin S. W. , Webb D. J. , Davies G. J. , Maseri A.
Published: December 2017

Endothelin, a 21-amino acid peptide synthesized by cultured porcine aortic endothelial cells, has recently been identified and shown to produce a potent and prolonged constriction of mammalian blood vessels in vitro. We have studied the effect of local infusion of this peptide on resistance and capacitance vessels of normal volunteers. Infusion of endothelin (5 pmol/min) reduced forearm blood flow by 39 +/- 7% from control observations. The maximum response was seen after approximately 55 min of infusion. After stopping the infusion, return of flow to basal values took approximately 120 min. This contrasts with the short onset and duration of action observed when angiotensin II was infused. During coinfusion studies, reversal by nicardipine (0.3-10 micrograms/min) occurred at similar concentrations in both endothelin-induced and angiotensin-induced flow reduction. This observation suggests that nicardipine nonspecifically antagonizes the flow-reducing effects of endothelin. A pattern of slow onset of constriction was found on local infusion of endothelin (5 pmol/min) into dorsal hand veins. During coinfusion of nicardipine (1.5 microgram/min), no reversal of endothelin-induced (5 pmol/min) constriction of dorsal hand veins occurred. The pharmacological profile of this peptide in the peripheral circulation of humans suggests that it may be involved in long-term regulation of vascular tone.
Beneficial effect of a platelet-activating factor antagonist, WEB 2086, on endotoxin-induced lung injury
Authors: Chang S. W. , Fernyak S. , Voelkel N. F.
Published: December 2017

We tested the hypothesis that platelet-activating factor plays an important role in promoting endotoxin-induced lung injury by studying the effect of WEB 2086, a specific platelet-activating factor receptor antagonist, on lung vascular leak in endotoxin-treated rats. Intraperitoneal injection of Salmonella enteritidis endotoxin (2 mg/kg) increased the extravascular leakage of 125I-labeled albumin in perfused lungs at 30 min, 2 h, 6 h, and 48 h. Treatment with WEB 2086 (10 mg/kg ip) either 20 min before or 30 min after endotoxin injection significantly reduced lung injury at 2 h after endotoxin (leak index: control 0.74 +/- 0.03, endotoxin 1.79 +/- 0.14, endotoxin + pretreated WEB 1.23 +/- 0.09, endotoxin + posttreated WEB 1.21 +/- 0.13). In addition, posttreatment with WEB 2086 starting at 90 min after endotoxin injection markedly reduced lung leak at 6 h (control 0.74 +/- 0.03, endotoxin 1.29 +/- 0.14, endotoxin + WEB 0.71 +/- 0.06). The protective effect of WEB 2086 was not the result of cyclooxygenase blockade because the release of thromboxane B2 by endotoxin-treated lungs was not affected by WEB 2086. Furthermore, neither pretreatment nor posttreatment with WEB 2086 significantly reduced the endotoxin-induced increase in plasma glutathione disulfide, a marker of in vivo oxidative stress. In rats given a lethal dose of endotoxin (20 mg/kg ip), posttreatment with WEB 2086, starting at 2 h after endotoxin, significantly improved survival compared with vehicle treatment. We conclude that WEB 2086 ameliorated endotoxin-induced lung injury without reducing oxidative stress in the rat and suggest that blockade of platelet-activating factor receptor may be an important therapeutic consideration in sepsis-induced acute lung vascular injury.
Open-channel subconductance state of K+ channel from cardiac sarcoplasmic reticulum
Authors: Hill J. A. , Coronado R. , Strauss H. C.
Published: December 2017

We have characterized the K+ channel of canine cardiac sarcoplasmic reticulum in terms of its gating kinetics and conductance states. We demonstrate that the open channel dwells in two states, O1 and O2, where O1 is a true subconductance state of O2. The two open states are linked with a closed state by a cyclic gating scheme. Under certain circumstances, however, important information can be derived using a binary model. Each open state separately exhibited an ohmic current-voltage relation with unitary conductance values of 105 (O1) and 189 (O2) pS in 0.1 M K+. Gating between closed and open states was weakly voltage dependent, and we derive reaction rate constants for the state transitions. Finally, we postulate three models to explain the existence of a subconductance state (blockade, stenosis, flutter). We argue that a flutter model best accounts for our observations of O1.
Wavefront myocyte injury and relationship to function in right ventricular ischemia
Authors: Spinale F. G. , Carabello B. A. , Schulte B. A. , Crawford F. A.
Published: December 2017

Past studies of acute canine right ventricular (RV) ischemia have failed to demonstrate early irreversible injury or decreased function. However, the dog frequently has an extensive collateral circulation not found in all humans. The aim of this study was to measure RV global and regional function after right coronary occlusion in 32 closed-chest pigs. RV function was assessed by biplane ventriculography, and myocardial injury was examined by immunohistochemical localization of creatine kinase (CK) and by electron microscopy. Global RV ejection fraction and apical and midventricular regional function declined significantly after 10 min of occlusion. Injury to the myocardium progressed from the endocardium to the epicardium. Significant injury was observed in myocytes of the endocardium, midmyocardium, and epicardium at 10, 30, and 60 min of occlusion, respectively. Regional RV function and the extent of myocardial injury showed a high correlation (r = 0.96, P less than 0.01). The strong CK immunostaining seen in control hearts was diminished in myocytes along the endocardium at 15 min of occlusion. Depletion of immunoreactive CK in myocytes progressed toward the epicardium with longer ischemic times. These findings demonstrate that RV ischemic injury progresses in a wavefront fashion in the pig, which has similar coronary anatomy to humans, and irreversible myocardial injury occurred after 15-30 min of ischemia.
Cerebrovascular and metabolic responses to hypoxia during hypoglycemia in dogs
Authors: Derrer S. A. , Sieber F. E. , Saudek C. D. , Koehler R. C. , Traystman R. J.
Published: December 2017

The effects of insulin-induced hypoglycemia on the response of cerebral blood flow (CBF-microspheres), electroencephalogram (EEG), and cerebral uptake/production of oxygen (CMRO2), glucose (CMRglu), lactate, pyruvate, beta-hydroxybutyrate, and acetoacetate to isocapnic hypoxic hypoxia were studied in pentobarbital-anesthetized, mechanically ventilated dogs. Hypoglycemia [1.3 +/- 0.2 mumol/ml, (+/-SE); n = 9] did not produce an isoelectric EEG and did not affect base-line CBF or CMRO2. When arterial O2 content was reduced from 17.4 +/- 0.6 to 7.5 +/- 0.5 and 5.1 +/- 0.2 vol% during hypoglycemia, CBF increased from 25 +/- 3 to 54 +/- 6 and 84 +/- 8 ml.100 g-1.min-1, respectively. This response was not different from that during normoglycemia (3.5 +/- 0.3 mumol/ml; n = 12). During normoglycemia, hypoxia increased CMRglu from 17.0 +/- 1.2 to 32.2 +/- 4.7 and 49.9 +/- 6.6 mumol.100 g-1.min-1, respectively. Hypoglycemia did not affect CMRglu during normoxia, but the hypoxia-induced increase in CMRglu was abolished. CMRO2 during hypoxia was unaffected by hypoglycemia. We conclude that levels of hypoglycemia that do not produce an isoelectric EEG may impair the normal increase in CMRglu during hypoxia but do not alter the global CBF response to hypoxia.
Interaction between V1 and V2 effects in hemodynamic response to vasopressin in dogs
Authors: Liard J. F.
Published: December 2017

We investigated in conscious, chronically instrumented dogs whether actions mediated by V1 receptors affect cardiovascular effects elicited by V2-like receptors in response to vasopressin or vasopressin analogues. Infused arginine vasopressin (AVP) (220 pg.kg-1.min-1) did not have any significant effect on arterial pressure, cardiac output (CO), and heart rate (HR) when it was preceded by administration of a V1 receptor antagonist. However, when the same antagonist was administered 1 h after the start of the same infusion of AVP, CO, and HR increased significantly above control pre-AVP values, and total peripheral resistance (TPR) fell significantly below control. When a combined V1+V2 receptor antagonist was administered after 1 h of AVP infusion at the same rate, CO, HR, and TPR returned to, but not beyond, control values. When a selective V1 agonist was infused for 1 h, the administration of a V1 antagonist also returned hemodynamic values to, but not beyond, control. These results suggest that 1-h administration of AVP sensitized V2-like receptors to moderate levels of circulating AVP. In another set of experiments, the administration of a selective V1 agonist blunted significantly the CO and HR increase as well as the decrease in TPR normally associated with injection of a selective V2 agonist. However, administration of phenylephrine did not reduce these V2-mediated effects. We conclude that there are significant interactions between V1 and V2-like receptors in the cardiovascular system of conscious dogs, whereby V1 effects appear to 1) immediately antagonize the action of V2 agonists and 2) sensitize the organism to cardiovascular effects mediated by V2-like receptors after a prolonged exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
Differential sensitivity of exchange vessel hydraulic conductivity to atrial natriuretic peptide
Authors: Meyer D. J. , Huxley V. H.
Published: December 2017

Acute plasma volume reduction by atrial natriuretic peptide (ANP) may be mediated, at least in part, by increased exchange vessel water conductivity (Lp). The present study tests the hypothesis that physiological levels of ANP acutely and reversibly elevate single capillary Lp. Paired, in situ measurements of Lp were obtained using the modified Landis technique in individually perfused mesenteric capillaries of the frog, Rana pipiens. Control Lp measurements ranged from 0.1 to 40 x 10(-7) cm.s-1.cmH2O-1 (with a median value of 2.5 x 10(-7] in 81 microvessels perfused with frog Ringer solution containing dialyzed bovine serum albumin. Vessels were recannulated and perfused with one or more concentrations of human ANP (hANP) spanning the physiopathological range: 0.01, 0.1, 1, 10, and 100 nM. When possible, a final recannulation and Lp determination was performed in the absence of hANP. A median 2.2-fold rapid Lp increase was observed compared with control at each peptide concentration. Lp changes persisted for the duration of exposure to hANP, returning to control levels on withdrawal of the peptide. True and venular capillaries exhibited similar Lp responses: median 2.2- and 2.4-fold elevations, respectively. Sixty percent of true and venular capillaries exhibited twofold or greater hANP-induced increases in Lp, whereas only 25% of arteriolar capillaries exhibited such a response. Thus a differential sensitivity to the peptide exists across the exchange vessel network. The observations of this study demonstrate that physiological levels of ANP are capable of modulating exchange vessel Lp, one means by which the peptide may acutely alter plasma volume.(ABSTRACT TRUNCATED AT 250 WORDS)
Sepsis-induced diastolic dysfunction in chronic canine peritonitis
Authors: Stahl T. J. , Alden P. B. , Ring W. S. , Madoff R. C. , Cerra F. B.
Published: December 2017

A chronic canine model of hyperdynamic sepsis was achieved by cecal ligation and puncture (SEP) in conjunction with continuous high-volume fluid resuscitation. Cardiac function was evaluated using ultrasonic cardiac crystals placed across the major, minor, and wall thickness axes of the left ventricle, together with simultaneous arterial and ventricular pressure measurement. Seven to 10 days after crystal implantation, animals were randomized to either SEP (n = 10) or sham laparotomy control (n = 7). SEP dogs became febrile and lethargic, with elevated leukocyte counts and positive blood cultures for enteric organisms. They were also hyperdynamic, with significant increases in heart rate and cardiac output and a fall in systemic vascular resistance. Systolic blood pressure, stroke volume, and ejection fraction remained stable. Relative to control, the SEP group demonstrated a significant reduction in intrinsic contractility during systole, as measured by the heart rate and load-independent index of left ventricular performance Emax (P less than 0.01), confirming the observations of others. In addition, however, diastolic function also became markedly abnormal with a progressive increase in unstressed and end-diastolic ventricular volumes (P less than 0.05) and a significant decrease in myocardial compliance as quantitated by transmural pressure vs. volume-strain analysis. It is hypothesized that this increase in diastolic volume helps to maintain global cardiac performance during the hyperdynamic response to sepsis in the presence of adequate volume support.
Flow-induced resistance artery tone: balance between constrictor and dilator mechanisms
Authors: Bevan J. A. , Joyce E. H.
Published: December 2017

Infusion of physiological saline solution into the lumen of an isolated segment of a resistance artery results in constriction when the vessel is relaxed and in dilation when it is contracted. There is a level of wall tone at which infusion causes no change. In the small rabbit ear arteries used in this study (approximately 200 microns OD) this balance (null) point for infusion rates of 35 microliters/min is 69 +/- 4% of the maximum possible tone development. When tone is set at different levels by norepinephrine, infusion tends to change the level of wall force in the direction of the null point for that artery. The magnitude of flow-induced relaxation can be correlated positively (r = 0.74; P less than 0.001) and the flow-induced constriction correlated negatively (r = -0.67; P less than 0.001) with the level of wall tone. The 95% confidence prediction bands for flow relaxation and contraction against level of wall tone overlap when extrapolated to zero response. These results are consistent with the hypothesis that flow-induced change in resistance artery tone is the result of a balance between independent constrictor and dilator influences.
Mechanism of L-glucose, raffinose, and inulin transport across intact blood-brain barriers
Authors: Lucchesi K. J. , Gosselin R. E.
Published: December 2017

Brain capillary permeability-surface area products (PS) of hydrophilic solutes were evaluated in terms of a conventional two-compartment model. In rats whose blood-brain barrier (BBB) was presumed to be intact, metabolically inert carbohydrates with different molecular weights were injected in pairs to elucidate whether their transfer into the brain proceeds by diffusion through water- or lipid-filled channels or by vesicular transport. The distribution volume of 70 kDa dextran 10 min after intravenous injection was used as a measure of the residual volume of plasma in brain tissue after death. The two-compartment model yielded larger PS values for inulin and raffinose than for L-glucose, and the PS values of inulin and L-glucose were found to decrease as the labeling time was lengthened (10, 30, and 60 min). These observations were interpreted to mean that a rapidly equilibrating compartment was present between blood and brain, rendering the two-compartment model inadequate for computing true transfer rate constants. When multiple-time uptake data were reanalyzed using the three-compartment graphical analysis of Patlak, Blasberg, and Fenstermacher (J. Cereb. Blood Flow Metab. 3: 1-7, 1983), solutes of differing molecular size were found to enter the brain at approximately equal rates. This observation suggested that the predominant transport mechanism across an intact BBB is vesicular. Specifically, unidirectional transport is likely to be initiated by solute binding to the glycocalyx on the luminal surface of brain capillary endothelium. Apparently more inulin than L-glucose is absorbed, which may account for its slightly faster transfer across the BBB. We suggest that this adsorptive surface is the location of the rapidly equilibrating compartment on the plasma side of the BBB.
Inhibition of renal sympathetic activity and heart rate by vasopressin in hemorrhaged diabetes insipidus rats
Authors: Peuler J. D. , Schmid P. G. , Morgan D. A. , Mark A. L.
Published: December 2017

Hypotensive hemorrhage paradoxically decreases renal sympathetic nerve activity (SNA) and heart rate (HR) in normal rats. Interruption of vagal reflexes by cervical vagotomy prevents these inhibitory responses but does not unmask expected increases in either renal SNA or HR. Arginine vasopressin (AVP), which increases markedly during hemorrhage, may also exert an inhibitory action on responses of renal SNA and HR to hemorrhage. We tested the hypothesis that inhibition of renal SNA and HR by hemorrhage is absent in AVP-deficient diabetes insipidus (DI) rats and is restored by intravenous AVP replacement (1 mU.kg-1.min-1 before hemorrhage and 10 mU.kg-1.min-1 during hemorrhage). We also determined whether vagotomy unmasks significant increases in renal SNA and HR during hemorrhage in DI rats and whether AVP replacement prevents these increases. Under chloralose anesthesia, hemorrhage to 50 mmHg mean arterial pressure for 8 min did not decrease renal SNA or HR in AVP-deficient DI rats but decreased (P less than 0.05) renal SNA and HR in normal Long-Evans rats and in DI rats receiving AVP replacement. After vagotomy, hemorrhage increased (P less than 0.05) renal SNA and HR in AVP-deficient DI rats but did not alter renal SNA or HR in Long-Evans rats and AVP-treated DI rats. Thus renal SNA and HR during hemorrhage were consistently higher (P less than 0.05) in AVP-deficient DI rats compared with Long-Evans or AVP-treated DI rats both before and after vagotomy. In addition, vagotomy attenuated the inhibitory action of AVP on the response of HR but not the response of renal SNA to hemorrhage in DI rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Xanthine oxidase-derived H2O2 contributes to reperfusion injury of ischemic skeletal muscle
Authors: McCutchan H. J. , Schwappach J. R. , Enquist E. G. , Walden D. L. , Terada L. S. , Reiss O. K. , Leff J. A. , Repine J. E.
Published: December 2017

We hypothesized that xanthine oxidase (XO)-derived hydrogen peroxide (H2O2) contributes to ischemic skeletal muscle injury during reperfusion. We found that after ischemia (3 h) and then reperfusion (4 h) rat gastrocnemius muscles had decreased contractile function following direct stimulation. Three lines of investigation suggested that XO-derived H2O2 contributes to reperfusion injury of ischemic skeletal muscle. First, treatment with dimethylthiurea (DMTU), a highly permeant O2 metabolite scavenger, but not urea, just before reperfusion improved muscle function in legs subjected to ischemia and then reperfusion. Second, gastrocnemius muscles from rats fed tungsten or allopurinol had negligible XO activities and increased muscle function after ischemia and reperfusion. Third, as assessed by measurement of skeletal muscle catalase activity in the presence of aminotriazole, H2O2 was measured during reperfusion of ischemic muscles from untreated or urea-treated rats but not during reperfusion of muscles from rats treated with DMTU, tungsten, or allopurinol.
Role of cardiac work in regulating myocardial biochemical characteristics
Authors: Hornby L. , Hamilton N. , Marshall D. , Salerno T. A. , Laughlin M. H. , Ianuzzo C. D.
Published: December 2017

The purpose of this study was to determine the extent to which functional demand regulates the biochemical character and enzyme capacities of the rat myocardium. Hearts from donor rats were heterotopically transplanted onto the abdominal aorta and inferior vena cava of isogenic recipients. The procedure results in a perfused but nonpumping heart that has a reduced heart rate (HR) and performs essentially no stroke work (SW). After 30 days, metabolic enzyme activities (phosphorylase, 6-phosphofructokinase, citrate synthase, and 3-hydroxyacyl-CoA dehydrogenase) were significantly lower (40-60%) in the nonworking heart. Specific sarcoplasmic reticulum Ca2(+)-adenosinetriphosphatase (ATPase) activity was unchanged, but activity per gram of heart was 41% lower. Myosin isozymes were 58% V1, 21% V2, and 21% V3 in the nonworking heart compared with 100% V1 in the working heart. Myosin and myofibrillar ATPase activities each decreased by 28%. These findings suggest that both HR and SW play major and specific roles in regulating myocardial biochemical capacities and determining the myosin phenotype.
Comparative responses to endothelin 2 and sarafotoxin 6b in systemic vascular bed of cats
Authors: Minkes R. K. , Kadowitz P. J.
Published: December 2017

Cardiovascular responses to endothelin 2 (ET-2) and sarafotoxin 6b (S6b) were investigated in the cat. ET-2 (0.1-1 nmol/kg iv) decreased or elicited biphasic changes in arterial pressure (AP), whereas S6b (0.1-1 nmol/kg iv) only decreased AP. Central venous pressure (CVP), cardiac output (CO), and pulmonary arterial pressure (PAP) were increased. ET-2 produced biphasic changes in systemic vascular resistance (SVR), whereas S6b decreased SVR at the two lower doses and caused a biphasic change at the 1 nmol/kg dose. The effects of ET-1 and ET-2 were similar, whereas the effects of S6b were similar to ET-3. ET-2 and S6b had small effects on right ventricular contractile force and caused transient increases in heart rate. Distal aortic blood flow was increased in response to all doses of both peptides, whereas increases in carotid blood flow were observed only in response to the higher doses of ET-2 and S6b. ET-2 produced dose-dependent decreases in superior mesenteric artery (SMA) blood flow, whereas decreases in SMA flow in response to S6b were observed only at the 1 nmol/kg dose. Renal blood flow was decreased significantly only at the higher doses of ET-2 and S6b. The present data show that ET-2 and S6b can produce both vasodilation and vasoconstriction in the systemic and regional vascular beds of the cat and demonstrate previously unrecognized vasodilator activity in response to S6b. It is concluded that ET-2 and S6b produce complex cardiovascular responses in the anesthetized cat.
Cerebrovascular transport of [125I]quinuclidinyl benzilate, [3H]cyclofoxy, and [14C]iodoantipyrine
Authors: Sawada Y. , Hiraga S. , Patlak C. S. , Ito K. , Pettigrew K. D. , Blasberg R. G.
Published: December 2017

The transport rate constants across rat brain capillaries of a muscarinic acetylcholine receptor antagonist, [125I]quinuclidinyl benzilate (IQNB), an opiate receptor antagonist, [3H]cyclofoxy (CF), and a highly diffusible blood flow indicator, [14C]iodoantipyrine (IAP), were determined by the indicator-diffusion technique and a model that includes a distribution of capillary transit times and a homogeneous distribution of the test compound in the tissue parenchyma. The mean influx extraction ratio (E1) of IAP was greater than 0.91, and E1 for CF and IQNB was 0.56-0.79 and 0.34-0.46, respectively. The order of lipid solubility was IQNB greater than IAP greater than CF; the apparent discrepancy (high lipid solubility and low permeability) of IQNB was partly due to intravascular binding to plasma protein and red blood cells. The observed initial tissue distribution volumes (lambda 1, ml/g brain) for IQNB (0.09-0.17), CF (0.51), and IAP (0.71) were compared with those estimated for the unbound free ligand in blood (lambda a, ml/g brain; IQNB = 1.3-2.3, CF = 0.88, and IAP = 1.4). These findings suggest that the binding of lipid-soluble radioligands and drugs to plasma proteins and red blood cells can be a major determinant of transport across the blood-brain barrier and the apparent distribution volume of the ligand in brain tissue.
Enhanced alpha-adrenergic vasoconstriction by n-3 fatty acids in conscious dogs
Authors: Kenny D. , Brooks H. L. , Warltier D. C.
Published: December 2017

The effect of dietary fish oil supplementation on cardiac function and the pressor response to selective agonists of postjunctional alpha 1- and alpha 2-adrenoceptors was investigated in chronically instrumented dogs (n = 12). Following ganglionic, cholinergic, and beta-adrenergic blockade, dose responses to phenylephrine (0.3-1.2 micrograms/kg iv), a selective alpha 1-adrenoceptor agonist, and azepexole (B-HT 933, 5-20 micrograms/kg iv), a selective alpha 2-adrenoreceptor agonist, were obtained in conscious dogs. Fish oil capsules containing eicosapentaenoic acid (1.12 g) and docosahexaenoic acid (480 mg) were administered orally twice daily for 1 wk, and dose-response curves were repeated. Dose-response curves were again obtained 1 wk after fish oil was discontinued. Fish oil supplementation resulted in significantly (P less than 0.05) increased arterial pressure at rest, and after autonomic nervous system blockade there was an increase in peripheral vascular resistance. Cardiac output was reduced in fish oil-treated dogs during autonomic nervous system blockade. The pressor response to selective alpha 1- and alpha 2-adrenoceptor stimulation was increased secondary to elevated peripheral vascular resistance. Hemodynamics and exaggerated vascular reactivity returned to control 1 wk after dietary fish oil was discontinued. The results of this study demonstrate that dietary fish oil supplementation produces an increase in arterial pressure via peripheral vasoconstriction and that the vascular response to alpha-adrenergic stimulation is exaggerated.
Effect of fish oil n-3 fatty acids on cerebral microcirculation
Authors: Ellis E. F. , Police R. J. , Yancey L. M. , Grabeel M. N. , Heizer M. L. , Holt S. A.
Published: December 2017

Dietary fish oil containing the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA, 20:5) and docosahexaenoic acid (DHA, 22:6) is being consumed by many individuals in an effort to reduce thrombosis and heart disease. However, little is known about how these fatty acids can affect cerebrovascular function. The purpose of the present study was to begin to examine the effects of these fatty acids on cerebral arteriolar diameter and to compare their effects with that of arachidonic acid (AA). Pial arteriolar diameter responses to the topically applied fatty acids [0.2-200 micrograms/ml cerebrospinal fluid (CSF)] were measured in rabbits using in vivo microscopy and the acute cranial window technique. Prostaglandin E2 (PGE2) formed by the brain in response to AA, EPA, and DHA was measured in CSF using radioimmunoassay. EPA induced a dose-dependent dilation response of which the maximum was 29%, whereas the maximal dilation produced by AA was 100%. The arteriolar effect of EPA was reduced by indomethacin or superoxide dismutase plus catalase, indicating vasoactivity due to oxygen radicals formed by cyclooxygenase metabolism of EPA. DHA itself had no effect on diameter or adenosine-induced dilation but reduced dilation by AA when coapplied with AA. AA induced a 65-fold maximal increase in PGE2, whereas EPA and DHA had comparatively little effect. These results imply that substitution of n-3 fatty acids for AA in brain phospholipids may result in less cyclooxygenase-dependent cerebrovascular reactivity. This alteration in reactivity may produce important effects with respect to the brain's blood flow response to a number of physiological and pathological challenges.
Differential sensitivity of cardiac pacemakers to exogenous adenosine in vivo
Authors: Pelleg A. , Hurt C. , Miyagawa A. , Michelson E. L. , Dreifus L. S.
Published: December 2017

Adenosine exerts pronounced depressant effects on cardiac pacemakers. Previous studies in vitro have indicated that different pacemakers exhibit variable sensitivity to adenosine: ventricular greater than junctional greater than sinus node pacemakers. This study tested the hypothesis that ventricular pacemakers are more sensitive to adenosine than sinus node pacemakers in vivo in an experimental canine model and determined the mechanism involved in this phenomenon using specific pharmacological interventions. For this purpose, dogs with chronic atrioventricular block, stable ventricular escape rhythm, and bilateral stellectomy and cervical vagotomy were studied. Dose-response curves for negative chronotropic action of adenosine in the sinus node and ventricular pacemakers were obtained in group 1 under base-line conditions, during isoproterenol infusion, and after subsequent administration of propranolol; in group 2 before and after administration of quinidine; in group 3 before and after administration of aminophylline; and in group 4 before and after administration of 1,3-dipropyl-8-phenylxanthine amine congener (XAC). Adenosine exerted a dose-dependent negative chronotropic effect on sinus node and ventricular pacemakers. At all doses tested, this action was more pronounced in the ventricle. Isoproterenol accentuated the action of adenosine in the sinus node (by 60-138%; P less than 0.05) but suppressed it in the ventricle (-37 to 53%; P less than 0.05). These effects of isoproterenol were attenuated by propranolol. Quinidine suppressed the action of adenosine in the sinus node (-38 to -52%; P less than 0.05) but not in the ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)