bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemorrhage decreases arterial pressure sooner in pregnant compared with nonpregnant dogs: role of baroreflex
Authors: Brooks V. L. , Keil L. C.
Published: December 2017

This study was performed to test the hypothesis that smaller reflex increases in vasopressin, cortisol, adrenocorticotropic hormone (ACTH), and angiotensin II (ANG II) concentrations are produced by hemorrhage in pregnant compared with nonpregnant conscious dogs. Equivalent hemorrhages (1% of the initial blood volume per minute) produced larger decreases in arterial pressure [P < 0.01; 107 +/- 6 to 73 +/- 10 mmHg (pregnant); 109 +/- 6 to 90 +/- 5 mmHg (nonpregnant)] but produced similar increases in plasma vasopressin concentration in the pregnant animals. As a result, the slope of the arterial pressure-to-vasopressin relationship was reduced (P < 0.05). During pregnancy, smaller increases in plasma cortisol concentration and heart rate were also produced for a given decrease in arterial pressure, but the relationship between pressure and ACTH was not significantly affected. In contrast, higher levels of plasma renin activity and plasma ANG II concentration were achieved in the pregnant dogs. In general, the relationships between plasma hormone levels and either left or right atrial pressure were not significantly altered. These results indicate that reflex increases in heart rate, vasopressin, and cortisol concentration are attenuated in pregnant dogs and that this attenuation may contribute to the inability of pregnant animals to achieve normal cardiovascular homeostasis during hemorrhage.
EDRF suppresses chaotic pressure oscillations in isolated resistance artery without influencing intrinsic complexity
Authors: Griffith T. M. , Edwards D. H.
Published: December 2017

It is now widely recognized that nonlinear oscillatory systems can exhibit simple periodicity, characteristic repetitive patterns of odd and even integral periodicity and specific pathways for the transition to irregular, so-called "chaotic," dynamics. In the present study we have identified such behavior in the highly irregular rhythmic vasomotor activity induced by histamine in isolated rabbit ear resistance arteries, thus suggesting a deterministic rather than random etiology. In this experimental model nonlinearity arises at the level of the vascular smooth muscle cell, since oscillatory behavior was not abolished by endothelial denudation. To quantify the complexity of the responses induced by histamine, we applied the analysis of Grassberger and Proccacia (Physica D 9: 189-208, 1983) to calculate a scaling parameter known as fractal dimension, which estimates the minimum number of control variables participating in the genesis of an irregular time-varying signal. The findings suggest the involvement of at least three such variables, because its average numerical value was generally found to be between 2 and 3. Neither the absolute concentration of histamine employed nor pharmacological manipulation (i.e., stimulation/inhibition) of endothelium-derived relaxing factor (EDRF) activity significantly affected the fractal dimension of the pressure fluctuations, although both influenced their superficial form. Histamine and EDRF consequently do not determine the fundamental interactions responsible for generating the chaotic nature of the responses and may be regarded as permissive and modulatory influences, respectively. The well-known unpredictability of nonlinear systems to perturbation may explain why EDRF can either suppress or enhance rhythmic vasomotor activity in different artery types.
Fractal analysis of role of smooth muscle Ca2+ fluxes in genesis of chaotic arterial pressure oscillations
Authors: Griffith T. M. , Edwards D. H.
Published: December 2017

We have investigated the role of vascular smooth muscle Ca2+ fluxes in the genesis of chaotic pressure oscillations induced by histamine in isolated resistance arteries from the rabbit ear. The responses exhibited distinct "fast" and "slow" components, with periods of 5-20 s and 1-5 min, respectively, which could be dissociated pharmacologically. The fast subsystem involved ion movements at the cell membrane and was inhibited by both low (< 2 mM) and high (> 5 mM) extracellular Ca2+ concentration ([Ca2+]o) by verapamil (which inhibits voltage-dependent Ca2+ influx) and by charybdotoxin (ChTX) and apamin (which block Ca(2+)-activated K+ channels). In contrast, the slow subsystem was intracellular and was selectively attenuated by ryanodine, which inhibits Ca(2+)-induced Ca2+ release from sarcoplasmic reticulum. The effects of these interventions on the complexity of the responses were quantified by calculating their fractal dimension, a parameter that estimates the minimum number of independent variables contributing to an irregular time series. Its mean value was generally > 2 under control conditions but decreased to < 2 in a concentration-dependent fashion in the presence of verapamil, ChTX, apamin, or ryanodine and when [Ca2+]o was outside the range of 2-3 mM. Each intervention thus removed one dimension of complexity from the mechanisms generating the rhythmic activity. We conclude that the interaction of a fast membrane oscillator, which involves Ca2+ influx, Ca(2+)-activated K+ efflux, and therefore presumably changes in membrane potential, and a slow intracellular oscillator involving Ca2+ sequestration and release from stores is responsible for vascular chaos in our model. The coupling between these subsystems is likely to be mediated by cytosolic [Ca2+].
Characteristics of myocytes isolated from hearts of renovascular hypertensive guinea pigs
Authors: Naqvi R. U. , del Monte F. , O'Gara P. , Harding S. E. , MacLeod K. T.
Published: December 2017

A model of renovascular hypertension has been developed in the guinea pig using the Goldblatt (2-kidney, 1-clip) operation. Systolic and diastolic blood pressures were significantly increased 3 and 7 wk after the operation, but levels fell to control values at 11 wk. The two-dimensional areas of myocytes isolated from the hearts of Goldblatt-operated (GB) animals were larger than those in control cells at 3 wk (cf. 3,397 +/- 87 and 2,208 +/- 125 microns 2, P < 0.01), and the difference was maintained at 7 and 11 wk. No change in cell contraction or relaxation characteristics were seen at either 3 or 7 wk after clipping. Myocytes from the 11-wk GB group showed a significantly reduced contraction amplitude and velocity at 32 degrees C in maximally activating Ca2+ or isoproterenol concentrations (%cell shortening in Ca2+, cf. 6.8 +/- 0.4 and 10.0 +/- 0.9, P < 0.01). Concentrations eliciting 50% of maximal response for Ca2+ or isoproterenol were unchanged, as was the ratio of isoproterenol to Ca2+ effect in the same cell. Increases in time to peak contraction (TTP) and time to 50% relaxation (R50) were observed in 11-wk GB myocytes, but only at room temperature. There was no lengthening of TTP or R50 of the Ca2+ transient, nor was there any change in Ca2+ current density or inactivation kinetics in these myocytes.
Blockade of platelet-mediated relaxation in rat aortic rings exposed to xanthine-xanthine oxidase
Authors: Yang B. C. , Khan S. , Mehta J. L.
Published: December 2017

Platelet-induced relaxation of endothelium-intact vascular tissues, mediated via release of endothelium-derived relaxing factor (EDRF), is diminished or lost after ischemia and reperfusion. Release of oxygen free radicals during ischemia-reperfusion may degrade EDRF and influence response of vascular tissues to platelets. To determine platelet modulation of tone of blood vessels treated with oxygen free radicals, rat aortic rings with intact endothelium were exposed to xanthine (X) plus xanthine oxidase (XO) 5 min before contraction with norepinephrine followed by exposure of rings to platelets. Treatment of aortic rings with X+XO caused a modest contraction, potentiated norepinephrine-mediated contraction, and inhibited platelet-mediated vasorelaxation. Exposure of aortic rings to X+XO also decreased ADP- as well as acetylcholine-mediated relaxation. Pretreatment of rings with superoxide dismutase or catalase did not change X+XO-induced inhibition of platelet-mediated relaxation, but it abolished the X+XO-induced contraction of rings as well as subsequent potentiation of norepinephrine-mediated contraction. Pretreatment of rings with hydroxyl radical scavengers dimethyl-2-thiourea, dimethyl sulfoxide, mannitol, or histidine attenuated the X+XO-induced inhibition of platelet-mediated relaxation, although these agents did not affect X+XO-induced contraction of rings. This study indicates that the vasoconstriction on exposure of aortic rings to X+XO is due to generation of superoxide anions, whereas inhibition of platelet-mediated relaxation after exposure of vessels to X+XO is due, at least in part, to release of hydroxyl radicals. Release of superoxide anions and hydroxyl radicals after temporary arterial occlusion may be the basis of subsequent modulation of vascular tone.
Analysis of responses to bradykinin in the pulmonary vascular bed of the cat
Authors: DeWitt B. J. , Cheng D. Y. , McMahon T. J. , Nossaman B. D. , Kadowitz P. J.
Published: December 2017

Responses to bradykinin (BK) were investigated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was elevated to a high steady level. Under elevated-tone conditions, BK caused dose-related decreases in lobar arterial pressure. After administration of Hoe-140, a BK B2-receptor antagonist, vasodilator responses to BK were reduced in a selective manner. Vasodilator responses to BK were unchanged by atropine, glibenclamide, meclofenamate, or bronchial occlusion, suggesting that responses are not dependent on the activation of muscarinic receptors or K+ATP channels, the release of vasodilator prostaglandins, or changes in bronchomotor tone. The nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine benzyl ester and N omega-nitro-L-arginine reduced vasodilator responses to BK in a selective manner, indicating that responses to BK are mediated in part by the release of NO. Methylene blue, an inhibitor of the activation of soluble guanylate cyclase, increased lobar arterial pressure and decreased responses to BK. The increases in lobar arterial pressure in response to methylene blue were partially reversed by the administration of superoxide dismutase, indicating that generation of O2- may inactivate basally released NO. The duration of the response to BK was enhanced by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor Zaprinast, suggesting that responses to BK involve increases in cGMP levels. Responses to BK were enhanced by captopril, indicating that BK is rapidly inactivated by kininase II in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparative effects of L-NNA and alkyl esters of L-NNA on pulmonary vasodilator responses to ACh, BK, and SP
Authors: Cheng D. Y. , DeWitt B. J. , McMahon T. J. , Kadowitz P. J.
Published: December 2017

The comparative effects of the nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine (L-NNA), N omega-nitro-L-arginine methyl ester (L-NAME), and N omega-nitro-L-arginine benzyl ester (L-NABE) on baseline tone and on vasodilator responses to acetylcholine (ACh), bradykinin (BK), and substance P (SP) were compared in the pulmonary vascular bed of the cat under constant flow conditions. After administration of the NO synthase inhibitors in intravenous doses of 100 mg/kg, the increase in lobar arterial pressure and the attenuation of vasodilator responses to ACh, BK, and SP were similar, whereas responses to adenosine and felodipine, endothelium-independent vasodilator agents, were not altered. In addition to inhibiting responses to ACh, BK, and substance P, the NO synthase inhibitors enhanced vasodilator responses to S-nitroso-N-acetylpenicillamine and NO. Moreover, atropine inhibited pulmonary vasodilator responses to ACh but not to SP or BK, and L-NAME or L-NABE had no effect on the decrease in heart rate in response to efferent vagal stimulation, a muscarinic receptor-mediated response that is independent of NO release. The similar inhibitory effects of L-NNA, L-NAME, and L-NABE on vasodilator responses to ACh, BK, and SP suggest that the L-arginine analogue, L-NNA, as well as the methyl and benzyl esters of L-NNA are useful probes for studying NO-mediated endothelium-dependent responses in the pulmonary vascular bed of the intact-chest cat.(ABSTRACT TRUNCATED AT 250 WORDS)
Muscle metaboreflex triggers parallel sympathetic activation in exercising and resting human skeletal muscle
Authors: Hansen J. , Thomas G. D. , Jacobsen T. N. , Victor R. G.
Published: December 2017

Activation of a metabolically generated reflex in exercising skeletal muscle (muscle metaboreflex) in humans is known to trigger increases in sympathetic nerve activity (SNA) to resting skeletal muscles. In seven healthy human subjects, to determine whether this reflex mechanism also increases SNA to the exercising muscles, we recorded muscle SNA with microelectrodes in the right peroneal nerve and in fascicles of the left peroneal nerve selectively innervating the exercising muscles of the left foot. Subjects performed static toe extension at 20% maximal voluntary contraction alone or in combination with foot ischemia. Only static toe extension at 20% MVC during ischemia activated the muscle metaboreflex. This paradigm caused increases in SNA to exercising muscle that paralleled those to the resting muscles: during the first minute of exercise SNA was unchanged, but during the second minute SNA increased from 29 +/- 2 to 38 +/- 2 bursts/min (P < 0.05) to the exercising muscles and from 30 +/- 3 to 40 +/- 2 bursts/min (P < 0.05) to the resting muscles. These bilateral increases in SNA were maintained when metaboreflex activation was sustained by postexercise foot ischemia. In conclusion, these data provide neurophysiological evidence that the muscle metaboreflex evokes parallel sympathetic activation in exercising and resting human skeletal muscle.
Mechanism of action of 2,3-butanedione monoxime on contracture during metabolic inhibition
Authors: Hajjar R. J. , Ingwall J. S. , Gwathmey J. K.
Published: December 2017

The effect of 2,3-butanedione monoxime (BDM) was investigated during metabolic inhibition (MI) in papillary muscles. MI caused a rapid decrease in developed force and an increase in resting force, along with a decrease in ATP and creatine phosphate (CrP). Addition of BDM before MI decreased maximal contracture force, increased the time, and slowed the rates of ATP and CrP depletion. BDM addition at the peak of contracture did not alter the level of developed contracture. To simulate MI in skinned fiber preparations, we decreased the [MgATP] at pCa 8. [MgATP] of 3.2 microM resulted in a large increase in resting force. The force developed was less in BDM-pretreated muscles. Addition of 10 mM BDM at steady state did not affect force development ([MgATP] 3.2 microM, pCa 8.0). Cross-bridge kinetics in intact and skinned muscle fibers with and without BDM in the presence and absence of MI were studied. Intact muscles with MI revealed no frequency dependence at peak contracture and had elevated stiffness values. In skinned fibers, at [MgATP] of 3.2 microM and pCa of 8, no frequency dependence was observed, and the muscles had similarly high stiffness values. BDM pretreatment in both intact and skinned fibers inhibited rigor formation. These results suggest that BDM inhibits cross-bridge formation in the weak-binding state or actively cycling cross bridges.
Interaction among ET-1, endothelium-derived nitric oxide, and prostacyclin in pulmonary arteries and veins
Authors: Zellers T. M. , McCormick J. , Wu Y.
Published: December 2017

Endothelin-1 causes vasodilation of the intact porcine pulmonary vascular bed. To determine the cause of this vasodilation, we investigated the interactions of endothelin-1 (ET-1), endothelium-derived nitric oxide (EDNO), and prostacyclin in isolated small porcine pulmonary arteries and veins under in vitro conditions. ET-1 caused concentration-dependent contractions in arteries and veins, augmented by the nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine, in pulmonary veins. BQ-123 (ETA-receptor antagonist) depressed the ET-1-induced contractions. Sarafotoxin S6C, an ETB-receptor agonist, caused contractions of pulmonary veins only. Endothelium-dependent relaxations to bradykinin and ET-1 were greater in pulmonary veins compared with arteries, inhibited by N omega-nitro-L-arginine, and reversed by L-arginine. BQ-123 augmented ET-1-induced arterial relaxation. ET-3 and sarafotoxin S6C, ETB-receptor agonists, caused comparable endothelium-dependent relaxations in arteries and veins. ET-1 caused a fourfold greater increase in prostacyclin release in pulmonary veins compared with arteries. We conclude that ET-1 is a potent vasoconstrictor of porcine pulmonary vessels and stimulates the release of EDNO and prostacyclin, which oppose the contractions to the peptide. The release of these endothelium-derived vasodilators appears greater in pulmonary veins.
Nonglucose substrates increase glycogen synthesis in vivo in dog heart
Authors: Laughlin Maren R. , Taylor Joni , Chesnick A. Scott , Balaban Robert S.
Published: December 2017

The effects of circulating nonglucose substrates on insulin-stimulated cardiac glycogen synthesis were studied in the dog heart in vivo using13 C-nuclear magnetic resonance (-NMR) and arteriovenous difference techniques. [1-13C]glycogen was monitored in hearts during an intravenous infusion of 20 mU/min insulin and glucose while [1-13C]glucose (10 mg/min) was infused into the left anterior descending coronary artery. When 1 mmol/min of lactate, pyruvate, or beta-hydroxybutyrate was added to the venous infusion, the measured rate of glycogen synthesis was increased, on average, sixfold. It was not increased further after a subsequent 10-min infusion of 5 μg/min epinephrine. Lactate extraction increased from 0.18 ± 0.05 to 0.62 ± 0.11 μmol·min-1·g wet wt-1 during lactate infusion, whereas glucose extraction did not change significantly (0.15 ± 0.05 μmol·min-1·g wet wt-1 at 45 min of insulin and glucose infusion to 0.09 ± 0.02 μmol·min-1·g wet wt-1 at 45 min of the lactate infusion). Therefore, the uptake and oxidation of circulating nonglucose substrates redirects the fate of extracted glucose from glycolysis to glycogen synthesis in the dog heart in vivo.

carbon-13-nuclear magnetic resonance; lactate; pyruvate; β-hydroxybutyrate

Submitted on October 19, 1993

Accepted on February 3, 1994
Coupling of cerebral blood flow to neuronal activation: role of adenosine and nitric oxide
Authors: Dirnagl U. , Niwa K. , Lindauer U. , Villringer A.
Published: December 2017

We studied the role and relationship of the putative mediators of coupling of cerebral blood flow (CBF) and neuronal activation, adenosine (Ado) and nitric oxide (NO). Topical brain application over the whisker barrel cortex of anesthetized rats (n = 24) of the Ado receptor antagonist theophylline (Theo, 5 x 10(-5) M) for 30 min reduced the CBF response to deflection of the contralateral whiskers from 17.9 +/- 3.0% of baseline to 10.6 +/- 2.7% (P < 0.05). Coapplication of Theo (5 x 10(-5) M) and the NO synthase blocker N omega-nitro-L-arginine (L-NNA, 10(-3) M) for 30 min led to a further reduction in the CBF response to whisker stimulation to 7.5 +/- 1.3% (P < 0.05 compared with Theo alone). The CBF effect of sodium nitroprusside (10(-5) M) was not affected by Theo-L-NNA coapplication (122 +/- 25 vs. 140 +/- 25%, n = 5). Application of adenosine deaminase (1 U/ml, n = 5) reduced the CBF response to whisker stimulation from 18.2 +/- 0.7 to 10.7 +/- 1.9% (P < 0.05). Superfusion of L-NNA (10(-3) M, 30 min, n = 7) attenuated the CBF response to application of Ado (10(-4) M) from 39.4 +/- 10.4 to 22.9 +/- 10.5% (P < 0.05). N omega-nitro-D-arginine did not affect the CBF response to Ado (n = 5). We conclude that 1) Ado is involved in coupling of CBF to neuronal activation, 2) NO is involved in this response as well, and 3) there is an interaction between the vasodilator pathways of Ado and NO.
Modulation of platelet function by reactive oxygen metabolites
Authors: Ambrosio G. , Golino P. , Pascucci I. , Rosolowsky M. , Campbell W. B. , DeClerck F. , Tritto I. , Chiariello M.
Published: December 2017

Reactive oxygen metabolites have been reported to affect platelet aggregation. However, this phenomenon is still poorly understood. In the present study we investigated the effects of superoxide radical and hydrogen peroxide (H2O2) on platelet function in vitro and correlated those effects to possible changes of platelet concentrations of cyclic nucleotides and thromboxane, since these systems play a key role in the response of platelets to activating stimuli. Human platelets were exposed to xanthine-xanthine oxidase (X-XO), a system that generates both superoxide radicals and H2O2. Sixty seconds of incubation with X-XO impaired aggregation in response to ADP (by 48%), collagen (by 71%), or the thromboxane mimetic U-46619 (by 50%). This effect was reversible and occurred in the absence of cell damage. Impairment of aggregation in platelets exposed to X-XO was due to H2O2 formation, since it was prevented by catalase but not by superoxide dismutase. Similarly, incubation with the pure H2O2 generator glucose-glucose oxidase also markedly inhibited ADP-induced platelet aggregation in a dose-dependent fashion. Impaired aggregation by H2O2 was accompanied by a > 10-fold increase in platelet concentrations of guanosine 3',5'-cyclic monophosphate (cGMP), whereas adenosine 3',5'-cyclic monophosphate levels remained unchanged. The inhibitory role of increased cGMP formation was confirmed by the finding that H2O2-induced impairment of platelet aggregation was largely abolished when guanylate cyclase activation was prevented by incubating platelets with the guanylate cyclase inhibitor, LY-83583. Different effects were observed when arachidonic acid was used to stimulate platelets. Exposure to a source of H2O2 did not affect aggregation to arachidonate. Furthermore, in the absence of exogenous H2O2, incubation with catalase, which had no effects on platelet response to ADP, collagen, or U-46619, virtually abolished platelet aggregation and markedly reduced thromboxane B2 production (to 44% of control) when arachidonic acid was used as a stimulus. In conclusion, our data demonstrate that H2O2 may exert complex effects on platelet function in vitro. Low levels of endogenous H2O2 seem to be required to promote thromboxane synthesis and aggregation in response to arachidonic acid. In contrast, exposure to larger (but not toxic) concentrations of exogenous H2O2 may inhibit aggregation to several agonists via stimulation of guanylate cyclase and increased cGMP formation.
Sympathetic neural reactivity to stress does not increase with age in healthy humans
Authors: Ng A. V. , Callister R. , Johnson D. G. , Seals D. R.
Published: December 2017

Sympathetic nervous system reactivity to stress is though to increase with age in humans. We tested this hypothesis by recording postganglionic sympathetic nerve activity to skeletal muscle (MSNA) (peroneal microneurography) and by measuring plasma norepinephrine concentrations (PNE), heart rate, and arterial pressure before (prestress control) and during cognitive challenge (mental arithmetic and colored word test), thermal stress (i.e., the cold pressor test), and exhaustive isometric handgrip exercise (40% of maximum voluntary force)/postexercise ischemia in 15 older (60-74 yr, mean +/- SE = 64 +/- 1) and 15 young (19–30 yr, mean +/- SE = 25 +/- 1) healthy men and women (8 males, 7 females each). The initial prestress control level of MSNA was higher in the older subjects (P < 0.01 vs. young), but there were no significant differences for PNE, heart rate, or arterial pressure. The MSNA and PNE responses to mental stress were small and not different in the two groups. MSNA and PNE increased markedly in response to the cold pressor test and isometric handgrip exercise/post exercise ischemia in both groups. The absolute unit increases in MSNA were similar in the two groups, but the relative (percentage) increases were actually smaller in the older subjects (P < 0.05 vs. young) due to their elevated baseline levels. The stress-evoked increases in arterial pressure were similar in the groups, but the older subjects tended to demonstrate smaller increases in heart rate. In general, no gender differences were noted in either age group. These findings fail to support the long-held concept that stress-induced sympathetic nervous system stimulation becomes exaggerated with age. Thus, sympathetic neural hyperreactivity does not appear to be a fundamental property of the aging process in humans.
Preischemic glycogen reduction or glycolytic inhibition improves postischemic recovery of hypertrophied rat hearts
Authors: Allard M. F. , Emanuel P. G. , Russell J. A. , Bishop S. P. , Digerness S. B. , Anderson P. G.
Published: December 2017

The purpose of this study was to determine whether metabolites produced by glycolysis during ischemia significantly contribute to myocardial injury of hypertrophied hearts. The accumulation of glycolytic metabolites during ischemia was reduced by means of glycogen reduction or by treatment with the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG) before ischemia. Hearts from aortic-banded (Band) and sham-operated (Sham) rats (8 wk postop) were isolated, perfused with Krebs buffer, and had a left ventricular (LV) balloon to measure developed pressure. A 15-min perfusion with hypoxic buffer (glycogen reduction, GR) or a 10-min perfusion with 10 mM 2-DG (glycolytic inhibition) was followed by 25 min global, normothermic, no-flow ischemia and 30 min normoxic reperfusion. Heart weights were greater in Band than Sham [2.76 +/- 0.06 vs. 1.5 +/- 0.04 (mean +/- SE) g; P < 0.001]. GR and 2-DG each resulted in reduced ATP levels measured at the beginning of ischemia in both Band and Sham groups compared with untreated groups, but there were no differences among groups after 25 min of ischemia. Myocardial lactate levels at the end of ischemia were significantly reduced in both Band and Sham hearts with GR or 2-DG compared with untreated controls. Recovery of LV function after ischemia and reperfusion was significantly improved in Band after GR (206% increase) and after 2-DG treatment (126% increase) compared with their respective untreated controls. Diastolic dysfunction during reperfusion was ameliorated in Band by preischemic GR but not by 2-DG treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
cAMP can raise or lower cardiac actomyosin ATPase activity depending on alpha-adrenergic activity
Authors: McClellan G. , Weisberg A. , Winegrad S.
Published: December 2017

Adenosine 3',5'-cyclic monophosphate (cAMP) or beta-adrenergic stimulation has been shown to increase actomyosin adenosinetriphosphatase (ATPase) activity in cardiac muscle. Because the major catecholamine transmitters have both alpha- and beta-adrenergic activity, the possibility of a role for alpha-adrenergic stimulation in the regulation of ATPase activity has been investigated. Histochemical measurement of actomyosin ATPase activity in quickly frozen rat hearts has been used as the assay of enzymatic function of the contractile proteins. The dose-response curve of ATPase activity to cAMP shows an increase in ATPase activity at a threshold concentration of 0.01 microM, a peak effect at 0.5–1.0 microM, and a decline beyond 1.5 microM to a level below control at 10 microM cAMP. Kinetic studies varying ATP concentration from 0.5 to 10 mM indicated the existence of multiple forms of actomyosin ATPase activity in the absence of cAMP and only one form with a higher maximum velocity in the presence of 1 microM cAMP. Apparently cAMP raises the enzymatic activity of the individual actomyosin molecule rather than increasing the number of active molecules. The addition of an alpha-adrenergic blocker had no significant effect in the absence of added cAMP, but in the presence of the cyclic nucleotide, 1 microM prazosin always produced a negative effect on ATPase activity. Over the entire range of 0.01–10 microM, cAMP lowered ATPase activity when the alpha-adrenergic antagonist was present. The integrity of the cAMP regulatory system was sensitive to the tissue oxygen tension at the time the heart was quickly frozen. At certain oxygen tension, the stimulatory component of the cAMP regulation was observed without any inhibitory component, suggesting that there are two relatively independent parts of the regulatory mechanism, an inhibitory and a stimulatory. In the presence of gamma-labeled [32P]ATP, 32P was incorporated into several proteins, including the inhibitory subunit of troponin (TNI), C protein, and the regulatory light chain of myosin. cAMP (1 microM) caused an increase in 32P labeling of TNI and C protein. The addition of prazosin with cAMP caused a decrease in the overall level of phosphorylation with specific dephosphorylation of C protein and TNI, the former to a degree similar to the decrease in actomyosin ATPase activity, the latter to a greater degree. These results indicate that alpha-adrenergic activity modulates the balance between kinase and phosphatase activity in the presence of cAMP, probably by inhibiting phosphatase activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Quantitation of myoglobin saturation in the perfused heart using myoglobin as an optical inner filter
Authors: Leisey J. R. , Scott D. A. , Grotyohann L. W. , Scaduto R. C.
Published: December 2017

Quantitation of metabolic parameters using the technique of cardiac surface fluorescence is complicated by motion and changes in tissue absorption. Because ratio fluorescence methodology can be applied to eliminate motion-induced errors, in the current study, we used a ratio fluorescence technique to evaluate myoglobin saturation in the perfused rat heart, since myoglobin is the major oxygen-dependent light absorbing species in this tissue. Changes in myoglobin saturation can affect surface fluorescence measurements as a result of the inner filter effect. Optical scans of heart extracts indicated the major absorption peak is due to myoglobin and its peak wavelength shifts from 415 to 430 nm upon deoxygenation. To monitor this shift in hearts, the isolated perfused heart was loaded covalently with the fluorescent dye 7-diethylaminocoumarin-3-carboxylic acid by brief perfusion with the succinimidyl ester. This dye has an excitation maximum in the region of maximal absorption by myoglobin and allows for monitoring myoglobin oxygenation using the inner filter effect. The dye localized to endothelial cells and increased the surface fluorescence in this wavelength region approximately 50-fold above background levels without affecting cardiac function. An equation was derived to estimate the fraction of myoglobin in the oxygenated state from changes in the fluorescence 415/430 excitation ratio. From this fraction, the average PO2 in the environment of myoglobin was estimated under several perfusion conditions. We report that retrograde perfusion in the Langendorff mode at either 60 or 120 mmHg pressure resulted in full oxygenation of myoglobin with use of cell-free perfusate equilibrated with 95% O2.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood flow-dependent functional recovery in a rat model of focal cerebral ischemia
Authors: Dalkara T. , Morikawa E. , Panahian N. , Moskowitz M. A.
Published: December 2017

The reduction in focal infarct volume after L-arginine has been attributed to an increase in regional cerebral blood flow (rCBF) within ischemic tissue. We tested the hypothesis that L-arginine-induced rCBF increases precede the recovery of spontaneous electrical activity [electrocorticogram (ECoG)] in spontaneously hypertensive rats subjected to middle cerebral artery (MCA) occlusion. ECoG was recorded from the penumbral region of parietal cortex by a glass microelectrode inserted into 1-mm3 cortical tissue from which blood flow was sampled by laser-Doppler flowmetry. rCBF dropped to 21 +/- 8% of the preischemic level, and ECoG was depressed by 64 +/- 13% after distal MCA occlusion. L-Arginine infusion (300 mg/kg i.v.) increased rCBF in 14 out of 18 rats, and ECoG significantly recovered in seven rats in which rCBF exceeded 31% of preischemic flow. Increases in rCBF anticipated the functional improvement in every case. Saline (n = 6) or D-arginine (n = 5) administration was ineffective. These data demonstrate that increasing rCBF can promote functional recovery in the ischemic brain and suggest that early administration of L-arginine or other vasodilators may enhance tissue survival by increasing rCBF.
Chronic intravenous administration of V1 arginine vasopressin agonist results in sustained hypertension
Authors: Cowley A. W. , Szczepanska-Sadowska E. , Stepniakowski K. , Mattson D.
Published: December 2017

Despite the well-recognized vasoconstrictor and fluid-retaining actions of vasopressin, prolonged administration of arginine vasopressin (AVP) to normal animals or humans fails to produce sustained hypertension. The present study was performed to elucidate the role of the V1 receptor in determining the ability of AVP to produce sustained hypertension. Conscious Sprague-Dawley rats with implanted catheters were infused with the selective V1 agonist, [Phe2,Ile3,Orn8]vasopressin (2 ng.kg-1.min-1), for 14 days in amounts that were acutely nonpressor. Blood pressure (MAP), heart rate (HR), body weight, and water intake (WI) were determined daily. Plasma AVP, plasma catecholamines norepinephrine and epinephrine, plasma osmolality, and electrolyte concentration were determined before and on days 1 and 7 of infusion. MAP increased significantly by 10.4 +/- 4.5 mmHg on day 1 and rose to 22 +/- 5 mmHg above control by day 14 (transient decrease on days 6-9) and then fell to control levels after the infusion was stopped. HR did not change significantly. Plasma AVP immunoreactivity increased from 2.5 +/- 0.3 to 10.9 +/- 2.1 pg/ml, whereas norepinephrine tended to fall only on day 1, with epinephrine only slightly elevated on day 7. No evidence of fluid retention was found, and rats lost sodium only on the first day of V1 agonist infusion. Body weight increased throughout the study but was unrelated to the changes of MAP. We conclude that chronic stimulation of V1 receptors results in sustained hypertension in rats.
Mechanical regulation of cardiac muscle by coupling calcium kinetics with cross-bridge cycling: a dynamic model
Authors: Landesberg A. , Sideman S.
Published: December 2017

This study describes the regulation of mechanical activity in the intact cardiac muscle, the effects of the free calcium transients and the mechanical constraints, and emphasizes the central role of the troponin complex in regulating muscle activity. A “loose coupling” between calcium binding to troponin and cross-bridge cycling is stipulated, allowing the existence of cross bridges in the strong conformation without having bound calcium on the neighboring troponin. The model includes two feedback mechanisms: 1) a positive feedback, or cooperativity, in which the cycling cross bridges affect the affinity of troponin for calcium, and 2) a negative mechanical feedback, where the filament-sliding velocity affects cross-bridge cycling. The model simulates the reported experimental force-length and force-velocity relationships at different levels of activation. The dependence of the shortening velocity on calcium concentration, sarcomere length, internal load, and rate of cross-bridge cycling is described analytically in agreement with reported data. Furthermore, the model provides an analytic solution for Hill's equation of the force-velocity relationship and for the phenomena of unloaded shortening velocity and force deficit. The model-calculated changes in free calcium in various mechanical conditions are in good agreement with the available experimental results.
Histamine can induce leukocyte rolling in rat mesenteric venules
Authors: Ley K.
Published: December 2017

Rolling is a retarded movement of leukocytes that depends on the function of the selectin class of adhesion molecules. In venules of internal organs, rolling is rapidly induced on tissue exposure by unknown mediator(s). Rolling was investigated with intravital microscopy in venules of the exteriorized mesentery of anesthetized rats. Immediately after exteriorization, rolling leukocyte flux was very low (10 +/- 4 min-1) and increased rapidly to reach a peak of 76 +/- 10 min-1 at 30 min. Intraperitoneal pretreatment of rats with histamine induced near-maximal rolling in mesenteric venules immediately after exteriorization. Leukocyte rolling was significantly inhibited by intravenular microinfusion of monoclonal antibody PB1.3 that recognizes and functionally blocks human and rat P-selectin. The effect of histamine was blocked by pretreatment with ranitidine, an H2-receptor antagonist, but not with diphenhydramine, which blocks H1 receptors. However, ranitidine did not block the subsequent increase of rolling leukocyte flux, and rolling leukocyte flux was similar in all groups 20 min after exteriorization. Histological investigation revealed degranulation of mast cells, suggesting release of histamine and other mediators. These findings indicate that histamine can induce leukocyte rolling in vivo via H2 receptors, most likely by inducing endothelial expression of P-selectin. In addition, mediators other than histamine released from mast cells and/or other cells are likely to promote sustained rolling.
Comparison of cardiovascular effects of mu- and delta-opioid receptor antagonists in dogs with congestive heart failure
Authors: Imai N. , Kashiki M. , Woolf P. D. , Liang C. S.
Published: December 2017

We have shown previously that right heart failure (RHF) in dogs is associated with activated endogenous opiate systems, and that administration of the opioid receptor antagonist, naloxone, increases arterial pressure, cardiac contractile function and organ blood flows. To study whether the cardiovascular effects of naloxone are mediated via the mu- or delta-opioid receptors, we administered ICI-154,129, a delta-receptor antagonist, and naloxonazine, a mu-receptor antagonist, to 10 conscious dogs with RHF on 2 separate days. Like naloxone, ICI-154,129 increased mean aortic pressure, cardiac output, peak positive first derivative of left ventricular pressure, and blood flows to the myocardium, kidneys, splanchnic beds, and skeletal muscle. These changes were associated with increases in plasma epinephrine and norepinephrine. In contrast, naloxonazine had no effects on systemic hemodynamics, regional blood flow distribution, and plasma catecholamines in RHF. These findings suggest that the increased endogenous opioids during heart failure act on the delta-opioid receptors to decrease myocardial mechanical performance and alter regional blood flow distribution. Opioid receptor-blocking agents may exert beneficial cardiovascular effects in heart failure.
NO donors prevent integrin-induced leukocyte adhesion but not P-selectin-dependent rolling in postischemic venules
Authors: Kubes P. , Kurose I. , Granger D. N.
Published: December 2017

The objective of this study was to examine the effect of nitric oxide (NO) donors on polymorphonuclear leukocyte (PMN) interactions in the microvasculature of postischemic tissue and to compare the antiadhesive properties of NO donors with the responses observed after immunoneutralization of three key adhesion glycoproteins (CD11/CD18, intercellular adhesion molecule-1, and P-selectin). Rolling and firm adhesion (adherence) of leukocytes and shear rate were monitored in cat mesenteric venules subjected to 60 min of ischemia (blood flow reduced to 20% of control), followed by 60 min of reperfusion. Immediately before reperfusion, the mesentery was superfused with a NO donor (3-morpholinosydonimine-N-ethyl-carbamide or spermine-NO) or a monoclonal antibody (MAb) against an adhesion glycoprotein that was administered intravenously. In untreated animals, a profound influx in rolling PMNs was observed during reperfusion that was subsequently followed by increased firm adhesion. The anti-P-selectin antibody completely abolished the rise in the flux of rolling PMNs, whereas the anti-CD18 antibody prevented firm adhesion. Both NO donors attenuated ischemia/reperfusion-induced leukocyte adhesion to a level comparable with that observed after administration of a MAb against CD11/CD18 without affecting PMN rolling. The antiadhesive effect of the NO donors could not be attributed solely to an improvement of venular wall shear rate. In vitro data did not reveal a direct effect of NO donors on the expression of CD18 or neutrophil adhesion to endothelial cells. These observations suggest that NO donors may provide protection from tissue injury by preventing PMN adhesion.(ABSTRACT TRUNCATED AT 250 WORDS)
Basic FGF enhances endothelium-dependent relaxation of the collateral-perfused coronary microcirculation
Authors: Sellke F. W. , Wang S. Y. , Friedman M. , Harada K. , Edelman E. R. , Grossman W. , Simons M.
Published: December 2017

The effect of chronic, periadventitial administration of basic (b) fibroblast growth factor (FGF) on endothelial dysfunction in the collateral-dependent and normally perfused coronary microcirculation was examined. Ameroid constrictors were placed on the proximal left circumflex coronary artery (LCX) in 23 pigs. In 11 pigs, bFGF was released from calcium alginate microcapsules into the perivascular space of the proximal left anterior descending coronary artery (LAD) and LCX. After 5-8 wk, coronary arterial microvessels (80-170 microns) were studied in a pressurized (40 mmHg) no-flow state with video microscopy. Receptor-mediated endothelium-dependent relaxations to ADP and serotonin were reduced while contraction to acetylcholine was enhanced in the collateral-dependent LCX microvessels of non-bFGF-treated control hearts. Relaxation of vessels to the non-receptor-mediated, endothelium-dependent agent A-23187; endothelium-independent relaxation to nitroprusside; and contraction to KCl were similar in all groups. Chronic treatment with bFGF normalized responses to ADP, serotonin, and acetylcholine in the collateral-dependent LCX region but had no effect on the responses of vessels in the normally perfused LAD region. Arteriolar density in the collateral-perfused LCX region of bFGF-treated hearts was markedly increased (4-fold compared with that in untreated hearts, suggesting a link between the angiogenic effect of bFGF and its action on endothelial preservation. Thus the periadventitial, sustained delivery of bFGF preserves receptor-mediated, endothelium-dependent responses in the collateral-dependent LCX region but has no effect on responses of microvessels in the normally perfused LAD region or on non-receptor-mediated endothelium-dependent relaxation.
Ischemic preconditioning stimulates anaerobic glycolysis in the isolated rabbit heart
Authors: Janier M. F. , Vanoverschelde J. L. , Bergmann S. R.
Published: December 2017

Preconditioning decreases ischemic injury, preserves tissue ATP content, and enhances the salutary effects of reperfusion. To evaluate whether preserved ATP is related to reduced utilization or increased production, 28 paced isolated rabbit hearts, perfused at constant flow, were subjected to 3 min of transient no-flow ischemia followed 12 min later by 1 h of low-flow ischemia and 45 min of reperfusion. Results were compared with those from 34 control hearts subjected to ischemia and reperfusion without preconditioning. Preconditioning delayed the onset of ischemic contracture and decreased its amplitude. At the end of ischemia, tissue ATP content was higher in hearts subjected to preconditioning (9.8 +/- 3.3 vs. 4.5 +/- 1.1 mumol/g dry wt; P < 0.01), accounted for by increased anaerobic ATP production using exogenous glucose. Preconditioning decreased ischemic damage (creatine kinase release 373 +/- 199 vs. 587 +/- 291 U/g dry wt; P < 0.05) and resulted in better functional recovery with reperfusion (74 +/- 11% of baseline developed pressure vs. 60 +/- 23%; P < 0.05). Thus preconditioning appears to protect ischemic myocardium by enhancing anaerobic glycolytic production of ATP using exogenous glucose.
Effects of nitroglycerin on diameter and pulsation amplitude of subendocardial arterioles in beating porcine heart
Authors: Yada T. , Hiramatsu O. , Goto M. , Ogasawara Y. , Kimura A. , Yamamoto T. , Tsujioka K. , Kajiya F.
Published: December 2017

We examined the effect of nitroglycerin (NTG) on the diameter and diastolic-to-systolic pulsation amplitude of large (ID > 100 microns) and small (ID < 100 microns) subendocardial arterioles with their segmental responses. In 10 open-chest, anesthetized pigs, subendocardial arterioles of beating hearts (n = 18) were videorecorded using a needle-probe videomicroscope. Subendocardial arteriolar diameter was determined before and 1-2 min after NTG administration (25 micrograms/kg i.v.). In an additional experiment using three pigs, we monitored the transient response of subendocardial small arterioles (n = 5) from the time before NTG administration until 3 min after NTG. NTG dilated large subendocardial arterioles by 13 +/- 4% (means +/- SD, n = 10, P < 0.001) at about 1.5 min after NTG, but not small subendocardial arterioles (2 +/- 2%, n = 8, not significant). However, the small arterioles responded transiently to NTG in an earlier phase, especially to a higher dose. The percent diameter change of large subendocardial arterioles between diastole and systole at 1.5 min after NTG administration was 32 +/- 4%, which was larger than that under control conditions (19 +/- 8%, P < 0.05). The pulsation amplitude of small subendocardial arterioles at this time was almost unchanged by NTG (16 +/- 8 vs. 17 +/- 6%, NS) but increased transiently in an earlier phase. In conclusion, NTG dilated large subendocardial arterioles on the plateau phase of its impulse (intravenously) response (approximately 1.5 min after NTG).(ABSTRACT TRUNCATED AT 250 WORDS)
Regional electromechanical alternans in anesthetized pig hearts: modulation by mechanoelectric feedback
Authors: Murphy C. F. , Lab M. J. , Horner S. M. , Dick D. J. , Harrison F. G.
Published: December 2017

Electrical and mechanical alternans have often been found to coexist. However, the factors controlling their interdependence are not known. In this study we measure regional electrical and mechanical activity during mechanical alternans to investigate this relationship. Mechanical alternans was induced by rapid atrial pacing in 18 anesthetized, open-chest pigs. Regional segmental contraction and monophasic action potential were measured in three areas of left ventricle using epicardial tripodal strain gauges and suction electrodes. Electrical alternans always accompanied pulsus alternans. The phase of electrical alternans was not related to any measure of regional mechanical activity but did show a constant discordant relation to peak ventricular pressure. This suggested that mechanically dependent changes in action potential duration (mechanoelectric feedback) may be important in modulation electrical alternans. In support of this, pulsus alternans simulated by clamping the proximal aorta on alternate beats was associated with electrical alternans comparable to that produced with rapid atrial pacing. Mechanoelectric feedback modulates regional electrophysiology in the intact heart and may be important in the generation of electrical alternans.