bluuebunny/crossref_metadata_2025 huggingface dataset:
Stability of myocardial O2 consumption-pressure-volume area relation in red cell-perfused rabbit heart
Authors: Yaku H. , Slinker B. K. , Myhre E. S. , Watkins M. W. , Lewinter M. M.
Published: December 2017

We evaluated the mechanical and energetic stability of the isolated rabbit heart perfused with a suspension of bovine red cells in Krebs-Henseleit buffer in terms of the pressure-volume area (PVA) concept. PVA, the area surrounded by the end-systolic and end-diastolic pressure-volume (P-V) relations and the systolic P-V trajectory of the P-V diagram, represents the total mechanical energy generated by each cardiac contraction. Myocardial O2 consumption (VO2) per beat has been reported to be highly linearly correlated with PVA. We used the slope and VO2-axis intercept of the VO2-PVA relation as energetic parameters and the maximum P-V ratio (Emax) as a contractility index of the left ventricle (LV) and compared them every 30 min for 120 min. Emax, the slope, and VO2 intercept of the VO2-PVA relation did not change significantly over 120 min compared with their control values [7.3 +/- 2.9 mmHg.ml-1.100 g LV, (1.67 +/- 0.40) x 10(-5) ml O2.mmHg-1.ml-1, and (3.26 +/- 1.01) x 10(-2) ml O2.beat-1.100 g LV-1, respectively]. However, the goodness of the linear fit of the VO2-PVA relation decreased after 90 min (r = 0.94 control, 0.62 at 90 min, and 0.64 at 120 min). Therefore, we conclude that the isolated bovine red cell-perfused rabbit heart preparation is stable for mechanical and energetic studies for at least 60 min.
Dichloroacetate reduces sympathetic nerve responses to static exercise
Authors: Ettinger S. , Gray K. , Whisler S. , Sinoway L.
Published: December 2017

Lactic acid is thought to be a stimulant of muscle metaboreceptors. The goal of the present study was to determine if inhibition of lactic acid production by dichloroacetate (DCA) would attenuate muscle sympathetic nerve activity (MSNA) during static forearm exercise. DCA increases pyruvate dehydrogenase levels. Thus, for a given amount of pyruvate produced, less lactic acid is formed. Seven subjects performed static forearm exercise at 20% maximal voluntary contraction until fatigue followed by posthandgrip circulatory arrest (PHG-CA) (trial.1). Subjects then received DCA (35 mg/kg) and repeated the exercise protocol (trial 2). We observed an attenuated rise in forearm venous lactate and MSNA. The trial 2 MSNA value during PHG-CA was 51 +/- 11% less than the value during trial 1 (P less than 0.01). In seven control subjects, two bouts of static forearm exercise were performed with an intervening saline infusion. This intervention had no effect on lactate or MSNA responses to exercise. We conclude that DCA attenuates lactate responses to static exercise, and this is associated with a blunted MSNA response.
Role of sinoaortic afferents in modulating BP and pulse-interval spectral characteristics in unanesthetized cats
Authors: Di Rienzo M. , Parati G. , Castiglioni P. , Omboni S. , Ferrari A. U. , Ramirez A. J. , Pedotti A. , Mancia G.
Published: December 2017

Sinoaortic denervation (SAD) is accompanied by an increase in blood pressure (BP) and a reduction in pulse-interval (PI) variance. Little is known, however, about the effect of SAD on the complex BP and PI variability pattern, which is identified by spectral analysis. In nine unanesthetized cats in which intra-arterial BP was monitored before and 7-10 days after SAD, spectral powers (estimated by fast Fourier transform) were calculated for the low frequency (LF, 0.025-0.07 Hz), midfrequency (MF, 0.07-0.14 Hz), and high frequency (HF, 0.14-0.60 Hz) band. The very low frequency (VLF) BP and PI components (VLF less than 0.025 Hz) were also estimated. SAD increased systolic BP variance and decreased PI variance. The reduction of PI variance was paralleled by significant and marked reductions in all PI powers including the VLF components. In contrast, the increase in systolic BP variance was accompanied by a marked increase in LF power, a decrease in MF power, and no change in HF power. The VLF BP components increased after SAD for frequencies between 0.025 and 0.0012 Hz, whereas a sudden marked reduction was observed below 0.0012 Hz. Similar results were obtained for diastolic BP powers. Thus the reduction in PI variance induced by SAD is paralleled by a reduction in all PI fluctuations identified by spectral analysis. This is not the case for the SAD-related increase in BP variance, which is accompanied by an increase, no change, or even a reduction in the different BP spectral components.(ABSTRACT TRUNCATED AT 250 WORDS)
Myocardial protection by R 56865: a new principle based on prevention of ion channel pathology
Authors: Ver Donck L. , Borgers M.
Published: December 2017

Intracellular Ca2+ overload is considered to be the final pathway leading to cell death under pathological conditions. However, both the route of Ca2+ entry and the site of action of cardioprotective drugs remain obscure. This was investigated using isolated adult rat and rabbit cardiomyocytes exposed to the experimental pathological stimuli veratridine, singlet O2, lysophosphatidylcholine, and ouabain. Under these conditions, the majority of cells displayed irreversible hypercontraction as a consequence of intracellular Ca2+ overload. Nifedipine did not prevent Ca2+ overload, but tetrodotoxin (TTX) and reduction of the extracellular Na+ concentration protected against the above pathological stimuli. This strongly suggests that intracellular Ca2+ overload after exposure to these pathological stimuli may be mediated via fast Na+ channel dysfunction, causing excessive entry of Na+, followed by Ca2+ overload via Na(+)-Ca2+ exchange. The new cardioprotective drug R 56865 dose dependently prevented hypercontracture induced by each of these stimuli, suggesting that R 56865 may interfere with this modified Na+ channel that is in a way different from class I antiarrhythmic drugs. This is regarded as a new cardiac cytoprotective principle.
Carotid baroreceptor control of right atrial mechanics in dogs
Authors: Carlson D. E. , Brunner M. J. , Gann D. S.
Published: December 2017

To investigate the influence of the carotid arterial baroreceptors on right atrial mechanics, the carotid sinus region was isolated surgically in eight dogs prepared acutely under pentobarbital. Right atrial pressure and conductance volume were measured with a strain-gauge tip catheter and a conductance catheter, respectively. Reduction of carotid sinus pressure from 225 to 50 mmHg elicited significant increases in the a wave in right atrial pressure, in atrial stroke volume, in atrial stroke work (2.5-fold), and in atrial stroke power (4-fold). Mean central venous pressure and atrial volume at the onset of each beat did not change. These responses were unchanged after bilateral cervical vagotomy. Head-up tilt was applied at carotid sinus pressures less than or equal to 150 mmHg in four dogs to oppose any contribution of decreased systemic venous capacity to the responses through increased atrial filling. Tilt did not change atrial stroke work or atrial filling during late ventricular systole before vagotomy but inhibited these variables significantly after vagotomy. The slope of the relationship between right atrial stroke work and atrial volume at the onset of contraction increased significantly with reduction of carotid sinus pressure. This response was unaffected by either vagotomy or tilt. Carotid arterial hypotension appears to augment right atrial stroke work and stroke volume through an increase in atrial contractility. A decrease in venous capacity may contribute to this response especially after vagotomy.
Fluid restitution and shift of blood volume in anesthetized rabbits subject to cyclic hemorrhage
Authors: LaForte A. J. , Lee L. P. , Rich G. F. , Skalak T. C. , Lee J. S.
Published: December 2017

We investigated the effect of a 10% cyclic blood volume change with a period of 2 or 4 min to study the short-term control of blood volume. In experiments with pentobarbital-anesthetized rabbits, the blood density variation over a 2-min cycle is 0.94 +/- 0.04 (SE) g/l, and the plasma density variation is 0.17 +/- 0.04 g/l. The plasma density variation could result from a fluid restitution from the extravascular space (with a density 1,005 g/l), with a volume equal to 14% of the withdrawn blood volume. This restitution cannot account, however, for the entire observed density change in arterial blood. Because of the Fahraeus effect in microvascular flow, a shift in blood volume from the microvasculature is another mechanism that could lead to a decrease in the density of arterial blood. An analysis of the blood and plasma density variations indicates that a blood volume (49% of the shed volume) is shifted from the micro- to macrocirculation. This volume compensation by fluid restitution and volume shift acts to minimize the effect of hemorrhage on the filling of the venous system. We found that the blood density waveform parallels the change in blood volume. When the blood volume change reverses its direction, the density change also reverses direction with a time delay less than 8 s. The blood density variations are not altered by bilateral vagotomy or its combination with hexamethonium (a sympathetic ganglionic blocker). These observations of anesthetized rabbits indicate that the short-term compensation is primarily due to the volume shift from the microcirculation and is not regulated by humoral or neural mechanisms but by local mechanisms such as autoregulation and the passive response due to changes in microvascular pressure.
An evaluation of pulsus alternans in closed-chest dogs
Authors: Freeman G. L. , Widman L. E. , Campbell J. M. , Colston J. T.
Published: December 2017

Pulsus alternans is a condition in which the arterial pressure generated by the heart oscillates between two levels on a beat-to-beat basis. We evaluated the onset of pulsus alternans in chronically instrumented dogs subjected to tachycardia and inferior vena caval occlusion. During pulsus alternans, the left ventricular (LV) end-diastolic volume (EDV) was larger before the strong beats (28.7 +/- 5.3 vs. 25.9 +/- 4.5 ml, P less than 0.001 by paired t test), suggesting that the Frank-Starling mechanism participates in the alternating difference in end-systolic pressure. In addition, however, the ratio of pressure to volume at end systole was greater in the strong beats (2.01 +/- 0.36 vs. 1.46 +/- 0.45, P less than 0.005 by paired t test), a difference that cannot be explained by the Frank-Starling mechanism alone. This indicates that there is also a difference in end-systolic inotropic states between strong and weak beats. These changes occurred without significant alterations in beat-to-beat levels of coronary flow. The time constant of isovolumic pressure fall (T) was faster for the strong beats (37.5 +/- 4.2 vs 61.1 +/- 12.7 ms, P less than 0.002 by paired t test). The onset of oscillation in T preceded the onset of changes in LVEDV and LV systolic pressure in every case by an average of seven beats (range 3-11), suggesting that abnormalities of intracellular calcium handling led to the occurrence of pulsus alternans.(ABSTRACT TRUNCATED AT 250 WORDS)
Oxygen free radicals affect cardiac and skeletal cell membrane potential during hemorrhagic shock in rats
Authors: Yokota J. , Chiao J. J. , Shires G. T.
Published: December 2017

Oxygen free radical (OFR) damage of excitable cell membranes (heart and skeletal muscle) during hemorrhagic shock and after resuscitation was studied in control rats and in rats pretreated with superoxide dismutase (SOD) and catalase (CAT; 6,000 U each) before hemorrhage. Their mean arterial pressure (MAP) was lowered to and maintained at 45 mmHg until 30% of the shed blood was spontaneously reinfused. The remaining blood and twice that volume of lactated Ringer solution were then infused. Cardiac output and organ blood flow were measured by the microsphere technique. The resting membrane potential (Em) and tissue ATP content in the heart and skeletal muscle were determined. There was no significant difference between the control and SOD + CAT groups in shock duration, maximal shed blood, hemodynamics, regional blood flow, or in ATP content in both heart and skeletal muscle, both during shock and after resuscitation. Radical scavenger treatment did not prevent muscle depolarization during shock. After resuscitation, however, significant repolarization in hearts and skeletal muscle of the SOD + CAT group (heart, -70.0 +/- 1.1; muscle, -87.0 +/- 0.6 mV) was noted when compared with the controls (heart, -62.5 +/- 1.2; muscle, -82.7 +/- 1.1 mV; P less than 0.05). This implicates OFRs as mediators of excitable cell membrane injury following resuscitation.
Ventricular fibrillation is not an anodally induced phenomenon in open-chest dogs
Authors: Chen P. S.
Published: December 2017

It is generally assumed that ventricular fibrillation evoked by electrical stimulation depends on anodal excitation. To test this hypothesis, six open-chest dogs were studied with computerized mapping techniques. A plaque electrode array containing 56 closely (2.5-5 mm) spaced bipolar electrodes was placed on the right ventricle. The patterns of activation after premature stimulation and at the onset of multiple responses or ventricular fibrillation were determined when the baseline driving stimuli (S1) were given to the center, and when a 5-ms bipolar single premature stimulus (S2) was given via two electrodes (one anodal and one cathodal) at the opposite edges of the plaque electrode array. The results showed that the classical anodal and cathodal strength-interval curves could be demonstrated by this method. A relatively supernormal period was observed only in the anodal strength-interval curve and coincided with the most vulnerable phase of the cardiac cycle. Although a supernormal period was found only at the anodal site, the origins of excitation at the onset of multiple responses or ventricular fibrillation could be anodal, cathodal, or both. When the S2 polarity was reversed, the origin of multiple responses or ventricular fibrillation stayed at the same site and did not change according to the polarity of the S2. These findings indicate that ventricular fibrillation is not an anodally induced phenomenon. The preexisting electrophysiological state at the site of stimulation determines the initiation and maintenance of multiple responses or ventricular fibrillation.
Serotonin and norepinephrine vasoconstriction in rat hindlimb have different oxygen requirements
Authors: Dora K. A. , Richards S. M. , Rattigan S. , Colquhoun E. Q. , Clark M. G.
Published: December 2017

Serotonin (5-HT) and norepinephrine (NE) are potent vasoconstrictors in the non-erythrocyte constant-flow perfused hindlimb at 25 degrees C. Because 5-HT inhibits and NE stimulates oxygen uptake, these agonists may exert control at different sites in the vasculature that have different metabolic requirements. In this study, it was found that hypoxia, cyanide, or azide had no significant effect on 5-HT-mediated vasoconstriction; however, in the presence of cyanide and absence of glucose, vasoconstriction was transient. NE-mediated vasoconstriction displayed two prazosin-sensitive components. At low concentrations (less than 50 nM), NE-mediated vasoconstriction was totally blocked by hypoxia, cyanide, or azide. At concentrations of NE significantly greater than 50 nM, oxygen-independent vasoconstriction was observed. In conclusion, NE and 5-HT sites are biochemically distinguishable, with 5-HT sites probably located on larger vessels and supportable by anaerobic metabolism and oxygen-dependent NE sites probably located on smaller arteries or arterioles. Supraphysiological concentrations of NE may interact with a subgroup of vascular alpha 1-adrenoceptors on larger vessels giving results similar to 5-HT, thus highlighting problems with high levels of NE in the perfused rat hindlimb.
Mechanical, energetic, and biochemical changes in long-term volume overload of rabbit heart
Authors: Gibbs C. L. , Wendt I. R. , Kotsanas G. , Young I. R.
Published: December 2017

The mechanical and energetic consequences of long-term volume-overload (VOL) hypertrophy have been investigated in rabbits and compared with the consequence in sham-operated controls (SOC). Hypertrophy was induced by creating an aortocaval shunt, and the mechanical, biochemical, and energetic properties of the compensated heart were examined approximately 12 wk later. At 27 degrees C and a stimulus frequency of 1 Hz there were no significant changes in peak stress development, 10-90% rise times, shortening velocity, work, and mechanical power output. There was, however, a prolongation of contractile duration. The inverse relationship between peak stress and cross-sectional area was unchanged in the VOL and SOC groups. Polarographic and myothermic experiments were made on papillary muscles. Hypertrophy produced a small increment in basal metabolism. In isometric studies there were no significant changes in either the activation heat magnitude or the slope of the heat-stress relationship. In isotonic contractions there was no change in work output or total enthalpy (heat + work), and as a result mechanical efficiency was unchanged. A force-length-area (FLA) analysis of the isotonic data showed no significant change in intercept or FLA contractile efficiency. Biochemical studies showed no significant difference in the myosin isoenzyme profile at the time of death. The Ca(2+)-stimulated adenosinetriphosphatase activity of the sarcoplasmic reticulum was unchanged as were the enzymatic activities of mitochondrial citrate synthase and alpha-ketoglutarate dehydrogenase. Interestingly essentially the same data were obtained from the hearts of four animals in failure and from the hearts of seven compensated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Neurally mediated renal vasoconstriction during isometric muscle contraction in cats
Authors: Matsukawa K. , Wall P. T. , Wilson L. B. , Mitchell J. H.
Published: December 2017

The aim of this study was to determine if the reflex increase in renal sympathetic nerve activity (RSNA) during static (isometric) muscle contraction evokes renal vasoconstriction and decreases renal blood flow. RSNA, renal blood flow velocity, and arterial pressure were measured simultaneously during isometric contraction of the hindlimb triceps surae muscle in eight chloralose-anesthetized cats. A 1-min contraction was evoked by stimulating the peripheral ends of the cut L7 and S1 ventral roots. RSNA and mean arterial pressure (MAP) increased 41 +/- 14% (SE) and 50 +/- 10 mmHg during static contraction, whereas mean renal blood flow velocity (MRBV) decreased 14 +/- 5%. Calculated renal vascular resistance increased 73 +/- 20% during the contraction. The increase in RSNA preceded the decrease in MRBV by 20 s. Passive mechanical stretch of the muscle increased RSNA 21 +/- 12% but did not alter MRBV. Renal denervation abolished the decrease in MRBV during isometric contraction but only attenuated the rise in MAP. Cutting the L4-S1 dorsal roots or muscle paralysis abolished the MRBV and MAP responses. Thus reflex stimulation of RSNA from the contracting muscle can induce renal vasoconstriction and decrease renal blood flow.
Fatty acid oxidation and mechanical performance of volume-overloaded rat hearts
Authors: el Alaoui-Talibi Z. , Landormy S. , Loireau A. , Moravec J.
Published: December 2017

Chronic volume overload was induced in 2-mo-old rats by surgical opening of the aortocaval fistula. Rats were killed 3 mo later and their hearts were atrially perfused. During the perfusions with 1.2 mM palmitate, mechanical performance of volume-overloaded hearts was significantly decreased both under conditions of a moderate work load and, mainly, after the clamp of the aortic outflow line. Respective O2 consumption rates as well as the rates of 14CO2 production from [U-14C]palmitate were decreased to the same extent. When 2.4 mM octanoate was used as the exogenous substrate, both the O2 consumption rates and the rates of CO2 production of volume-overloaded hearts became comparable to those of control hearts perfused with same substrate. Mechanical activity of volume-overloaded hearts returned to control values and remained stable during the entire perfusion period tested. Total tissue L-carnitine was decreased by approximately 30% in volume-overloaded hearts, which may suggest that palmitate oxidation has been limited at the level of carnitine-acylcarnitine translocase. However, our polarographic studies of the respiratory activity of isolated mitochondria indicated that the palmitoylcarnitine translocation proceeds normally. On the other hand, state 3 respiration of the mitochondria from volume-overloaded hearts supplemented with either palmitate or palmitate and L-carnitine was significantly lower than that of control ones. This may suggest that an alteration of the enzymes involved in long-chain fatty acid activation and/or long-chain fatty acyl transfer to L-carnitine has developed under conditions of chronic mechanical overloading of the heart.
Cardiac contractile effects of ethanolism and hemorrhagic shock
Authors: Horton J. W.
Published: December 2017

Moderate ethanol consumption, associated with cardiac depression, occurs in greater than 50% of trauma. Hemorrhagic shock, a significant component of trauma in the clinical setting, causes intrinsic cardiac contractile dysfunction. In this study, we used an isolated heart model to determine whether acute ethanolism increases the cardiovascular risk associated with hemorrhagic shock. We hypothesized that hemorrhagic shock in the acutely intoxicated subject would cause significantly greater cardiac dysfunction compared with that observed in a nonintoxicated subject. A total of 116 guinea pigs was divided into four groups: control (no ethanol, no shock), ethanol intoxication alone (1 mg/kg iv), hemorrhagic shock alone (mean arterial blood pressure, 30 mmHg for 2 h), and a combination of hemorrhagic shock plus ethanol. Half of the hearts in each group were used for isolated heart studies, and half were used to assess myocardial cell membrane integrity. Ethanol alone reduced peak isovolumic pressure by 36%, maximal rate of left ventricular pressure (LVP) rise by 27%, and maximal rate of LVP fall by 35%; however, contractile depression was significantly greater in the intoxicated, hemorrhaged, group compared with the nonintoxicated, hemorrhaged, group (P less than 0.05). Both ethanol and hemorrhage independently altered myocardial cell volume regulation; however, abnormalities in myocardial cell volume regulation induced by hemorrhage were similar in the intoxicated and nonintoxicated groups. Our data show that hemorrhagic shock causes significantly greater cardiac contractile dysfunction in the intoxicated subject.
Elevated mean systemic filling pressure due to intermittent positive-pressure ventilation
Authors: Chihara E. , Hashimoto S. , Kinoshita T. , Hirose M. , Tanaka Y. , Morimoto T.
Published: December 2017

To clarify the effect of intermittent positive-pressure ventilation (IPPV) on systemic circulation, mean systemic filling pressure (Psf) and circulating blood volume were measured together with other hemodynamic parameters of capacitance vessel. Change in circulating blood volume was determined by dilution with 51Cr-labeled erythrocytes. Vascular compliance (Cvas) was measured from the change in Psf caused by a bolus injection of blood. These parameters were measured during both spontaneous respiration and IPPV in male Wistar rats anesthetized with pentobarbital sodium. The shift from spontaneous respiration to IPPV reduced cardiac output (CO) by 20.9%. Psf increased significantly, from 7.1 +/- 1.2 to 8.6 +/- 1.1 mmHg. Central venous pressure (Pcv) also increased significantly. The pressure gradient for venous return decreased by 15.6% (from 6.4 to 5.4 mmHg). The resistance to venous return did not change significantly, but there was a significant increase in total peripheral resistance. Neither Cvas nor circulating blood volume was changed significantly by IPPV. These results indicate that during IPPV the increased Pcv attenuates the pressure gradient for venous return and decreases CO and that the compensatory increase in Psf is caused by a blood shift from unstressed to stressed blood volume.
Porous medium finite element model of the beating left ventricle
Authors: Huyghe J. M. , Arts T. , van Campen D. H. , Reneman R. S.
Published: December 2017

The axisymmetric model described represents myocardial tissue as a spongy anisotropic viscoelastic material. It includes torsion around the axis of symmetry of the ventricle, transmural variation of fiber angle, and redistribution of intracoronary blood in the myocardial wall. In simulations, end-systolic principal strains were equal to 0.45, -0.01, and -0.24 at two-thirds of the wall thickness from the epicardium and 0.26, 0.00, and -0.19 at one-third of the wall thickness from the epicardium. The direction of maximal shortening varied by less than 30 degrees from epicardium to endocardium, whereas fiber direction varied by greater than 100 degrees from epicardium to endocardium. During a normal cardiac cycle peak, equatorial intramyocardial pressure differed by less than 5% from peak intraventricular pressure. When redistribution of intracoronary blood in the ventricular wall was suppressed, peak equatorial intramyocardial pressure was found to exceed peak intraventricular pressure by greater than 30%. Simulated contraction of an unloaded left ventricle (left ventricular pressure = 0 kPa) produced similar magnitude for systolic intramyocardial pressures as the normal cardiac cycle. Transmural systolic fiber stress distribution was very sensitive to the chosen transmural fiber angle distribution.
Phosphorylation-independent regulation of cardiac IK by guanine nucleotides and isoproterenol
Authors: Freeman L. C. , Kwok W. M. , Kass R. S.
Published: December 2017

We tested for direct G protein regulation of delayed rectifier K+ (IK) channels, by measuring IK currents in guinea pig ventricular cells using patch-clamp procedures. In excised inside-out patches, IK was enhanced by adding guanosine triphosphate or guanosine 5'-O-(3-thiotriphosphate) to the cytoplasmic side, even in the presence of phosphorylation inhibitors. Enhancement of patch IK did not require extracellular agonist; however, enhancement of IK was also seen when isoproterenol was included in the pipette solution. Whole cell IK currents were increased by isoproterenol when phosphorylation pathways were blocked. These data demonstrate that guanine nucleotides and beta-adrenergic agonists can enhance IK by a phosphorylation-independent pathway. Our findings are consistent with a direct coupling of the beta-adrenergic receptor to the cardiac IK channel via a membrane-delimited G protein pathway, in addition to the well-established indirect pathway.
Canine coronary vasodepressor responses to hypoxia are attenuated but not abolished by 8-phenyltheophylline
Authors: Lee S. C. , Mallet R. T. , Shizukuda Y. , Williams A. G. , Downey H. F.
Published: December 2017

The purpose of this study was twofold: 1) to verify a report that a suspension of 8-phenyltheophylline (8-PT) completely abolished hypoxia-induced coronary vasodilation [H. M. Wei, Y. H. Kang, and G. F. Merrill. Am. J. Physiol. 257 (Heart Circ. Physiol. 26): H1043-H1048, 1989] and 2) to determine the effect of dissolved 8-PT on hypoxic hyperemia. The left anterior descending coronary artery of anesthetized dogs was cannulated and perfused at either constant flow or constant pressure. An 8-PT suspension (40 micrograms.kg-1.min-1) produced a twofold elevation of coronary perfusion pressure at constant flow, a 97% decrease in coronary flow at constant pressure, and regional akinesia in both conditions. The coronary vasculature was unresponsive to 60-s coronary occlusion, exogenous adenosine, and hypoxia after infusion of the 8-PT suspension. These findings are consistent with obstruction of the coronary microvasculature by the 8-PT suspension. An 8-PT solution (40 micrograms.kg-1.min-1) produced 95 +/- 3% (P less than 0.001, n = 6) attenuation of exogenous adenosine-induced vasodilation at constant pressure, a 28 +/- 5% (P less than 0.01, n = 6) attenuation of reactive hyperemia, and a 24 +/- 6% (P less than 0.05, n = 6) decrease in hypoxia-induced vasodilation. An 8-PT solution had no effect on systolic segment length shortening and myocardial oxygen consumption. We conclude that 8-PT, when in solution, attenuates but does not abolish the coronary vasodilatory response to hypoxia. Hence, adenosine appears to contribute to hypoxia-induced vasodilation but is not uniquely responsible for the hyperemic response.
Dipyridamole-induced capillary growth in normal and hypertrophic hearts
Authors: Torry R. J. , O'Brien D. M. , Connell P. M. , Tomanek R. J.
Published: December 2017

Chronic increases in myocardial blood flow have been shown to stimulate capillary proliferation in normal growing hearts. It is unknown, however, if elevated myocardial blood flow stimulates precapillary and/or capillary growth in hearts undergoing hypertrophy. Accordingly, renal hypertension was produced in rabbits (Page, 1-kidney, 1-wrap model) in which one group of Page (n = 9) and one group of normotensive sham (n = 10) rabbits were given dipyridamole (4.0 mg/kg sc) twice daily for 2 mo. Another group of Page (n = 7) and sham (n = 12) rabbits received vehicle injections. In separate acute studies performed on conscious rabbits, this does of dipyridamole increased myocardial blood flow 35-60% over time without altering transmural distribution of flow or systemic blood pressure. Two months later, minimal coronary vascular resistance (MCVR/100 g) was calculated from perfusion during maximal coronary vasodilation in conscious animals. Histomorphometric methods were then utilized to evaluate various indexes of capillarity in perfuse-fixed hearts. Systolic pressure and left ventricle weight-to-body weight ratios were significantly higher in Page vs. sham rabbits; dipyridamole treatment did not alter these parameters within either group. Similarly, dipyridamole treatment did not significantly alter MCVR/100 g values in either normotensive or hypertensive rabbits. In contrast, dipyridamole treatment increased endomyocardial capillary length density by 33% in the hypertensive group (P less than 0.05) and 11% in the sham group (P not significant) compared with the respective vehicle-treated rabbits. In addition, intercapillary distance was significantly reduced in the endomyocardial region of both groups receiving dipyridamole injections.(ABSTRACT TRUNCATED AT 250 WORDS)
Cerebrovascular reactivity to adenosine analogues in 0.6-0.7 gestation and near-term fetal sheep
Authors: Kurth C. D. , Wagerle L. C.
Published: December 2017

During acute hypoxia, fetal sheep less than 0.7 gestation increase cerebral blood flow (CBF) relatively less than fetal sheep near term. We hypothesized that cerebrovascular reactivity to a hypoxic vasodilator metabolite such as adenosine might be diminished in immature fetuses. This study examined cerebral vasoreactivity to adenosine analogues in nine sheep fetuses less than 0.7 gestation (90-103 days) and nine near term (129-143 days). Fetuses were equipped in utero with a closed cranial window, and pial arterioles were studied by intravital microscopy. 5'-(N-ethylcarboxamido)-adenosine (NECA; 10(-9)-10(-5) M) and N6-cyclopentyladenosine (CPA; 10(-9)-10(-4) M) each caused a dose-dependent increase in arteriolar diameter that was attenuated in the presence of the adenosine receptor antagonist 8-phenyltheophylline (8-PT; 5 x 10(-6) M). Dose-response curves to the agonists were similar for both age groups. NECA was a more potent vasodilator than CPA, in keeping with their affinity for the A2 receptor. Suffusion of 8-PT alone at less than 10(-5) M had no effect on arteriolar diameter. We conclude that adenosine is able to dilate fetal cerebral arterioles as young as 0.6 gestation by acting at an A2 receptor, although resting tone is not influenced by adenosine. The immature fetal sheep CBF response to hypoxia is not attributable to undeveloped vasoreactivity to adenosine.
Inhibition of endothelium-derived relaxing factor-dependent circulatory control in intact rats
Authors: Loeb A. L. , Longnecker D. E.
Published: December 2017

The effects of the endothelium-derived relaxing factor (EDRF) inhibitors NG-monomethyl-L-arginine (L-NMMA) and methylene blue (MB) on resting hemodynamics and responses to vasodilators were studied in the intact rat anesthetized with pentobarbital sodium. L-NMMA infusions (100 mg/kg) significantly increased mean blood pressure by 48%; this effect was rapidly reversed by L-arginine (300 mg/kg). MB (50 mg/kg) decreased mean blood pressure by 24%. Both MB and L-NMMA significantly attenuated the vasodepressor responses to acetylcholine, ATP, and adenosine. By use of radiolabeled microspheres, it was determined that the blood pressure increase after L-NMMA was due to a marked increase in systemic vascular resistance (SVR; from 1.3 +/- 0.1 to 3.1 +/- 0.3 mmHg.ml-1.min-1) and decreased cardiac output. L-NMMA increased vascular resistance in brain, cerebellum, skin, skeletal muscle, ear, white and brown fat, kidney, spleen, hepatic artery, and gastrointestinal tract. Flow decreased in the skin, kidneys, ear, white and brown fat, gastrointestinal tract, portal venous circulation, and liver in response to L-NMMA. In contrast, MB decreased heart rate, blood pressure, and SVR significantly. MB increased blood flow and decreased vascular resistance in several organs, including the brain, and skeletal muscle. These results indicate that both MB and L-NMMA can inhibit agonist-induced EDRF-mediated vasodepressor responses. However, inhibition of agonist-induced responses did not predict the general and regional hemodynamic responses to L-NMMA or MB infusion.
Internalized basic fibroblast growth factor translocates to nuclei of venular endothelial cells
Authors: Hawker J. R. , Granger H. J.
Published: December 2017

To begin to understand the molecular mechanisms by which basic fibroblast growth factor (bFGF) stimulates proliferation of coronary venular endothelial cells (CVEC), we have characterized the kinetic interactions of bFGF with various binding sites on CVEC and determined the kinetics of nuclear translocation of bFGF. We report that bFGF rapidly binds to its receptor and is immediately internalized at 37 degrees C with a half-time for receptor binding of 0.9 min. After internalization bFGF is processed by two kinetically and biochemically distinguishable pathways. Up to 40-50% of total internalized bFGF is translocated to the nuclei of serum-starved, quiescent cells at early time points (0-2 h). This proportion declines to less than or equal to 20% by 24 h. Cytoplasmic accumulation continued to increase for up to 24 h. Nuclear-bound 125I-labeled bFGF consisted primarily of the intact 18-kDa species with small amounts of a 16-kDa degradation fragment. Nuclear-bound 125I-labeled bFGF showed little evidence of degradation even after 24 h, whereas cytoplasmic 125I-labeled bFGF showed increased degradation to smaller fragments with time. Nuclear-binding of bFGF reached equilibrium by 8 h, just before initiation of DNA synthesis, which began 9-12 h after growth factor addition. These results suggest that nuclear-bound bFGF may function in triggering division (proliferation) of CVEC subsequent to binding of the growth factor to cell surface receptors.
Mathematical modeling of human cardiovascular system for simulation of orthostatic response
Authors: Melchior F. M. , Srinivasan R. S. , Charles J. B.
Published: December 2017

This paper deals with the short-term response of the human cardiovascular system to orthostatic stresses in the context of developing a mathematical model of the overall system. It discusses the physiological issues involved and how these issues have been handled in published cardiovascular models for simulation of orthostatic response. Most of the models are stimulus specific with no demonstrated capability for simulating the responses to orthostatic stimuli of different types. A comprehensive model incorporating all known phenomena related to cardiovascular regulation would greatly help to interpret the various orthostatic responses of the system in a consistent manner and to understand the interactions among its elements. This paper provides a framework for future efforts in mathematical modeling of the entire cardiovascular system.
Effect of changing afterload and inotropic states on inner and outer ventricular wall thickening
Authors: Matsuzaki M. , Tanaka N. , Toma Y. , Miura T. , Katayama K. , Ozaki M. , Ono S. , Yano M. , Kohno M. , Kusukawa R.
Published: December 2017

Effect of changing afterload and inotropic states on inner and outer ventricular wall thickening. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H109-H116, 1992.--To study the differing behaviors of the inner (IH) and outer halves (OH) of the left ventricular (LV) free wall during an increasing afterload and changing inotropic states, we determined the LV pressure (LVP) and transmural (TM) and OH wall thickness (WTTM and WTOH) by sonomicrometry in 11 anesthetized dogs. The percent systolic wall thickening (% delta WT) and the fractional contribution (FC) were calculated. At rest, % delta WT of TM, IH, and OH were 22 +/- 1 (mean +/- SE), 33 +/- 3, and 13 +/- 2 (P less than 0.01 vs. IH), respectively. The FC of IH and OH were 74 +/- 5 and 29 +/- 4% (P less than 0.01 vs. IH), respectively. During increasing afterload by aortic constriction (AC) without drugs, % delta WT in IH was reduced to 22 +/- 2%, associated with unchanged % delta WT in OH (12 +/- 3%), whereas the FC of IH and OH were not altered from resting values. During AC with dobutamine infusion (3 micrograms.kg-1.min-1), the % delta WT and FC in each layer were not reduced from resting values. On the other hand, during AC with propranolol (2 mg bolus iv), the reduction of % delta WT in IH was greater (from 29 +/- 4 to 15 +/- 6%, P less than 0.01) than that in OH (from 11 +/- 2 to 10 +/- 3%; P less than 0.01 vs. IH). The FC in the IH was decreased (56 +/- 16%) by AC with propranolol, so that the difference in FC between IH and OH became insignificant (FCOH 40 +/- 13%, P greater than 0.1 vs. FCIH).(ABSTRACT TRUNCATED AT 250 WORDS)
Uterine prostaglandin production in ovine pregnancy: effects of angiotensin II and indomethacin
Authors: Magness R. R. , Rosenfeld C. R. , Faucher D. J. , Mitchell M. D.
Published: December 2017

The ovine and human uteroplacental vascular beds are more refractory to angiotensin II (ANG II)-induced vasoconstriction than the systemic vasculature. ANG II increases in vitro prostacyclin (PGI2) production by uterine but not omental arteries from pregnant sheep. Thus vasodilator prostaglandins may account for this difference in vascular responsiveness. We measured uterine and systemic eicosanoid production and hemodynamic responses in pregnant sheep before and during intravenous ANG II (1.15 and 11.5 micrograms/min). ANG II caused dose-related increases in arterial pressure and systemic and uterine vascular resistance (P less than 0.05). PGI2 metabolite (6-keto-PGF1 alpha) in the uterine vein rose from 166 +/- 70 (SE) to 223 +/- 114 and 631 +/- 323 pg/ml, respectively (P less than 0.05), and arterial levels increased from 67 +/- 24 to 145 +/- 78 and 312 +/- 173 pg/ml, respectively (P less than 0.05). Basal uterine venoarterial differences of 6-keto-PGF1 alpha were 99 +/- 43 pg/ml and increased during 11.5 micrograms ANG II/min to 295 +/- 181 pg/ml (P less than 0.05) but not during 1.15 micrograms/min (64 +/- 30 pg/ml). Responses were similar in gravid and nongravid uterine horns. Unilateral uterine prostaglandin inhibition with indomethacin did not alter basal uterine blood flow or systemic responses to ANG II (0.573-11.5 micrograms/min); however, ipsilateral uterine prostaglandin production fell and uterine vasoconstrictor responses increased (P less than 0.05). During ovine pregnancy ANG II increases uterine PGI2 production. PGI2 appears in part to attenuate ANG II-induced uterine vasoconstriction.
Angiotensin II receptor antagonism in ovine heart failure: acute hemodynamic, hormonal, and renal effects
Authors: Fitzpatrick M. A. , Rademaker M. T. , Charles C. J. , Yandle T. G. , Espiner E. A. , Ikram H.
Published: December 2017

The hemodynamic, hormonal, and renal effects of angiotensin II-type 1 receptor antagonism (AT1A) have not been documented previously in heart failure (HF) or compared with angiotensin-converting-enzyme inhibition (ACEI). Accordingly, we investigated the acute (2-h) response to losartan (1 and 10 mg/kg iv) or vehicle (N saline) followed by captopril (12.5 mg) on separate days in an ovine model of HF induced by 7 days of rapid ventricular pacing. Losartan induced a significant rise in plasma renin activity (PRA) and plasma angiotensin II levels (P less than 0.01 and P less than 0.001, respectively), in association with a fall in the plasma aldosterone-to-PRA ratio (P less than 0.001) and plasma atrial natriuretic peptide (P less than 0.05). Mean arterial and left atrial pressure both fell significantly after losartan (P less than 0.001), whereas the rise in cardiac output was not sustained. The response to captopril was similar except for plasma angiotensin II, which declined (P less than 0.001). Glomerular filtration and urine sodium excretion were maintained despite a fall in renal perfusion pressure. In conclusion, the vasodilatation and renal effects of AT1A were similar to ACEI. Thus AT1A may be a useful therapeutic alternative to ACEI in HF.
Effects of mechanical vibration on left ventricular diastolic properties during global ischemia
Authors: Kikuchi J. , Koiwa Y. , Takagi T. , Honda H. , Hoshi N. , Butler J. P. , Takishima T.
Published: December 2017

To examine the effect of mechanical vibration on ventricular relaxation and diastolic chamber stiffness under global ischemia, we studied eight coronary perfused, isolated, isovolumic canine left ventricles (LV). To produce varying degrees of impaired relaxation, graded coronary flow reduction and paced tachycardia were imposed. A mechanical 50-Hz, 2-mm-amplitude vibration was applied during diastole and was turned off during systole. Without diastolic vibration, the relaxation time constant of LV pressure (tau) increased with the severity of ischemia. The chamber stiffness index (K) from the diastolic pressure-volume relationship showed a slight increase during ischemia; tau decreased with diastolic vibration. The change in tau with vibration increased with ischemia and was dependent on vibration amplitude but not heart rate. The ratio of tau to the diastolic interval (DI, the time from peak negative rate of LV pressure change to end diastole) always decreased with vibration and was linearly correlated with K (r = 0.93; P less than 0.01). K decreased with vibration when tau/DI was greater than 0.3. We conclude that diastolic vibration improves impaired relaxation and chamber stiffness under myocardial ischemia.
Role of Na-activated K channel, Na-K-Cl cotransport, and Na-K pump in [K]e changes during ischemia in rat heart
Authors: Mitani A. , Shattock M. J.
Published: December 2017

The contribution of Na-activated K channel, the furosemide-sensitive (Na-K-Cl) cotransport, and Na-K pump to extracellular potassium accumulation during global ischemia was investigated using pharmacological blockade of these pathways. R 56865 (a blocker of the Na-activated K channel), furosemide, or ouabain was included in the perfusate before ischemia in the isolated rat heart preparation, and the extracellular K concentration ([K]e) was monitored during 30 min of global ischemia. In control hearts, [K]e showed an early rise (up to 9.0 +/- 0.2 mM from the baseline of 5.9 mM), a fall (to a minimum of 6.7 +/- 0.2 mM), and a late rise (to 14.1 +/- 0.4 mM by the end of ischemia). R 56865 (0.1 and 1 microM) suppressed the early [K]e rise to 50% of the control level. The late rise in [K]e was also significantly suppressed by the higher dose of R 56865. Furosemide (0.1 and 1 mM) reduced the early K accumulation by 35% but did not affect the rise of [K]e during the late ischemic phase. Blockade of Na-K pump by 10 microM ouabain did not increase [K]e during any phase of ischemia and, in fact, 100 microM ouabain profoundly suppressed the early rise in [K]e. We therefore suggest that the Na-activated K channel, the furosemide-sensitive cotransport, and changes in the activity of the Na-K pump may all contribute to extracellular K accumulation during ischemia. However, in addition to these pathways, it seems likely that other pathways for transsarcolemmal K efflux contribute to cellular K loss during ischemia in the isolated rat heart.
Influence of long-chain acylcarnitines on voltage-dependent calcium current in adult ventricular myocytes
Authors: Wu J. , Corr P. B.
Published: December 2017

Long-chain acylcarnitines (LCAC) increase 3.5-fold within 2 min in ischemic myocardium in vivo, and previous studies have suggested, through indirect evidence, that LCAC can stimulate the voltage-dependent L-type Ca2+ current [ICa(L)] in both cardiac and smooth muscle cells. In the present study, whole cell voltage-clamp procedures were performed in isolated adult guinea pig ventricular myocytes to assess the direct effect of LCAC on ICa(L). The intracellular solution contained (in mM) 80 CsCl, 40 K-aspartic acid, and 5 ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). Maximal current density of ICa(L) at 0 mV was 10.1 +/- 0.5 pA/pF (n = 22) at extracellular Ca2+ concentration ([Ca2+]o) = 2.7 mM. LCAC induced a concentration (1-25 microM, n = 23)- and time-dependent, reversible decrease in ICa(L). When delivered extracellularly for 10 min, LCAC (5 microM) inhibited the maximal current of ICa(L) by 48.1 +/- 1.3% (n = 9, P less than 0.01) and shifted the half-maximal voltage of steady-state activation and inactivation from -13.1 +/- 0.5 to -6.8 +/- 0.4 mV (n = 4; P less than 0.05) and from -21.8 +/- 0.2 to -16.5 +/- 0.6 mV (n = 4; P less than 0.01), respectively. Intracellular delivery of LCAC (5 microM) also suppressed ICa(L) to a similar degree (47.5 +/- 1.5%, n = 4; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Synthesis and transport of lipoprotein lipase in perfused guinea pig hearts
Authors: Liu G. , Olivecrona T.
Published: December 2017

Total lipoprotein lipase (LPL) activity did not differ significantly between hearts from fed or fasted guinea pigs. Incorporation of [35S]methionine into immunoprecipitable LPL was also the same. The rates at which perfused hearts from fed or fasted guinea pigs released LPL activity into the medium were, however, different (2 vs. 4 mU.g-1.min-1). These rates remained constant over 60 min of perfusion. Addition of heparin to the medium resulted in a peak of LPL activity during the first 2 min, followed by a shoulder of relatively high activity, which gradually declined to a constant rate from 30 min. The peak and shoulders were less with hearts from fed animals than with hearts from fasted animals, but the constant rates were similar. Cycloheximide added at the start of the perfusion had no effect on the peak or on the early part of the shoulder, but the LPL activity released from 30 min continuously decreased so that at 60 min it was less than half of that in controls. Studies in which the enzyme was pulse labeled by perfusion 15 min with medium containing [35S]methionine and then chased up to 75 min with unlabeled medium showed no differences in how LPL is transported and metabolized in hearts from fed vs. fasted guinea pigs. Thus the data suggest that factors outside the heart influence the disposition of heart LPL in vivo.