bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of thapsigargin in normal and pretreated with ryanodine guinea pig cardiomyocytes
Authors: Lewartowski B. , Rozycka M. , Janiak R.
Published: December 2017

We compared the effects of thapsigargin (TG), a selective blocker of Ca(2+)-adenosinetriphosphatase of sarcoplasmic reticulum (SR), and ryanodine (Ry) in the single isolated myocytes of guinea pig ventricular myocardium loaded with indo 1 acetoxymethyl ester (AM). TG (2 x 10(-7) M) inhibited the rapid phase of Ca2+ transient, increased time to peak intracellular Ca2+ concentration ([Ca2+]i) from 158 +/- 12 to 391 +/- 60 ms and decreased the total amplitude of the transient to 89 +/- 4% of the pre-TG control. Time to peak of contractions increased from 350 +/- 47 to 410 +/- 37 ms and total duration from 666 +/- 62 to 850 +/- 198 ms. Total amplitude of contractions was hardly affected. In the cells not loaded with indo 1-AM TG decreased the amplitude of contractions to 71 +/- 3% of control. When the effects of TG were fully developed, the cells ceased to respond to 1 s of superfusion with 15.0 mM caffeine with transient elevation of [Ca2+]i and/or transient contracture. TG did not affect the amplitude or time course of Ca2+ current (ICa) or the current-voltage relation. We propose that Ca2+ transients and contractions in the cells treated with TG were initiated by sarcolemmal Ca2+ influx. Ry (1.0 microM) initiated similar changes in the time course of Ca2+ transients and contractions as TG; however, total amplitude of the transients and contractions was reduced to 78 +/- 5 and 55 +/- 7% of the control, respectively. The SR Ca2+ was also depleted by Ry. TG superfused over the cells pretreated with Ry increased the amplitude of Ca2+ transients and respective contractions to the pre-Ry level. TG did not affect the ICa in the cells pretreated with Ry nor did it change configuration of action potentials to increase the Ca2+ influx. We propose that the effect of Ry on amplitude of Ca2+ transients and contractions results from the trapping of a fraction of sarcolemmal Ca2+ influx by the SR and its rapid release into subsarcolemmal space. From there it is extruded out of the cell by Na(+)-Ca2+ exchange before ever reaching the contractile system.
PGD2 is an intermediate in agonist-stimulated nitric oxide release in rabbit skin microcirculation
Authors: Warren J. B. , Loi R. K. , Wilson A. J.
Published: December 2017

We investigated the role of endogenous prostaglandins and NO in the blood flow response of skin microcirculation in vivo. Test agents were injected intradermally in anesthetized rabbits and changes in skin blood flow measured with a laser-Doppler flow probe. Skin blood flow increased 75% at 7.33, 6.77, 11.63, 10.30, 10.55, 8.20, and < 7 -log mol/site with acetylcholine, ATP, bradykinin, prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), NO gas in solution, and nitroprusside respectively. Co-injection of indomethacin (3 x 10(-9) mol/site) or NG-nitro-L-arginine methyl ester (L-NAME; 10(-7) mol/site) with either acetylcholine or bradykinin abolished the effects. This suggests a link between NO and prostaglandin release. Arachidonic acid increased blood flow, which was inhibited by indomethacin, L-NAME, or the PGD2-receptor antagonist BW-A868C. Blood flow responses to either intradermal acetyl-choline or bradykinin, but not to NO in solution, were abolished by co-injection with BW-A868C. PGD2-mediated vasodilation was abolished by L-NAME or BW-A868C, but not by indomethacin. There was no evidence of a link between NO and prostaglandin release in precontracted rabbit aortic rings in vitro. The results suggest that, in the microcirculation of rabbit skin, acetylcholine- and bradykinin-mediated vasodilation involve the arachidonic acid-PGD2-NO pathway.
Angiotensin II enhances norepinephrine spillover during sympathetic activation in conscious rabbits
Authors: Noshiro T. , Shimizu K. , Way D. , Miura Y. , McGrath B. P.
Published: December 2017

To investigate the potential modulating influence of angiotensin II (ANG II) on sympathetic activity in response to changes in baroreflex activity, renal and total norepinephrine (NE) spillover rates were examined during sodium nitroprusside (SNP) and phenylephrine (PE) infusions in four groups of conscious rabbits: 1) saline (control); 2) subpressor ANG II (ANG II, 2 ng.kg-1.min-1); 3) enalaprilat (MK-422, 200 micrograms/kg and 3.3 micrograms.kg-1.min-1); and 4) MK plus ANG II (MK+ANG II). Upper plateaus of baroreflex-NE spillover curves for renal and total NE spillover were reduced in the MK group (25 and 81 ng/min) compared with control (38 and 125 ng/min) and MK+ANG II (37 and 155 ng/min). To investigate the interaction of ANG II and sympathetic activity during treadmill exercise, hindlimb NE spillover rate was examined in three groups of rabbits: 1) control, 2) MK, and 3) MK+ANG II. Exercise at 6 and 12 m/min produced similar effort-related hemodynamic responses in the three groups. At maximal exercise, hindlimb NE spillover was reduced in the MK group (29 +/- 3 ng/min) compared with control (62 +/- 17 ng/min, P < 0.05) and MK+ANG II group (51 +/- 10 ng/min). It is concluded that endogenous ANG II enhances sympathetic activity during pharmacological (baroreflex) and physiological stimulation.
Coupling of M-cholinoceptors and A1 adenosine receptors in human myocardium
Authors: Bohm M. , Gierschik P. , Schwinger R. H. , Uhlmann R. , Erdmann E.
Published: December 2017

This study investigated the coupling of M-cholinoceptors and A1 adenosine receptors in human myocardium. Carbachol reduced force of contraction in atria and ventricles by 60 and 35% (in the presence of 0.03 microM isoprenaline), respectively. Addition of (-)-N6-(2-phenylisopropyl)adenosine (R-PIA) in the presence of carbachol did not further reduce force of contraction. R-PIA reduced force of contraction less than carbachol in atria (ventricles) by 35% (25%), but addition of carbachol after R-PIA reduced force of contraction further by 35% (15%). Carbachol increased 35S-labeled guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) binding maximally 14-fold only when GDP was present by an excess of > 100 times [35S]GTP gamma S, while R-PIA increased binding only 2-fold. Activation of [35S]GTP gamma S binding by A1 adenosine receptor and M-cholinoceptor stimulation was antagonized by theophylline and atropine, respectively. Addition of R-PIA to carbachol did not further increase [35S]GTP gamma S binding. Activation of high-affinity [35S]GTP gamma S binding by agonists showed that carbachol activated [35S]GTP gamma S binding to 20 pmol/mg protein [35S]GTP gamma S binding sites, i.e., 25% of the total number of binding sites (80 pmol/mg protein). With R-PIA, activation of high-affinity [35S]GTP gamma S binding could not reliably be detected with this technique. From the number of M-cholinoceptors (atria, 360 fmol/mg protein; ventricle, 270 fmol/mg protein), it is estimated that 1 M-cholinoceptor activates approximately 50-80 G protein alpha-subunits in atria and ventricles, respectively. It is concluded that stimulation of M-cholinoceptors but not A1 adenosine receptors is able to maximally activate a pool of G protein alpha-subunits.(ABSTRACT TRUNCATED AT 250 WORDS)
Dissociation of heart rate variability from parasympathetic tone
Authors: Goldberger J. J. , Ahmed M. W. , Parker M. A. , Kadish A. H.
Published: December 2017

Time and frequency domain measurements of heart rate variability have been used as indexes of parasympathetic tone. This study evaluates the effects of parasympathetic stimulation on these indexes. Ten normal subjects (5 females, 5 males; age 27.4 +/- 5.1 yr) were evaluated in the Clinical Research Center. Five-minute electrocardiographic recordings were obtained at baseline and during 1) combined alpha-adrenergic stimulation with baroreflex-increased cardiac parasympathetic activity produced by phenylephrine infusion; 2) parasympathetic blockade (atropine 0.04 mg/kg); and 3) isolated alpha-adrenergic stimulation produced by phenylephrine infusion after parasympathetic blockade. The infusion rate of phenylephrine was titrated to increase the systolic blood pressure by 20-30 mmHg. Heart rate variability analysis was performed using standard time and frequency domain parameters. Phenylephrine infusion resulted in a decrease in the time domain measures and in the high-frequency power. After parasympathetic blockade, alpha-adrenergic stimulation had no significant effect on the heart rate variability parameters. These findings suggest that the heart rate variability parameters traditionally associated with parasympathetic tone do not always reliably measure parasympathetic tone, since they decrease with baroreflex parasympathetic stimulation.
Adenosine attenuates phorbol ester-induced negative inotropic and vasoconstrictive effects in rat hearts
Authors: Lasley R. D. , Noble M. A. , Paulsen K. L. , Mentzer R. M.
Published: December 2017

Phorbol esters reduce cardiac contractility and produce coronary vasoconstriction presumably by stimulating protein kinase C (PKC). We tested whether adenosine altered the response to phorbol 12-myristate 13-acetate (PMA) in isolated rat hearts. Hearts, perfused at constant flow and constant heart rate, were exposed to PMA (10 nM) for 30 min and then allowed 30 min of recovery. PMA reduced left ventricular developed pressure (LVDP) from 81 +/- 2 to 49 +/- 3 and 40 +/- 2 mmHg (51 +/- 3% of baseline LVDP) after 30 min infusion and 30 min recovery, respectively. PMA also increased coronary perfusion pressure to 224 +/- 13% of baseline after 60 min. The PKC inhibitor bisindolylmaleimide (0.5 microM) blocked the PMA-induced negative inotropy and vasoconstriction. Adenosine (100 microM) and the A1-agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 0.1 microM) significantly attenuated the negative inotropic effect of PMA as LVDP was maintained at 81 +/- 4% and 99 +/- 7% of baseline, whereas CGS-21680, an A2-agonist, had no beneficial effect on function (54 +/- 4% of baseline). Adenosine and CGS-21680 (0.1 microM), but not CCPA, significantly attenuated PMA-induced coronary vasoconstriction. These results suggest that adenosine receptor activation may modulate myocardial PKC activity or attenuate the effects of increased PKC activity.
Changes in the neural drive to abdominal expiratory muscles in hemorrhagic hypotension
Authors: Fregosi R. F.
Published: December 2017

The purpose of this study was to test the hypothesis that hemorrhage-induced hypotension increases the neural drive to the abdominal expiratory muscles in chloralose-urethan-anesthetized cats that are studied under conditions of constant arterial PCO2 (PaCO2) and hyperoxia. A secondary aim was to describe in detail the concomitant changes in inspired pulmonary ventilation (VI) and the pattern of breathing under these conditions. The rectified and integrated electromyogram (EMG) of the external oblique and rectus abdominis muscles and VI were recorded in moderate and severe hemorrhagic hypotension, leading to reductions in mean blood pressure of approximately 30 and 60%, respectively. The PaCO2 was prevented from falling, and the arterial PO2 was maintained at a hyperoxic level (> 200 mmHg) by adding CO2 and O2 to the inspired gas mixture. VI increased by 2.5- and 5-fold in moderate and severe hypotension (P < 0.05). The changes in VI were mediated exclusively by changes in tidal volume, indicating that the reflex did not alter the activity of respiratory rhythm-generating structures. The EMG of external oblique muscles averaged 2, 44, and 100% in control conditions and in moderate and severe hypotension, respectively; corresponding values in rectus abdominis muscles were 10, 28, and 100% (P < 0.05 for both muscles). Bilateral cervical vagotomy caused a one- to three-fold decrease in the ventilatory response to hemorrhage and abolished the increase in abdominal muscle EMG activities. In conclusion, hemorrhagic hypotension reflexly increases pulmonary ventilation and the neural drive to the abdominal muscles. The reflex is vagally mediated, but the location of the receptors was not identified.
Role of endothelium-derived nitric oxide and adenosine in functional myocardial hyperemia
Authors: Maekawa K. , Saito D. , Obayashi N. , Uchida S. , Haraoka S.
Published: December 2017

To investigate the role of endothelium-derived nitric oxide (EDNO) and adenosine in functional myocardial hyperemia, we examined the effect of NG-nitro-L-arginine (L-NNA) and 8-p-sulfophenyltheophylline (8-SPT) on coronary vasodilation in response to increased myocardial oxygen consumption in pentobarbital sodium-anesthetized dogs. L-NNA significantly attenuated the increase in coronary conductance from 28 +/- 6 to 16 +/- 2% with atrial pacing, from 69 +/- 5 to 36 +/- 6% with isoproterenol, and from 25 +/- 6 to 9 +/- 4% with constriction of the aorta. 8-SPT given alone attenuated the increase in coronary conductance to the same extent as L-NNA. The combined administration of L-NNA and 8-SPT did not further change coronary conductance. These findings suggest that EDNO and adenosine play an important role in functional hyperemia. EDNO-induced functional hyperemia appears to be dependent on adenosine receptor activation.
Effect of dopamine on local segment work and O2 consumption in collateral-dependent myocardium
Authors: Kedem J. , Wright C. , Scholz P. M. , Weiss H. R.
Published: December 2017

To test the hypothesis that dopamine-stimulated work and myocardial O2 consumption (MVO2) in collateral-dependent myocardium would be reduced, Ameroid constrictors were implanted around the circumflex coronary artery (CFX) in nine dogs. Four weeks later, in an anesthetized open-chest preparation, segment length (ultrasonic dimension gauge) and force (miniature force transducer) were measured in myocardium supplied by the CFX and left anterior descending (LAD) coronary arteries. Work in each region was calculated as the systolic area under the force-length curve. Corresponding regional MVO2 was calculated from local O2 extraction (microspectrophotometry) and flow (radiolabeled microspheres). Dopamine infusion (15 micrograms.kg-1.min-1) increased regional work from 262 +/- 56 to 733 +/- 171 mm.g.min-1 in the control (LAD) region, but to a much smaller extent in the collateral-dependent (CFX) region (from 249 +/- 82 to 414 +/- 81 mm.g.min-1). However, regional MVO2 increased to about the same extent in the CFX (from 6.0 +/- 0.7 to 12.4 +/- 0.9 ml O2.min-1 times 100 g-1) and the LAD region (from 7.0 +/- 0.6 to 14.5 +/- 1.3 ml O2.min-1 times 100 g-1). O2 extraction was not elevated in the CFX region. Therefore, the functional impairment was not secondary to O2 supply or consumption limitations.
Vascular angiotensin and the sympathetic nervous system: do they interact?
Authors: Hilgers K. F. , Veelken R. , Kreppner I. , Ganten D. , Luft F. C. , Geiger H. , Mann J. F.
Published: December 2017

We tested the hypothesis that local vascular formation of angiotensin (ANG) II and the sympathetic nervous system potentiate each other. Isolated rat hindquarters were perfused with an artificial medium, and ANG I and II release was measured by high-performance liquid chromatography and radioimmunoassay. Electrical stimulation of the lumbar sympathetic chain (0.5, 2, and 8 Hz) did not affect vascular ANG release in Sprague-Dawley (SD) rats. Hypertensive, ren-2 transgenic (TG+) rat hindquarters released significantly more ANG I (110 +/- 19 vs. 65 +/- 21 fmol/30 min in SD rats) and ANG II (235 +/- 22 vs. 140 +/- 30 fmol/30 min); however, nerve stimulation did not alter ANG release in TG+ rats. Captopril inhibited vascular ANG II release by 90%, but neither captopril nor ANG II receptor blockade by losartan affected the pressor response to nerve stimulation in SD and TG+ rats. Isoproterenol failed to increase either vascular ANG release or pressor response to nerve stimulation in SD or spontaneously hypertensive rat hindquarters. Exogenous renin, which increased vascular ANG release approximately 100-fold, prolonged the pressor responses to nerve stimulation. We conclude that the vascular renin-ANG system does not interact with the sympathetic nervous system locally. However, high concentrations of ANG II, which can be induced by circulation-derived renin, may prolong the duration of sympathetic nerve-induced vasoconstriction.
Left ventricular systolic performance is depressed in chronic pulmonary emphysema in dogs
Authors: Gomez A. , Unruh H. , Mink S.
Published: December 2017

The effect of chronic right ventricular (RV) pressure overload on left ventricular (LV) systolic function in chronic obstructive lung disease is unclear. To examine LV systolic performance in pulmonary emphysema, a chronic canine model was developed in which pulmonary artery pressure could be elevated to a level found in human disease. Severe emphysema was produced by the repeated instillations of the enzyme papain into the lung. Sonomicrometry was used to assess LV dimensions along the septal-lateral, apex-base, and anterior-posterior orthogonal axes of the LV. With the animal conscious, measurements of LV systolic function were obtained over a wide range of LV circumferential end-ejection stresses at baseline and after 1 yr of emphysema (post-1-yr study). In the emphysema group (n = 5), the results showed that at the post-1-yr study, measurements of LV ejection fraction, mean velocity of circumferential shortening, and rate of anterior-posterior dimensional shortening were reduced compared with those obtained at the baseline study. In the emphysema group, end-systolic volume was increased for a given end-systolic pressure or stress at the post-1-yr study compared with baseline values, while fractional shortening measured along the three axes was decreased. There were no similar changes in systolic parameters in control groups. We conclude that chronic RV pressure overload may cause an impairment in LV systolic performance in chronic emphysema.
Instantaneous changes in arterial compliance reduce energetic load on left ventricle during systole
Authors: Vrettos A. M. , Gross D. R.
Published: December 2017

We tested the hypothesis that arterial compliance changes during each cardiac cycle, and that these instantaneous changes are beneficial for energy conservation. Using an adaptive identification procedure, we were able to obtain an instantaneous impulse-response representation of the arterial system. By assuming a three-element windkessel model, we obtained the instantaneous compliance. The arterial compliance remained relatively constant during diastole but increased during systole. The calculated time trajectory was compared with an optimal compliance calculation based on minimum ventricular ejection energy criteria. The two compliance trajectories followed similar paths. We conclude that increases in arterial compliance during systole reduce the energy demands on the left ventricle.
Aftereffects of high-intensity DC stimulation on the electromechanical performance of ventricular muscle
Authors: Kodama I. , Shibata N. , Sakuma I. , Mitsui K. , Iida M. , Suzuki R. , Fukui Y. , Hosoda S. , Toyama J.
Published: December 2017

To clarify the mechanisms underlying cardiac dysfunction after electrical defibrillation, we investigated the effects of direct current field stimulation (10 ms, 1-80 V/cm) on isolated guinea pig papillary muscles. Shocks (S2) > 15 V/cm lowered the plateau height of the S2-induced action potential and inhibited its terminal repolarization. Subsequent responses to basic stimuli (S1, 1.0 Hz) for 1–3 min were characterized by a decrease in the maximum diastolic potential, a shortening of action potential duration, and an increase of the developed tension. With S2 > 30 V/cm, a marked delay in repolarization of the S2-induced action potential was followed by oscillation of membrane potential, resulting in repetitive spontaneous activity and often refractoriness to S1 stimulation. The aftereffects were independent of the phase of S2 application. Most of the aftereffects were preserved in the presence of nifedipine (1 microM) or ryanodine (1 microM). Only sodium channel blockade by tetrodotoxin (10 microM) modified the aftereffects by depressing the generation of spontaneous activity. These findings suggest that strong shocks (> 15 V/cm) will produce abnormal arrhythmogenic responses probably through a transient rupture of sarcolemmal membrane (electroporation) leading to a disturbance of the ionic equilibrium of the myocyte.
Identification of microvascular transport pathways in skeletal muscle
Authors: Wolf M. B.
Published: December 2017

The solvent-drag reflection coefficient (sigma f) was measured from plasma disappearance (integral-mass balance method) for native albumin and four fluorescent solutes of radii from 2 to 16 nm in the isolated, plasma-perfused cat hindlimb preparation. The data for the smallest solutes were measured > 2 h after tracer addition and at high filtration rates to avoid underestimation of sigma f due to tracer diffusion. A two-pore model was fit (small-pore and large-pore radii, approximately 3.5 and 23 nm, respectively, 84% of hydraulic capacity in small pores) to these data using an objective computer-based estimation procedure. In the model, membrane sigma f was determined by flow weighting the sigma f values for the two pathways. Also, the phenomenon of volume circulation among the pathways was included. In different limbs, the permeability-surface area (PS) product was measured for the smallest solute, alpha-lactalbumin, from its perfusate-disappearance transient and a linear diffusion model. The PS value estimated was 0.11 +/- 0.026 (95% confidence limits) ml.min-1 times 100 g muscle-1. These PS values were found to be coincident with those predicted using parameter sets derived from the multiparameter 95% confidence space consistent with the two-pore model fits. The two-pore model also closely predicted PS data for small solutes from other studies in skeletal muscle; however, it failed to adequately describe small-molecule transport data from osmotic transient studies. It was necessary to add a water-exclusive pathway (40% of total hydraulic capacity) to account for these latter data; however, the predictions with this addition were still consistent with the data measured in the present study. We conclude that pore models can describe both macromolecular and small solute reflection coefficient and PS data in skeletal muscle.
Cardiac contractile function following repetitive brief ischemia: effects of nucleoside transport inhibition
Authors: Kirkeboen K. A. , Ilebekk A. , Tonnessen T. , Leistad E. , Naess P. A. , Christensen G. , Aksnes G.
Published: December 2017

The effects of nucleoside transport inhibition on cardiac contractile function were examined in anesthetized pigs subjected to five 6-min left anterior descending coronary artery (LAD) occlusions, separated by 20-min reperfusion, and followed by 150-min reperfusion. In group 1 (n = 8), saline was infused. In group 2 (n = 9), endogenous myocardial accumulation of adenosine was increased by intracoronary infusion of the specific nucleoside transport inhibitor R-75 231. Left ventricular segment lengths were recorded by ultrasonic crystals in the inner one-third of the myocardium. Percent systolic segment length shortening (SS) (normalized to percent of preischemic value) was significantly better maintained in the R-75 231 group compared with the saline group after each occlusion. SS in the saline group reached a nadir of 30% (22-40) at 30-min reperfusion after the last occlusion compared with 66% (54–73) in the R-75 231 group. In the R-75 231 group, but not in the saline group, maximal postischemic decline in SS and decline at 20-min reperfusion were significantly reduced following the last occlusion. We conclude that R-75 231, which inhibits nucleoside transport, attenuates contractile dysfunction following repetitive brief ischemia and results in a preconditioning-like effect against stunning in the pig. On the basis of the well-documented biochemical effects of R-75 231, increased accumulation of endogenous adenosine most likely explains these findings.
Relative magnitude and asynchrony of directional components of contraction in sedated dog left ventricle
Authors: Nolan A. C. , Karwoski T. , Potel M. J. , Rubin J. M. , Sayre R. E.
Published: December 2017

The purpose of this study was to quantitate the temporal relationships and the extent and speed of shortening in segments of myocardium responsive to contraction in circumferential, longitudinal, and oblique fiber groups. Measurements were made in five sedated dogs (morphine, diazepam) with and without alterations in preload and afterload (nitroprusside, phenylephrine). The measurement interval was the phase of rapid contraction, determined by differentiation of the segment length vs. time. In the control state, percentage segment shortening was greater in circumferential than in longitudinal [15.2 +/- 0.24 (SE) vs. 10.5 +/- 0.80%; P = 0.0020] and in the subepicardial oblique than in the subendocardial oblique fiber directions (16.6 +/- 0.65 vs. 9.7 +/- 0.36%; P = 0.0010). Shortening was proportional to both maximum speed and duration of shortening (r = 0.735 +/- 0.015 and 0.757 +/- 0.017, respectively). Duration of shortening was significantly longer in circumferential than in longitudinal (mean difference 39.3 +/- 6.6 ms; P = 0.0039) and in subepicardial oblique than in subendocardial oblique directions (mean difference 27.7 +/- 5.5 ms; P = 0.0072). Velocities of up to 3.0 segment lengths/s were attained in response to nitroprusside. These data reveal the local anisotropy and asynchrony of contraction in the myocardium; however, they also support the concept of the myocardium as a functional continuum. The dominance of circumferential over longitudinal and subepicardial over subendocardial oblique contractile components indicates their relative contributions to the constriction of the midmyocardial shell.
Dynamic arterial baroreflex in rabbits with heart failure induced by rapid pacing
Authors: Masaki H. , Imaizumi T. , Harasawa Y. , Takeshita A.
Published: December 2017

Excessive sympathetic nerve activity in heart failure could be attributable to impaired arterial baroreflex function. Employing transfer function analysis, we evaluated the arterial baroreflex in control rabbits (n = 8) and in rabbits with rapid pacing-induced heart failure (n = 10) in a dynamic manner. Rabbits in the heart-failure group showed elevated filling pressures, depressed first derivative of left ventricular pressure, pulmonary congestion, and an increased level of plasma norepinephrine. Varying aortic pressure pseudorandomly and recording responses in renal nerve activity, we calculated the transfer function from aortic pressure to renal nerve activity. The gain of the transfer function was similar between control and heart-failure rabbits over 0.04–0.4 Hz as well as the phase and the coherence, indicating that the dynamic arterial baroreflex was preserved in our rabbit heart-failure model. Vagotomy increased the gain of the arterial baroreflex over 0.04–0.4 Hz in control (P < 0.05) but not in heart-failure rabbits, indicating that vagal afferents, which normally inhibit the dynamic arterial baroreflex, no more did so in heart failure. We conclude that excessive sympathetic nerve activity in heart failure may not be due to impaired dynamic arterial baroreflex, but that this apparently preserved arterial baroreflex in heart failure may be due to impaired cardiopulmonary baroreflex.
Heart failure due to chronic experimental aortic regurgitation
Authors: Magid N. M. , Opio G. , Wallerson D. C. , Young M. S. , Borer J. S.
Published: December 2017

Previously reported experimental models of aortic regurgitation generally have manifested normal systolic performance and have not developed heart failure [Magid et al. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H226–H233, 1992]. To determine whether more severe chronic experimental aortic regurgitation would generate systolic malperformance, heart failure, and emulate the human disease process, 11 New Zealand White rabbits underwent surgical induction of aortic regurgitation and 5 control animals underwent sham operation. Doppler echocardiography was performed serially for up to 3 yr, and pathological studies were performed at necropsy. Left ventricular internal dimension at end diastole increased 80% (P < 0.00002) and left ventricular weight increased 250% (P < 0.0002) in aortic regurgitant rabbits (regurgitant fraction 52 +/- 13%) compared with baseline values. Six of 11 aortic regurgitant animals died with pathological evidence of congestive heart failure at 1.5 +/- 0.8 yr postoperatively; 2 of these developed severe systolic malperformance, manifest as fractional shortenings of 15 and 19% at 1.6 and 1.7 yr, respectively. Five of 11 aortic regurgitant animals survived until killed at 2.9 +/- 0.1 yr. Thus moderate-to-severe chronic aortic regurgitation in rabbits frequently results in heart failure and systolic dysfunction and may usefully model chronic aortic regurgitation and heart failure in humans.
Biaxial elastic properties of rat arteries in vivo: influence of vascular wall cells on anisotropy
Authors: L'Italien G. J. , Chandrasekar N. R. , Lamuraglia G. M. , Pevec W. C. , Dhara S. , Warnock D. F. , Abbott W. M.
Published: December 2017

There is no consensus as to the degree of arterial anisotropy or to its relationship to vascular cell function. Given the relevance of the isotropic assumption in formulating elasticity models, reliable measures of biaxial displacements are needed. In this study, a video motion analyzer (VMA) was used to describe the biaxial in vivo dynamic elasticity of 22 carotid arteries and 5 abdominal aortas in 27 rats. The influence of vascular cell function was also examined by subjecting six rats to a photosensitive drug, chloroaluminum sulfonated phthalocyanine (CASPc), which is focally cytotoxic on activation by laser. Circumferential compliance (Ccirc) was greater than longitudinal compliance (Clong) for all vessels. Compliance pressure curves were nonlinear, and biaxial displacements were in phase. The circumferential elastic modulus was less than the longitudinal modulus at common stresses. CASPc + laser reduced Ccirc but not Clong, thus altering Poisson's ratio. In conclusion, rat arteries are biaxially, nonlinearly elastic and anisotropic in vivo. Vascular cells modulate Poisson's ratio by influencing Ccirc.
Role of endothelium and arterial K+ channels in mediating hypoxic dilation of middle cerebral arteries
Authors: Fredricks K. T. , Liu Y. , Rusch N. J. , Lombard J. H.
Published: December 2017

Isolated middle cerebral arteries of rats were perfused and superfused simultaneously with physiological salt solution (PSS) equilibrated with control (21% O2) or with reduced O2 concentrations (15, 10, 5, or 0% O2). Arterial dilation in response to reduced PO2 was unaffected by the nitric oxide synthase inhibitor N omega-nitro-L-arginine (10 microM) but was inhibited by selective perfusion of the lumen with 21% O2 PSS (0% O2 in the superfusion), endothelial removal, and 1 microM indomethacin. Arterial dilation during reduced PO2 was unaffected by 1 mM tetraethylammonium to block the Ca(2+)-dependent “maxi-K+” channel but was eliminated by 1 microM glibenclamide, a blocker of the ATP-sensitive K+ channel. Glibenclamide also inhibited dilation of the vessels in response to the stable prostacyclin analogue, iloprost. The results of this study suggest that dilation of rat middle cerebral arteries in response to reduced PO2 is mediated by an endothelium-dependent cyclooxygenase product, which activates glibenclamide-sensitive K+ channels.
Cardiovascular regulation in humans in response to oscillatory lower body negative pressure
Authors: Levenhagen D. K. , Evans J. M. , Wang M. , Knapp C. F.
Published: December 2017

The frequency response characteristics of human cardiovascular regulation during hypotensive stress have not been determined. We therefore exposed 10 male volunteers to seven frequencies (0.004–0.1 Hz) of oscillatory lower body negative pressure (OLBNP; 0–50 mmHg). Fourier spectra of arterial pressure (AP), central venous pressure (CVP), stroke volume (SV), cardiac output (CO), heart rate (HR), and total peripheral resistance (TPR) were determined and first harmonic mean, amplitude, and phase angles with respect to OLBNP are presented. AP was relatively well regulated as demonstrated by small oscillations in half amplitude (3.5 mmHg) that were independent of OLBNP frequency and similar to unstressed control spectra. Due to the biomechanics of the system, the magnitudes of oscillations in calf circumference (CC) and CVP decreased with increasing frequency; therefore, we normalized responses by these indexes of the fluid volume shifted. The ratios of oscillations in AP to oscillations in CC increased by an order of magnitude, whereas oscillations in CVP to oscillations in CC and oscillations in AP to oscillations in CVP both tripled between 0.004 and 0.1 Hz. Therefore, even though the amount of fluid shifted by OLBNP decreased with increasing frequency, the magnitude of both CVP and AP oscillations per volume of fluid shifted increased (peaking at 0.08 Hz). The phase relationships between variables, particularly the increasing lags in SV and TPR, but not CVP, indicated that efferent responses with lags of 5–6 s could account for the observed responses. We conclude that, at frequencies below 0.02 Hz, the neural system of humans functioned optimally in regulating AP; OLBNP-induced decreases in SV (by as much as 50%) were counteracted by appropriate oscillations in HR and TPR responses. As OLBNP frequency increased, SV, TPR, and HR oscillations increasingly lagged the input and became less optimally timed for AP regulation.
Regional myocardial flow and capillary permeability-surface area products are nearly proportional
Authors: Caldwell J. H. , Martin G. V. , Raymond G. M. , Bassingthwaighte J. B.
Published: December 2017

Analyses of data on the transcapillary exchange and cellular uptake in the normal heart have generally been based on the assumption that local membrane conductances and volumes of distribution are everywhere the same. The question is whether such an assumption is justified in view of the marked (sixfold) heterogeneity of local blood flows per gram tissue. The method was to estimate both flow and capillary membrane permeability-surface area products (PS) locally in the heart. For each of five dogs running on a sloped treadmill, the deposition of tracer microspheres and of [131I]iodophenylpentadecanoic acid (IPPA), after left atrial injection, was determined in 256 pieces of left ventricular myocardium by killing the animals at approximately 100 s after radiotracer injection. A hydraulic occluder stopped the flow to a portion of the myocardium supplied by the left circumflex coronary artery 30 s before tracer injection. Regional flows ranged from 0.1 to 7.0 ml.g-1.min-1. IPPA extractions ranged from 20 to 49%. Using the known flows, we assumed the applicability of an axially distributed blood-tissue exchange model to estimate the PS for the capillary (PSc) and the parenchymal cell. It was impossible to explain the data if the PSc values for membrane transport were uniform throughout the organ. Rather, the only reasonable descriptors of the data required that local PSc values increase with local flow, almost in proportion. Current methods of analysis using data based on deposition methods need to be revised to take into account the near proportionality of PS to flow for at least some substrates.
Inhomogeneity of cellular activation time and Vmax in normal myocardial tissue under electrical field stimulation
Authors: Taniguchi A. , Toyama J. , Kodama I. , Anno T. , Shirakawa M. , Usui S.
Published: December 2017

To clarify the mechanism underlying the ectopic excitation after countershock, the cellular activation processes of cardiac tissue with a low-potential-gradient electric field (LPEF) were investigated in experiments using guinea pig papillary muscles and in computer simulation. Action potential upstrokes in papillary muscles during longitudinal propagation (LP) or transverse propagation (TP) were different from those of nonpropagating ones in single ventricular cells in terms of lower maximum upstroke velocity (Vmax) (LP, 231 V/s; TP, 309 V/s) and the presence of a linear ascending segment in the phase-plane plot. High Vmax (409 V/s) close to the single cell (512 V/s) was obtained in the muscle at the collision of LP (LC). Field stimulation of the muscles with LPEF < 5 V/cm caused inhomogeneous excitation suggesting multiple wave fronts, which collide with each other, and a wide spatial dispersion of Vmax (132–388 V/s). Phase-plane plots of action potential with lower Vmax were similar to LP or TP, whereas those with higher Vmax were similar to LC. In the two-dimensional discrete sheet composed of 51 x 51 elements of modified Beeler-Reuter model, the inhomogeneous excitation induced by LPEF is mimicked by setting a random variation of stimulus onset in each element. LPEF may induce inhomogeneous excitation with multiple wave fronts through a complex electrotonic interaction. This would provide a basis for the genesis of ectopic focal excitation.
Role of diprotonated phosphate in evoking muscle reflex responses in cats and humans
Authors: Sinoway L. I. , Smith M. B. , Enders B. , Leuenberger U. , Dzwonczyk T. , Gray K. , Whisler S. , Moore R. L.
Published: December 2017

Lactic acid and H+ evoke muscle reflexes that raise sympathetic nerve activity. Whether these substances are direct afferent stimulants or markers for the acidification of other substances is unknown. Diprotonated phosphate (H2PO4-), a possible mediator of fatigue, increases as the cell acidifies and phosphate is produced. Its role in evoking muscle reflexes is unknown. We used 31P-nuclear magnetic resonance to measure forearm muscle H+ and H2PO4- and microneurography to measure muscle sympathetic nerve activity (MSNA, peroneal nerve) during a handgrip protocol designed to dissociate H+ from H2PO4-. Ischemic handgrip (50% maximal voluntary contraction x 2 min) was followed by a 1-min rest period during which the muscle was freely perfused. This was followed by a second bout of ischemic handgrip and a 5-min recovery. In seven of eight subjects, MSNA correlated with H2PO4-, whereas it correlated with pH in only one subject. To determine whether muscle reflex responses are evoked by H+, lactic acid, monoprotonated phosphate (HPO4(2-), or H2PO4-, we injected H+, lactate, H2PO4- [all 50 mM in 10 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) buffered to pH 6], and HPO4(2-) (50 mM, pH 7.5 in 10 mM HEPES) into the arterial supply of the triceps surae of the cat (n = 9) as we measured mean arterial blood pressure (MAP). H2PO4- increased MAP more than HPO4(2-), H+, or lactate (27.1 +/- 3.7 vs. 5.0 +/- 1.3, 4.6 +/- 3.1, and 7.7 +/- 3.2 rise in mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)
Smooth muscle cells affect endothelial membrane potential in rat aorta
Authors: Marchenko S. M. , Sage S. O.
Published: December 2017

The effects of vasoconstrictors on membrane potential of endothelium of intact rat aorta were investigated using the patch-clamp technique. Norepinephrine, endothelin (ET)-1, 5-hydroxytryptamine (5-HT), vasopressin, and angiotensin II evoked depolarization and oscillations in membrane potential. The alpha 1-adrenoreceptor agonist phenylephrine (PE), but not the alpha 2-agonist clonidine or the beta-agonist isoproterenol, evoked oscillations. The antagonist of 5-HT2-receptors, ketanserin, inhibited 5-HT-evoked oscillations. ET-3, unlike ET-1, did not evoke oscillations. The antagonists of voltage-operated Ca2+ channels, nifedipine and verapamil, inhibited vasoconstrictor-evoked oscillations, and the Ca2+ channel agonist BAY K 8644 enhanced oscillations. Acetylcholine and sodium nitroprusside inhibited PE-evoked oscillations. The inhibitors of NO synthase, N omega-nitro-L-arginine and NG-methyl-L-arginine, as well as methylene blue, enhanced oscillations. The intima of rat aorta with endothelium was removed from underlying smooth muscle. In this preparation, acetylcholine evoked a response similar to that in the intact vessel, but PE and ET-1 were without effect. These data suggest that vasoconstrictors acting on receptors on aortic smooth muscle evoke a response that is transferred to the endothelium and evokes depolarization and oscillations in endothelial membrane potential.
Distribution and function of cardiac angiotensin AT1- and AT2-receptor subtypes in hypertrophied rat hearts
Authors: Lopez J. J. , Lorell B. H. , Ingelfinger J. R. , Weinberg E. O. , Schunkert H. , Diamant D. , Tang S. S.
Published: December 2017

To determine distribution and function of cardiac angiotensin (ANG) II receptor AT1 and AT2 subtypes in left ventricular (LV) hypertrophy (LVH), ANG II (10(-8) M) was infused into isolated rat hearts with hypertrophy from aortic banding and into sham-operated controls. ANG II was infused alone or in the presence of AT1 inhibitor [losartan (10(-5) M) or CL-329167 (10(-7) M)] or AT2 inhibitor [CG-42112A (10(-8) M]. ANG II alone caused less increase in coronary vascular resistance (CVR) in LVH compared with control hearts (19 vs. 39%; P < 0.01), although baseline CVR was higher in LVH hearts. This was prevented by AT1 but not AT2 antagonists. ANG II also increased LV end-diastolic pressure in LVH hearts, signifying decreased diastolic relaxation that was prevented by AT1 but not AT2 inhibition. Characterization of ANG II binding sites in LV membrane preparations revealed similar dissociation constants between groups (1.6 +/- 0.95 vs. 2.2 +/- 2.0 nM; not significant) but lower maximum binding capacity in the LVH group (21.1 +/- 5.9 vs. 33.5 +/- 3.0 fmol/mg protein; P < 0.05). Competition assays demonstrated that control left ventricles contain predominantly the AT1 subtype (68.8 +/- 20%), whereas LVH ventricles contain primarily the putative AT2 subtype (59.8% +/- 10.8%; P < 0.05). This suggests that receptor subtype redistribution occurs in LVH with AT1 subtype down-regulation. Nonetheless, the AT1 subtype mediates the effects of ANG II on coronary tone and diastolic dysfunction in pressure-overload hypertrophy.
Pressure-flow relationships in isolated sheep prenodal lymphatic vessels
Authors: Eisenhoffer J. , Lee S. , Johnston M. G.
Published: December 2017

The objective of this study was to determine how isolated sheep prenodal popliteal lymphatic vessels responded to transmural and outflow pressure changes. Afferent lymphatics (0.5-1.0 mm diameter) were suspended in an organ bath with both inflow and outflow ends cannulated. Input to the duct was provided from a reservoir filled with Krebs solution. Two types of experiments were performed. In one group, a transmural pressure was applied to the ducts. In a second group of studies, the inflow pressure was fixed (at 2, 4, or 6 cmH2O) and the outflow pressure was increased in 4-cmH2O increments. The transmural pressure-flow relationship was expressed as a bell-shaped curve with pumping increasing up to 18-26 cmH2O and declining at higher pressures. Maximum flow rates averaged 1.4 +/- 0.6 ml/10 min. Greater than 50% of maximum pumping activity was available between approximately 12 and 43 cmH2O. In response to outflow pressures, variable responses were observed. In some vessels, elevations of outflow pressure had little impact on flow rates, until high outflow pressures were attained. In other ducts, pumping declined in response to outflow pressure challenge. With lower inflow pressures (2 or 4 cmH2O), flow rates occasionally increased with elevations of the outflow catheter. In ducts preset with inflow pressures of 6 cmH2O, the mean stop-flow pressure was 60 +/- 4.6 cmH2O. In comparison with previously published data on the pressure-flow relationships in postnodal lymphatics, prenodal vessels pumped over a larger range of transmural or outflow pressures.
Assessment of rate of O2 release from single hepatic sinusoids of rats
Authors: Seiyama A. , Chen S. S. , Imai T. , Kosaka H. , Shiga T.
Published: December 2017

Characteristics of O2 release from single hepatic sinusoids are described in relation to the sinusoidal O2 inflow for the first time. Microspectroscopic measurement of the rate of O2 release (RO2) from single sinusoids to surrounding hepatocytes was carried out at the edge of the liver of anesthetized rats. The oxyhemoglobin inflow ([HbO2] inflow) into sinusoids, which is a product of sinusoidal blood flow rate and inflowing oxyhemoglobin concentration ([HbO2]), was varied by exchange transfusion of blood with physiological saline. 1) RO2 from single hepatic sinusoids of control rats was fairly constant [0.66 +/- 0.14 (SD) nmol.cm-2.s-1, with 18 sinusoids of 9 rats] over a wide range of [HbO2] inflow (50-200 fmol/s). 2) In the cases of mild anemia, [HbO2] inflow scarcely decreased but RO2 increased, probably because of the increased metabolism of hepatocytes. 3) In the cases of severe anemia, [HbO2] inflow decreased below 50 fmol/s and RO2 decreased accordingly. 4) In all cases no difference was observed between the RO2 values obtained from periportal zone and those from pericentral zone. These results are discussed on the bases of the vascular structure and function of hepatic sinusoids and on the animal model of hemorrhagic shock.
Modulation of uterine resistance artery lumen diameter by calcium and G protein activation during pregnancy
Authors: D'Angelo G. , Osol G.
Published: December 2017

The purpose of this study was to determine whether the increased sensitivity of uterine resistance arteries from late pregnant (LP) rats to alpha-adrenergic stimulation is due to an alteration in the fundamental relationship between cytosolic calcium (Ca2+) and arterial lumen diameter. Uterine arcuate arteries were permeabilized with Staphylococcus aureus alpha-toxin under optimal conditions and constricted to varying degrees with discrete Ca2+ concentrations at a distending pressure of 50 mmHg. Arterial segments from nonpregnant (NP) and LP rats exhibited similar Ca2+/lumen diameter characteristics. Ca2+ (0.1 microM) produced appreciable constriction, and lumen diameter decreased steeply between 0.175 and 0.25 microM Ca2+; maximal responses were attained with 0.5 microM Ca2+. Activation of guanine nucleotide binding proteins (G proteins) with guanosine 5'-triphosphate (GTP; 1-100 microM), as reportedly occurs during alpha-adrenergic stimulation, potentiated the Ca(2+)-induced constriction by 121 and 79% in arteries from LP and NP rats, respectively. No significant differences between the two animal groups were noted. Guanosine 5'-O-(gamma-thiotriphosphate) (GTP gamma S; 0.1-10 microM), a nonhydrolyzable analogue of GTP, effected a larger potentiating effect over that maximal response caused by GTP in arteries from NP rats. Ca(2+)- and Ca2+/GTP-induced constrictions were more potently reversed by guanosine 5'-O-(beta-thiodiphosphate) (GDP beta S)., a competitive inhibitor of GTP, in arteries from NP rats. These data suggest that pregnancy-induced increases in sensitivity to alpha-adrenergic stimulation may be related to altered G protein cycling rates, such that G proteins in smooth muscle cells in arcuate arteries from NP rats are more susceptible to deactivation. Alternatively, consistent with the model of G protein-mediated inhibition of myosin light chain phosphatase, myosin light chain phosphatase activity may be enhanced in uterine vascular smooth muscle from NP rats relative to that from LP rats.