bluuebunny/crossref_metadata_2025 huggingface dataset:
Manganese-superoxide dismutase in endothelial cells: localization and mechanism of induction
Authors: Suzuki K. , Tatsumi H. , Satoh S. , Senda T. , Nakata T. , Fujii J. , Taniguchi N.
Published: December 2017

Mechanisms of Mn-superoxide dismutase (Mn-SOD) expression in human umbilical endothelial cells were investigated by Northern blot analysis, enzyme-linked immunosorbent assay, and immunoelectron microscopy. The Mn-SOD in human endothelial cells was markedly induced by the cytokines tumor necrosis factor (TNF), interleukin-1, and lipopolysaccharide as well as by phorbol esters [12-O-tetradecanoylphorbol 13-acetate (TPA)]. The induction was partially blocked by dexamethasone and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, a potent inhibitor of protein kinase C (PKC). In endothelial cells in which PKC had been desensitized to TPA by pretreatment for 24 h, addition of TNF caused overexpression of Mn-SOD. These facts suggested that at least two separate signal-transducing pathways are involved in expression of the Mn-SOD gene. Immunoelectron-microscopic studies showed that Mn-SOD was localized to the mitochondrial matrix of the capillary vascular endothelial cells of cardiac tissues and cultured endothelial cells. Mn-SOD, which is normally abundant in endothelial cells relative to other cell types, may play an important protective role against stresses such as ischemia and inflammation.
Reduced Na(+)-K+ pump activity in diabetic rabbit carotid artery: reversal by aldose reductase inhibition
Authors: Tesfamariam B. , Gupta S. , Oates P. J. , Ruderman N. B. , Cohen R. A.
Published: December 2017

This study addresses the question of whether a decrease in basal Na+ pump [Na(+)-K(+)-adenosinetriphosphatase (ATPase)] activity occurs in the carotid artery of an alloxan-diabetic rabbit and, if so, whether it is associated with altered 86Rb+ uptake and contractile response to ouabain and K(+)-free solution. Ouabain-sensitive 86Rb+ uptake, an index of Na+ pump activity, was diminished approximately 50% in carotid arteries from diabetic rabbits. Concurrent with this, contractions induced by incubating the carotid arteries in a K(+)-free solution (in the absence of phentolamine) were significantly larger in the diabetic group. Readdition of K+ (1 mM) to arteries contracted with the K(+)-free solution caused relaxations that were slower to occur and of lesser magnitude in diabetic than in control rabbits. In contrast to the contractions caused by the K(+)-free medium, contractions caused by incubation with ouabain (1 mM) in the presence of phentolamine were significantly smaller in the diabetic group. Treatment of diabetic rabbits with an aldose reductase inhibitor, zopolrestat, at both high and low doses restored the alterations in vascular reactivity toward normal. The results indicate that the Na+ pump activity is diminished in the carotid artery of diabetic rabbit, and this is associated with abnormal vascular responsiveness and increased polyol pathway flux.
Effects of ischemia on sarcoplasmic reticulum and contractile myofilament activity in human myocardium
Authors: Luciani G. B. , D'Agnolo A. , Mazzucco A. , Gallucci V. , Salviati G.
Published: December 2017

The effects of global ischemia on the contractile system and on sarcoplasmic reticulum (SR) function were studied by measuring the isometric tension and the SR Ca2+ release activity of chemically skinned cardiac fiber preparations from seven patients undergoing open-heart surgery. Ten minutes of ischemia caused 1) a decrease in the myofilament sensitivity to Ca2+ (expected Ca2+ concentration giving half-maximal tension; from 0.69 +/- 0.04 to 1.38 +/- 0.06 microM, n = 7) and in the cooperativity index (Hill coefficient; from 2.61 +/- 0.45 to 0.92 +/- 0.15, n = 7), 2) a decrease in myosin light chain phosphorylation, and 3) a 300% increase in the threshold caffeine concentration for SR Ca2+ efflux channel activation, with a 30% reduction in the rate of Ca2+ release by caffeine at threshold concentrations and a 23% reduction in the rate of release by 20 mM caffeine. After preincubation with 5 microM trifluoperazine, a calmodulin antagonist, the caffeine threshold of ischemic and control cardiac muscle became comparable. Most changes were reversed by reperfusion, while the caffeine threshold was still two times greater than control. These results indicate that ischemia caused alterations of the cardiac muscle contractile apparatus and the SR that were reversed only after reperfusion.
Effects of PDE inhibitors and carbachol on the L-type Ca current in guinea pig ventricular myocytes
Authors: Mubagwa K. , Shirayama T. , Moreau M. , Pappano A. J.
Published: December 2017

The phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX; 100 microM) and papaverine (100 microM) increased peak L-type Ca current (ICa) more than fivefold in a way similar to isoproterenol, forskolin, or intracellular adenosine 3',5'-cyclic monophosphate in guinea pig ventricular myocytes studied with the whole cell voltage-clamp technique at 22-24 degrees C. IBMX and papaverine could also induce a chloride current. Both drugs caused an apparent increase of ICa inactivation as revealed by 1) a negative shift of the ICa inactivation curve between -40 and 0 mV and 2) a suppression of the relief from inactivation at potentials positive to 0 mV. In the presence of IBMX or papaverine, the amplitudes of both the rapidly and slowly inactivating components of ICa were increased; the effect on the fast component was more pronounced. The drugs did not accelerate the inactivation time course of either component. Carbachol (CCh; 100 microM) reversed the increase in ICa produced by IBMX or papaverine. However, ICa could not be restored to its original magnitude on washout of CCh in the presence of phosphodiesterase inhibitors. In pertussis toxin-treated cells or in the presence of Ly-83583 (1-100 microM), IBMX retained its effect but CCh was unable to reduce ICa. Dialysis with guanosine 3',5'-cyclic monophosphate (cGMP; 0.1-100 microM) or 8-bromoguanosine 3',5'-cyclic monophosphate (30 microM) suppressed the increase of ICa by IBMX; the inhibition by cGMP was additive with that produced by CCh. We suggest that the major part of IBMX and papaverine effect is mediated by phosphodiesterase inhibition and involves an increase in intracellular adenosine 3',5'-cyclic monophosphate levels. CCh reversal of phosphodiesterase inhibitor action probably involves an elevation of cGMP levels and activation of cGMP-dependent protein kinase.
Inhibition by a stable factor derived from neutrophils of endothelium-dependent relaxation in rat aorta
Authors: Liu J. J. , Chen J. R. , Wiley J. , Johnston C. C. , Buxton B. F.
Published: December 2017

Polymorphonuclear leukocytes (PMNs) may play an important role in many pathophysiological states. The effect of a factor derived from PMNs on endothelium-dependent relaxation was studied using rat aortic rings in organ chambers. PMNs were obtained from cardiac surgical patients and healthy volunteers. After incubation in Krebs solution for 3 h, supernatants of PMN suspensions were isolated and used to pretreat the aortic rings for 30 min. The results showed that the supernatants derived from 1 x 10(4) to 5 x 10(6) cells/ml PMNs produced a concentration-dependent inhibition of endothelium-dependent relaxation to acetylcholine but not endothelium-independent relaxation to sodium nitroprusside. The effect could not be prevented by oxygen free radical scavenger superoxide dismutase (150 U/ml), catalase (1,200 U/ml), or mannitol (20 mM) used alone or in combination. Heating the supernatants at 95 degrees C for 30 min did not reduce the inhibitory effect. L-Arginine at 3 x 10(-5) to 3 x 10(-3) M did not significantly reverse the inhibitory effect of the PMN-derived factor. In conclusion, this study reveals that a heat-stable factor derived from human PMNs potently inhibits acetylcholine-induced endothelium-dependent relaxation but not sodium nitroprusside-induced endothelium-independent relaxation in rat aorta. This inhibitory effect is not caused by oxygen free radicals, a limitation of nitric oxide precursor or other unstable factors.
Lidocaine attenuates both mechanical and metabolic changes induced by hydrogen peroxide in the rat heart
Authors: Hara A. , Matsumura H. , Abiko Y.
Published: December 2017

The effect of lidocaine on the hydrogen peroxide (H2O2)-induced mechanical and metabolic changes was studied in the Langendorff rat heart, which was perfused aerobically at a constant flow rate and paced electrically. H2O2 (600 microM) increased the left ventricular end-diastolic pressure (i.e., mechanical dysfunction), decreased the tissue levels of ATP and creatine phosphate (i.e., metabolic change), and increased the tissue level of malondialdehyde (MDA). The mechanical and metabolic alterations induced by H2O2 were attenuated by lidocaine (50 or 200 microM). Lidocaine also attenuated the H2O2-induced increase in MDA. Nevertheless, lidocaine modified neither the myocardial ferrylmyoglobin level that was increased by H2O2 nor the H2O2 concentration in vitro and did not affect the mechanical function and energy metabolism of the normal heart. These results suggest that lidocaine attenuates both mechanical and metabolic changes induced by exogenous H2O2. The protective action of lidocaine on the H2O2-induced changes is due to neither energy-sparing nor H2O2-scavenging effect, but probably due to its effect to reduce the H2O2-induced lipid peroxidation.
Characterization of alpha-adrenoceptor gene expression in arterial and venous smooth muscle
Authors: Ping P. , Faber J. E.
Published: December 2017

Six genes coding for three unique alpha 1- (1A, 1B, 1C) and three unique alpha 2- (2A, 2B, 2C) adrenergic receptor (AR) subtypes have been cloned. Ligand binding and contractile studies have demonstrated that both alpha 1- and alpha 2-ARs can exist on vascular smooth muscle (VSM) cells, although less is known about the relative distribution and specific subtypes in different vascular segments. In the present study polymerase chain reaction (PCR) analysis was used to characterize the species of alpha-AR messenger RNA (mRNA) present in freshly isolated rat thoracic aortic media and vena cava and in cultured VSM cells (passage 2) derived from both sources. To prevent possible contamination of VSM mRNA, aortic media was separated from adventitia, and vessels were denuded of endothelial cells. Oligonucleotide primers specific for each of the six adrenergic genes were synthesized and used to probe for the presence of alpha-AR mRNA species after reverse transcription of total cellular RNA to cDNA. PCR-amplified AR transcripts were distinguished by the size of amplified DNA fragments and unique restriction endonuclease cleavage. Expression of alpha 1C- or alpha 2C-mRNA was not detected in vascular tissues or cultured VSM cells, although the alpha 2C-primers detected the expected alpha 2C expression in cerebral cortex. Only alpha 1A-mRNA was detected in aortic adventitia. VSM from aorta expressed alpha 1A-, alpha 1B-, and alpha 2A-mRNA, and this pattern was preserved in cultured aortic VSM. Vena cava also expressed both alpha 1A and alpha 1B; however only alpha 2B-mRNA was detected.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of hypoxemia on the cardiovascular response to intracranial hypertension in postnatal lambs
Authors: Kearney M. L. , Backofen J. E. , Koehler R. C. , Jones M. D. , Traystman R. J.
Published: December 2017

Large increases in intracranial pressure in fetal sheep result in more potent peripheral vasoconstriction and better maintenance of cerebral O2 consumption (CMRO2) than in postnatal sheep. The fetus is exposed to a lower PO2. We tested the hypothesis that low PO2 in postnatal lambs potentiates peripheral vasoconstriction and better maintains cerebral perfusion pressure and CMRO2. Pentobarbital-anesthetized lambs, 2-7 days old, were ventilated with either room air (n = 7) or a low O2 mixture to reduce arterial O2 saturation to 50% (n = 7). Elevation of intracranial pressure to within 3-5 mmHg of baseline mean arterial pressure for 30 min by ventricular fluid infusion initially caused a similar increase in arterial pressure in the normoxic [11 +/- 3 (SE) mmHg] and hypoxic (14 +/- 2 mmHg) groups. Plasma catecholamines increased more rapidly in the hypoxic group. However, plasma vasopressin levels were substantially elevated by hypoxia alone and failed to increase further with elevated intracranial pressure. Moreover, there was no significant difference between groups in the steady-state increase in arterial pressure, and microsphere-determined blood flow to intestines, kidney, skin, and muscle did not decrease in either group. Consequently, cerebral perfusion pressure, regional cerebral blood flow, and CMRO2 were reduced similarly in both groups. Therefore, hypoxemia failed to potentiate the postnatal pressor response. Low PO2 is unlikely to be the major mechanism for the potent Cushing response in the fetus.
Effects of hypothyroidism and hypertension on myocardial perfusion and vascularity in rabbits
Authors: Tomanek R. J. , Barlow P. A. , Connell P. M. , Chen Y. , Torry R. J.
Published: December 2017

We considered the role of thyroid hormones in the growth of the coronary microvasculature during various levels of afterload. Arterial pressure was increased for 3 mo in hypothyroid and euthyroid rabbits via the Page (1-kidney, 1-wrap) method. Systolic pressures (mmHg +/- SE) indicated that the groups could be characterized as follows: euthyroid sham normotensive (103 +/- 5), euthyroid Page hypertensive (158 +/- 24), hypothyroid Page normotensive (110 +/- 5), and hypothyroid sham hypotensive (87 +/- 5). The hypothyroid groups were characterized by bradycardia. Left ventricular weight-to-body weight ratios were higher in the Page groups than in the controls. Minimal coronary vascular resistance (MCVR) was elevated in the euthyroid Page group but was not affected by hypothyroidism. Lumen diameters of the major resistance vessels tended to be larger in the hypertensive rabbits. Capillary length density was greater in the hypothyroid than in the euthyroid groups. We conclude that 1) the elevated MCVR in the hypertensive rabbits is due mainly to a failure of the major resistance vessels to increase in size or number rather than to a decrease in vascular lumen diameter, and 2) hypothyroidism does not affect maximal myocardial perfusion or lumen diameter of resistance vessels but facilitates capillary growth. The latter may be due to the presence of bradycardia.
Effects of isoproterenol on myocardial relaxation rate: influence of the level of load
Authors: Coudray N. , Beregi J. P. , Lecarpentier Y. , Chemla D.
Published: December 2017

The present work was undertaken to test the hypothesis that the level of the load faced by the myocardium influences the effects of isoproterenol on relaxation rate. Responses to cumulative doses of isoproterenol (from 10(-10) to 10(-6) M) were studied in rat left ventricular papillary muscle stimulated 12 beats/min at 29 degrees C in 0.5 mM extracellular calcium and preloaded at initial muscle length corresponding to apex of length-active tension curve (Lmax; group 1, n = 20) or at 95% of Lmax (group 2, n = 9). A control group (group 3, n = 8) was studied every 15 min for 75 min. We measured maximum unloaded shortening velocity (Vmax), normalized positive and negative peak force derivatives (+dF and -dF, respectively) of the fully isometric twitch, and peak lengthening velocity of the isotonic twitch with preload only (Vlmax). In group 1, Vmax and +dF increased under 10(-10) and 10(-9) M isoproterenol, respectively, and -dF increased under 10(-9) M isoproterenol (115 +/- 13 vs. 96 +/- 12 mN.s-1.mm-2, P = 0.01). Conversely, Vlmax increased under 10(-7) M isoproterenol only (2.34 +/- 0.19 vs. 1.45 +/- 0.18 Lmax/s, P < 0.001). In group 2, both -dF and Vlmax increased under 10(-7) M isoproterenol only (P = 0.015 and 0.011, respectively). In group 3, -dF and Vlmax did not vary in time. Our results suggest a load-revealed (or length-revealed) difference in the dose dependence of the various biochemical processes involved in the effects of isoproterenol during myocardial relaxation.
Cell and oxygen flow in arterioles controlling capillary perfusion
Authors: Sarelius I. H.
Published: December 2017

Measurements of hemodynamic and oxygen transport characteristics in the arterioles that control capillary perfusion in striated muscle were used to compare oxygen flow into adjacent capillary networks. Observations were made in arterioles arising consecutively (branches 1-3 and the last branch) from a single transverse arteriole. During maximal dilation [after 5 min of exposure to superfusate with 10(-4) M adenosine (ADO)], mean cell flow into branches decreased significantly with increasing axial distance along the transverse arteriole, from 8.47 +/- 2.43 x 10(3) (SE) cells/s in branch 1 to 5.56 +/- 2.14 x 10(3), 3.21 +/- 1.30 x 10(3), and 4.00 +/- 1.33 x 10(3) cells/s in successive branches. During control, cell fluxes were not significantly different by position (2.21 +/- 1.12, 1.31 +/- 0.42, 0.97 +/- 0.31, and 1.23 +/- 0.40 cells/s in branches 1, 2, and 3 and the last branch, respectively). Branch diameters during ADO were not significantly different by position (26.2 +/- 2.9, 24.5 +/- 1.4, 22.0 +/- 2.8, and 26.7 +/- 2.7 microns, respectively). Hemoglobin saturations during ADO were not different (59.6 +/- 2.2, 60.6 +/- 2.3, 60.3 +/- 2.3, and 61.0 +/- 2.3%, respectively), whereas mean oxygen flow into branch 1 significantly exceeded that into branches 2 and 3 and the last branch (1.40 +/- 0.40 vs. 0.60 +/- 0.17, 0.53 +/- 0.22, and 0.66 +/- 0.22 pl/min, respectively). During control, oxygen flows were not significantly different between branches. Thus, both cell and oxygen flow into these arterioles vary in a systematic way dependent on their relative branch position; regulatory processes serve to make oxygen supply more uniform.
Why does pulmonary venous pressure rise after onset of LV dysfunction: a theoretical analysis
Authors: Burkhoff D. , Tyberg J. V.
Published: December 2017

One of the most important consequences of acute left ventricular dysfunction (LVD) is pulmonary edema resulting from a rise in pulmonary venous pressure (PVP). It is generally believed that the PVP rise is a direct hemodynamic consequence of LVD. While this paradigm seems plausible, especially if the LV is viewed as a sump pump, there is no specific evidence to support this simple explanation. A theoretical analysis was performed to assess the hemodynamic mechanisms responsible for the dramatic rise in PVP after acute LVD. The ventricles were modeled as time-varying elastances; pulmonary and systemic vascular systems were modeled as series of resistive and capacitive elements. In response to a 50% decrease in LV contractile strength [end-systolic elastance (Ees)], cardiac output (CO) and mean arterial pressure (MAP) dropped substantially, while PVP increased minimally from its baseline of 12 to approximately 15 mmHg. With LV Ees set at 50% of normal, the effects of sympathetic activation were tested. When heart rate and total peripheral resistance were increased, CO and MAP improved, yet PVP still did not rise. The only intervention that caused a substantial increase in PVP was to simulate the decrease in unstressed volume (VU) of the venous system known to occur with sympathetic activation. When VU was decreased by about 15-20% (comparable to experimentally observed shifts with acute heart failure), PVP increased above 25 mmHg. The effects of pericardial constraints were investigated, and the results suggest a major role of this organ in determining the overall hemodynamic response to acute LVD, sympathetic activation, and explaining the responses to therapy. Thus this analysis suggests that elevations of PVP do not occur simply as a direct hemodynamic consequence of acute LVD. Rather, changes in PVP may be dictated more by sympathetic control on venous capacity. If confirmed, recognition of this as a primary mechanism may prove important in directing development of new therapies and in understanding the mechanisms of disease progression in heart failure.
Ventriculographic evaluation in three rat models of cardiac dysfunction
Authors: Yang X. P. , Sabbah H. N. , Liu Y. H. , Sharov V. G. , Mascha E. J. , Alwan I. , Carretero O. A.
Published: December 2017

Chronic cardiac dysfunction was produced in rats by means of 1) aorto-caval fistula (A-V fistula), 2) coronary ligation, or 3) coronary embolization. Eleven to twelve weeks later, left ventricular ejection fraction (LVEF) was evaluated by ventriculography and compared with normal controls. A-V fistula decreased LVEF by 13% and increased cardiac output (CO) by 82%. Coronary ligation and embolization produced a greater decrease in LVEF (-36% and -30%) and a decrease in CO (-36% and -29%). Systemic vascular resistance was significantly decreased in the A-V fistula (-47%) model but increased in both ligation and embolization models (by 99 and 87%). LV end-diastolic volume was increased in fistula or ligation (by 68 and 36%), whereas there was no change in rats with embolization. LV end-systolic volume and LV end-diastolic pressure were significantly increased in all three models. Plasma atrial natriuretic factor was increased by 676% with fistula, 212% with ligation, and 113% with embolization. There was no significant change in plasma renin activity or catecholamines in any of the models. We concluded that coronary embolization and ligation are effective methods of producing chronic LV dysfunction in rats, as evidenced by the significant decrease in LVEF. On the other hand, A-V fistula is an appropriate model of myocardial hypertrophy with greatly increased plasma atrial natriuretic factor, but cardiac dysfunction was minimal as indicated by the mild decrease in LVEF.
Vasopressin and oxytocin: modulators of neurohypophysial blood flow
Authors: Hurn P. D. , Wilson D. A. , Hansen R. B. , Hanley D. F. , Traystman R. J.
Published: December 2017

We examined the role of arginine vasopressin (AVP) as a mediator of neurohypophysial (NH) blood flow regulation in anesthetized dogs. First, we evaluated the NH hyperemia that occurs during hemorrhagic hypotension in the presence (n = 7) and absence (n = 7) of the selective AVP-V1 receptor antagonist [d(CH2)5Tyr(Me)]AVP. AVP-V1 blockade did not alter NH transient or steady-state flow responses to a standardized decrease to 80 mmHg mean arterial blood pressure. We then determined whether exogenous AVP alters NH and regional cerebral blood flow (CBF) (n = 8). Sequential intracarotid infusions resulted in sagittal sinus blood AVP concentrations ranging from 6.97 +/- 3.3 x 10(3) to 2.45 +/- 0.47 x 10(6) pg/ml. No change in NH blood flow (control 428 +/- 162 vs. 487 +/- 75 ml.min-1.100 g-1) was observed even at the highest blood level. However, CBF at the highest AVP level increased from a control value of 20 +/- 3 to 40 +/- 4 ml.min-1.100 g-1, while cerebral oxygen consumption remained unchanged. Administration of a selective AVP-V1 receptor antagonist, [d(CH2)5Tyr(Me)]AVP, blocked AVP-induced elevation in CBF in a third set of dogs (n = 5). Oxytocin was also given by intracarotid infusion at a constant rate (1-200 micrograms/ml) in a final group (n = 5). NH blood flow was unchanged at all doses, whereas CBF increased from control (24 +/- 2 to 38 +/- 5 ml.min-1.100 g-1) at the highest dose. (ABSTRACT TRUNCATED AT 250 WORDS)
Ventricular interaction and septal deformation: a model compared with experimental data
Authors: Beyar R. , Dong S. J. , Smith E. R. , Belenkie I. , Tyberg J. V.
Published: December 2017

Diastolic ventricular interaction is associated with septal shift and deformation, the consequences of which have not been fully assessed. A model was therefore developed to describe the mechanisms involved in interaction between the ventricles under different loading conditions. We assumed a circular cardiac minor-axis geometry surrounded by a pericardial membrane with the left ventricle (LV) and septum described by three layers. To define the equilibrium condition, we required the net force-balance at the right ventricular (RV)-LV intersection points to equal zero. The model was tested with and without consideration of bending forces associated with a change of curvature of a thick-walled structure. Model results were compared with data from animal experiments subjected to aortic and pulmonary constriction. LV and RV end-diastolic pressures as well as pericardial pressure were measured. In six dogs, septal segment length was measured using sonomicrometry, and in seven dogs, endocardial curvature was measured using echocardiography. Model and experimental results show that 1) with severe RV loading, septal inversion occurs at a negative transseptal gradient, and 2) the end-diastolic septal segment length continues to shorten after septal inversion during pulmonary constriction. Model simulation suggests that bending moments account for the septal curvature at zero transseptal pressure. In addition, the model predicts the shift in the pressure-area relationship of each ventricle by a change in loading of the opposite ventricle and predicts that large transmural gradients in stress and strain are associated with septal inversion. Thus the model and the experimental data agree and describe the important factors that modulate diastolic septal mechanics during acute differential ventricular loading.
A vascular transport operator
Authors: King R. B. , Deussen A. , Raymond G. M. , Bassingthwaighte J. B.
Published: December 2017

A pulse or a sharp front in concentration of a tracer or a substrate in the blood within a vessel becomes dispersed while being transported along a vessel. Cross-stream mixing and pulsations in flow with the heartbeat cause the dispersion to be less than would occur with a parabolic velocity profile (Newtonian flow). These characteristics allow intravascular mass transport to be described well by a simple two-parameter differential operator, which is a one-dimensional representation of the rather complex real situation. The operator consists of two components in series, a pure delay and a fourth-order linear differential operator. The latter is merely two underdamped second-order operators in series, with fixed relationships between the natural frequencies and damping coefficients. The operator is useful because it provides a transport function with skewness and kurtosis suitable to intravascular transport where the mean velocity profile is blunter than in Newtonian parabolic flow. The parameters of the operator are its mean transit time, t, and its relative dispersion, RD, which is the standard deviation of the response impulse divided by t. The operator transport function describes blood transport through the human leg arterial system, where the RD values are approximately 15–20%.
Pharmacological evidence that calcitonin gene-related peptide is implicated in cerebral autoregulation
Authors: Hong K. W. , Pyo K. M. , Lee W. S. , Yu S. S. , Rhim B. Y.
Published: December 2017

In anesthetized rats, we examined the possibility that calcitonin gene-related peptide (CGRP, a neuropeptide) released in response to transient hypotension may contribute to the reflex autoregulation of cerebral blood flow. Changes in pial arterial diameter (mean 33.0 +/- 1.1 microns) with changes in systemic arterial blood pressure (mean 101.9 +/- 2.7 mmHg) were observed directly through a closed cranial window. In capsaicin-treated rats (depletor of CGRP and substance P, 50 nmol capsaicin injected intracisternally 24 h before experiment), vasodilatation, which was evoked on transient hypotension, and vasoconstriction on reverse of hypotension were markedly attenuated or almost abolished. When changes in pial arterial diameter were plotted as a function of changes in blood pressure, the slopes of regression lines for vasodilatation and vasoconstriction were markedly reduced after capsaicin treatment. Similar reductions were evidenced under suffusion of CGRP antibody serum (1:1,000) and after CGRP receptor desensitization but not after substance P receptor desensitization. Pretreatment with glibenclamide, a K(+)-channel antagonist, also caused severe alterations in the autoregulatory vasomotor responses to hypotension and its reverse. Suffusion with mock cerebrospinal fluid, containing either CGRP or cromakalim, a K(+)-channel opener, dilated the pial artery in a concentration-dependent manner, and their effects were antagonized by glibenclamide. Substance P produced a vasodilatation, which was unaffected by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)
Short-term cardiovascular responses to a step decrease in peripheral conductance in humans
Authors: Toska K. , Eriksen M. , Walloe L.
Published: December 2017

A step decrease in total peripheral conductance (TPC) was introduced in 10 healthy volunteers by rapid inflation to suprasystolic pressure of bilateral thigh cuffs. This provoked a sudden statistically significant increase in mean arterial blood pressure (MAP) of 5 mmHg during supine rest and of 8 mmHg during moderate supine exercise by the quadriceps muscles. Central venous pressure was not changed by cuff inflation. The increase in MAP was blunted by a rapid but transient decrease in both heart rate (HR) and cardiac stroke volume. At rest, a gradual increase in TPC, starting after 4 s, nearly fully restored MAP to its original value at 10 s. During exercise, MAP was halfway corrected at 10 s but then started to increase again, probably as a result of an ischaemic muscle pressor response. After cholinergic blockade by atropine, the immediate HR response was eliminated, but HR decreased gradually after a delay of 3 s. The time development of the slow increase in TPC was not changed by atropine. In conclusion, the regulatory correction of a sudden increase in arterial pressure in supine unanesthetized healthy humans is achieved through an immediate transient parasympathetic bradycardia during the first few seconds and a more gradual sympathetic peripheral vasodilation after 4 s. After cholinergic blockade, a slow presumably sympathetic HR response was observed.
Continual electric field stimulation preserves contractile function of adult ventricular myocytes in primary culture
Authors: Berger H. J. , Prasad S. K. , Davidoff A. J. , Pimental D. , Ellingsen O. , Marsh J. D. , Smith T. W. , Kelly R. A.
Published: December 2017

To model with greater fidelity the electromechanical function of freshly isolated heart muscle cells in primary culture, we describe a technique for the continual electrical stimulation of adult myocytes at physiological frequencies for several days. A reusable plastic cover was constructed to fit standard, disposable 175-cm2 tissue culture flasks and to hold parallel graphite electrodes along the long axis of each flask, which treated a uniform electric field that resulted in a capture efficiency of ventricular myocytes of 75–80%. Computer-controlled amplifiers were designed to be capable of driving a number of flasks concurrently, each containing up to 4 x 10(6) myocytes, over a range of stimulation frequencies (from 0.1 to 7.0 Hz) with reversal of electrode polarity after each stimulus to prevent the development of pH gradients around each electrode. Unlike quiescent, unstimulated myocytes, the amplitude of contraction, and velocities of shortening and relaxation did not change in myocytes paced at 3–5 Hz for up to 72 h. The maintenance of normal contractile function in paced myocytes required mechanical contraction per se, since paced myocytes that remained quiescent due to the inclusion of 2.5 microM verapamil in the culture medium for 48 h also exhibited a decline in contractility when paced after verapamil removal. Similarly, pacing increased peak calcium current compared with quiescent cells that had not been paced. Thus myocyte contraction at physiological frequencies induced by continual uniform electric field stimulation in short-term primary culture in defining medium maintains some biophysical parameters of myocyte phenotype that are similar to those observed in freshly isolated adult ventricular myocytes.
Tumor necrosis factor-alpha increases myocardial microvascular transport in vivo
Authors: Hansen P. R. , Svendsen J. H. , Hoyer S. , Kharazmi A. , Bendtzen K. , Haunso S.
Published: December 2017

Tumor necrosis factor-alpha (TNF-alpha) is a primary mediator in the pathogenesis of tissue injury, and high circulating levels of TNF-alpha are found in a variety of pathological conditions. In open-chest anesthetized dogs, the effects of intracoronary recombinant human TNF-alpha (rTNF-alpha; 100 ng/kg for 60 min) on myocardial microvascular transport of a small hydrophilic indicator was examined by the single-injection, residue-detection method. Intracoronary infusion of rTNF-alpha increased myocardial microvascular transport after 120 min. This increase was preceded by a sustained decline in cardiac output and was associated with the appearance of areas with myocardial necrosis in the regional left ventricular wall. The myocardial plasma flow rate and maximum plasma flow rate in response to a 30-s coronary occlusion were not influenced by rTNF-alpha, although a decrease in the myocardial plasma flow rate was observed after 180 min. Circulating neutrophil counts were increased by rTNF-alpha, but the increase in myocardial capillary permeability could not be ascribed to regional neutrophil infiltration. We conclude that picomolar levels of rTNF-alpha can influence the movement of small hydrophilic molecules across the myocardial microvascular barrier in vivo and induce a prolonged decrease in cardiac performance. These effects may be important elements in myocardial pathophysiology.
Myogenic tone of rabbit facial vein and posterior cerebral artery is influenced by changes in extracellular sodium
Authors: Henrion D. , Laher I. , Klaasen A. , Bevan J. A.
Published: December 2017

We examined the effect of small changes in extracellular Na+ concentration ([Na+]e) on myogenic tone (MT) in isometrically mounted ring segments of the rabbit facial vein and in pressurized cannulated posterior cerebral artery segments. Decreasing [Na+]e from 150 to 120 mM in the vein increased MT by 24%, and raising [Na+]e to 165 mM attenuated it by 30%. In pressurized posterior cerebral arteries, decreasing [Na+]e to 120 mM reduced the intraluminal diameter by 12%, whereas increasing [Na+]e to 165 mM increased it by 17%. MT was inhibited by amiloride [50% inhibitory concentration (IC50) = 17 +/- 6 microM], an inhibitor of Na(+)-H+ exchange. Diisothiocyanatostilbene sulfonic acid, a Na(+)-Cl(-)-HCO3- cotransporter blocker, inhibited MT with an IC50 of 4.4 +/- 0.65 microM. Ouabain increased MT [50% effective concentration (EC50) = 0.10 +/- 0.04 microM] as did the reintroduction of HCO3- (EC50 5.0 +/- 1.5 mM). Our study suggests that MT in the rabbit posterior cerebral artery and rabbit facial vein is modulated by changes in [Na+]e. This effect is independent of the method used to register changes in wall force. The sensitivity of the tone to changes in [Na+]e and the independence of vessel diameter at different pressures at various [Na+]e may reflect changes in the sensitivity of smooth muscle stretch or mechanoreceptors to [Na+]e.
Prostacyclin is required for t-PA release after venous occlusion
Authors: Iacoviello L. , De Curtis A. , D'Adamo M. C. , Amore C. , Buczko W. , De Gaetano G. , Donati M. B.
Published: December 2017

The role of vascular cyclooxygenase pathway on tissue-type plasminogen activator (t-PA) release after venous occlusion was studied in anesthetized rats. After the inferior vena cava was clamped for 30 min, fibrinolytic activity increased from 143.7 +/- 14.5 to 209.5 +/- 10.3 mm2 (mean +/- SE, P < 0.002). This increase was prevented by aspirin at high (100 mg/kg i.v.) but not at low doses (1 mg/kg i.v.). Dazoxiben (10 mg/kg i.v.), an inhibitor of thromboxane synthase, was ineffective on the fibrinolytic response. Both the basal levels of 6-ketoprostaglandin F1 alpha and its increase after venous occlusion were suppressed by 100 mg/kg aspirin administration (from 0.64 +/- 0.2 to 0.05 +/- 0.002 ng/ml before occlusion, P < 0.001; and from 1.08 +/- 0.2 to 0.06 +/- 0.002 ng/kg after occlusion, P < 0.001), whereas they were both unaffected by aspirin at low doses (from 0.53 +/- 0.06 before to 1.20 +/- 0.08 ng/ml after stasis). Moreover, iloprost, a stable analogue of prostacyclin, reversed the aspirin inhibitory effects on fibrinolytic activity by restoring t-PA vascular release after venous stasis. Our results provide experimental evidence that an intact cyclooxygenase pathway in vascular wall is required for the fibrinolytic activity increase after venous occlusion in rats.
Adaptive responses of coronary circulation and myocardium to chronic reduction in perfusion pressure and flow
Authors: Mills I. , Fallon J. T. , Wrenn D. , Sasken H. , Gray W. , Bier J. , Levine D. , Berman S. , Gilson M. , Gewirtz H.
Published: December 2017

We tested the hypothesis that chronic reduction in perfusion pressure and flow in the coronary circulation induces a state of myocardial "hibernation" characterized not only by a steady-state reduction in myocardial O2 consumption (MVO2) but also by evidence of persistent dilator reserve of the distal vasculature. Biochemical and morphological changes in the coronary vasculature were also assessed. Experiments were conducted in swine with an extraluminal coronary stenosis placed 4-32 wk before study. Stenosis reduced lumen diameter by approximately 80% at the time of final experimentation. Baseline, regional myocardial blood flow distal to the stenosis in both endocardial and epicardial layers was reduced vs. that of the normal zone. Vasodilator reserve persisted in both endocardial and epicardial layers of the stenosis zone. Flow increased in each layer in response to adenosine plus phenylephrine and failed to decline despite a marked reduction in perfusion pressure in response to adenosine alone. Regional MVO2 at baseline was reduced vs. historical controls without coronary stenosis. Protein synthesis rate in coronary vessels of the stenosis zone was reduced vs. that of the normal zone. Morphological responses of stenosis zone vessel walls were heterogeneous. Smaller microvessels exhibited mild hypertrophy of their walls, whereas walls of larger microvessels tended to atrophy. Thus chronic reduction in perfusion pressure and flow induces a state of myocardial hibernation characterized by a steady-state reduction in MVO2 in association with persistent dilator capacity. Biochemical and morphological changes occur in microvessel walls and may contribute to observed physiological responses.
Relation among regional O2 consumption, high-energy phosphates, and substrate uptake in porcine right ventricle
Authors: Schwartz G. G. , Greyson C. R. , Wisneski J. A. , Garcia J. , Steinman S.
Published: December 2017

Changes in phosphate metabolites may play a role in the regulation of myocardial oxidative phosphorylation in vivo. We tested the hypothesis that changes in phosphate metabolites with increased myocardial oxygen consumption (MVO2) depend on the mechanism by which MVO2 is increased. In 17 open-chest pigs, regional MVO2 of the right ventricular (RV) free wall was increased from control by isoproterenol infusion (Iso) and by pulmonary artery constriction (PAC). The phosphocreatine-to-ATP ratio (PCr/ATP), which is inversely related to free ADP concentration ([ADP]), was determined by 31P-nuclear magnetic resonance (NMR) spectroscopy. Regional MVO2 and lactate, glucose, and free fatty acid (FFA) uptake were determined in the myocardium directly beneath the NMR coil. Iso and PAC increased MVO2 nearly equally, to approximately twice control, but produced directionally opposite changes in PCr/ATP: a significant decrease with PAC (control 1.52 +/- 0.06, PAC 1.35 +/- 0.06, means +/- SE) but a significant increase with Iso (to 1.72 +/- 0.07). Thus increased [ADP] may have stimulated oxidative phosphorylation during PAC but could not have done so during Iso. With Iso, uptake of FFA was more than three times that with PAC, and the sum of the oxygen extraction ratios for lactate, glucose, and FFA was more than double that with PAC. Enhanced substrate uptake during Iso may have increased mitochondrial NADH, which in turn may have provided an alternative stimulus to the rate of oxidative phosphorylation. These results support multifactorial control of RV oxidative phosphorylation in vivo.
A mathematical model of sinus node function: validation by recording of sinus node electrograms
Authors: Kalman J. M. , Munawar M. , Power J. , Chen J. M. , Tonkin A. M.
Published: December 2017

We have applied a mathematical function to model sinus node recovery after atrial pacing at different cycle lengths in 13 autonomically denervated, anesthetized canines. This model provides “pure” indexes of sinoatrial conduction and of suppression of automaticity. We compared sinoatrial conduction computed from the model (SACTc) with sinoatrial conduction measured directly utilizing a catheter recording the sinus node electrogram (SACTd) to test the validity of the model. We used both the model and the sinus node electrogram to further define events after pacing. There was close agreement between SACTc and SACTd with correlation coefficients at pacing cycle lengths of 20 and 50% below resting of 0.86 (P < 0.0001) and 0.78 (P < 0.0001), respectively. We verified that the conventional sinus node recovery time is due both to suppression of automaticity and prolongation of sinoatrial conduction. Sinoatrial conduction time returned rapidly to normal over 1–3 beats, whereas automaticity recovered exponentially over 20–40 postpacing intervals. The model accurately describes postpacing phenomena and has the potential to provide a useful adjunct to the measurement of the sinus node electrogram for assessment of sinus node function in the experimental laboratory.
Coronary pressure-flow relationship and exercise: contributions of heart rate, contractility, and alpha 1-adrenergic tone
Authors: Duncker D. J. , Van Zon N. S. , Crampton M. , Herrlinger S. , Homans D. C. , Bache R. J.
Published: December 2017

We examined the impeding effects of exercise on coronary blood flow by analyzing exercise-induced changes in the pressure-flow relationship during maximal coronary vasodilation with adenosine in chronically instrumented dogs and assessed the individual contributions produced by heart rate, contractility, and alpha 1-adrenergic vasoconstriction. Treadmill exercise that increased heart rate from 118 +/- 6 beats/min at rest to 213 +/- 8 beats/min (P < 0.01) decreased maximum coronary blood flows by decreasing the slope of the linear part of the pressure-flow relationship for coronary pressures > or = 30 mmHg (slopeP > or = 30) from 12.3 +/- 0.9 to 10.9 +/- 0.9 ml.min-1 x g-1 x mmHg-1 (P < 0.01) and increasing the measured coronary pressure at zero flow (P zf,measured) from 12.6 +/- 1.2 to 23.3 +/- 2.0 mmHg (P < 0.01). Atrial pacing at 200 beats/min caused an increase of P zf,measured from 15.0 +/- 1.6 to 18.3 +/- 2.1 mmHg (P < 0.05) with no change in slopeP > or = 30. While pacing continued, infusion of dobutamine (20 micrograms.kg-1 x min-1 i.v.) increased contractility to levels similar to those during exercise but caused no significant change in coronary blood flow, as a decrease of the slopeP > or = 30 was compensated for by a slight decrease in P zf,measured. alpha 1-Adrenergic blockade with intracoronary prazosin (10 micrograms/kg) did not prevent the exercise-induced increase of P zf,measured but abolished the decrease of the slopeP > or = 30. When the increases in heart rate, contractility, and alpha 1-adrenergic vasoconstriction were prevented, exercise still increased P zf,measured from 15.8 +/- 2.1 to 21.8 +/- 2.6 mmHg (P < 0.05) but had no effect on the slopeP > or = 30. This residual increase in P zf,measured correlated with the concomitant increase in left ventricular filling pressure. In conclusion, exercise-induced decreases of maximum coronary blood flow were explained by increases in heart rate, alpha 1-adrenergic vasoconstriction, and left ventricular filling pressure, with a minimal contribution of contractility.
Cardioprotection provided by adenosine receptor activation is abolished by blockade of the KATP channel
Authors: Van Winkle D. M. , Chien G. L. , Wolff R. A. , Soifer B. E. , Kuzume K. , Davis R. F.
Published: December 2017

Adenosine agonists and openers of the ATP-sensitive potassium (KATP) channel have been reported to limit infarct size (IS). We tested the hypothesis that these phenomena are interdependent. Anesthetized swine underwent 60 min of coronary artery occlusion and 90 min of reperfusion. Preconditioning was elicited by two cycles comprising 10 min of occlusion and 10 min of reperfusion (n = 7 swine). An intracoronary infusion of adenosine (Ado; n = 10) or (-)-N6-(2-phenylisopropyl)-adenosine (R-PIA; n = 7) replaced preconditioning ischemia. KATP channels were blocked with sodium 5-hydroxydecanoate (5-HD) in the absence (n = 6) or presence (n = 8) of R-PIA. Control pigs (n = 7) received saline vehicle. IS was assessed with tetrazolium and normalized as percentage of area at risk. Preconditioning resulted in a reduced IS compared with Control (3.9 +/- 1.8 vs. 43.5 +/- 6.9%, respectively; P < 0.0005). Ado and R-PIA also reduced IS [21.1 +/- 6.8 (P < 0.01) and 11.2 +/- 7.4% (P < 0.005), respectively]. 5-HD alone did not alter IS, but it abolished R-PIA-induced cardioprotection (IS 5-HD + R-PIA = 48.6 +/- 13.2%). Thus Ado A1-receptor agonists mimicked the cardioprotection of ischemic preconditioning. The Ado-induced limitation of IS was abolished by blockade of the KATP channel. We conclude that both Ado A1 receptors and KATP channels may be involved in ischemic preconditioning.
Restoration of arterial blood oxygen tension increases arterial pressure in sinoaortic-denervated rats
Authors: Franchini K. G. , Cestari I. A. , Krieger E. M.
Published: December 2017

The objective of the present study was to analyze whether the hypoxemia produced by chemoreceptor elimination influences the arterial pressure level after sinoaortic denervation (SAD) in rats. Hypoxemia and hypercapnia were observed in acute (1 day) and chronic (20 days) SAD rats [arterial PO2 (PaO2) = 65 +2- 1.6 and 71 +2- 2.2 mmHg and arterial PCO2 (PaCO2) = 46 +/- 1.3 and 37 +/- 1.8 mmHg, respectively] compared with control rats (PaO2 = 85 +/- 1.6 mmHg, PaCO2 = 31 +/- 1.07 mmHg). Increasing inspired PO2 (PIO2) from 138 mmHg (room air) to 155 mmHg restored the PaO2 of SAD rats to control levels (acute = 81 +/- 2.21 mmHg, chronic = 85 +/- 2.35 mmHg). PaO2. restoration produced pronounced elevation of mean arterial pressure (MAP) of acute (from 121 +/- 4 to 147 +/- 3.5 mmHg) and chronic (from 121 +/- 3 to 134 +/- 3.5 mmHg) SAD rats. Progressive stepwise increase of PIO2 (from 138 to 175, 210, and 235 mmHg) produced no additional elevation of MAP of acute (113 +/- 4, 137 +/- 5, 143 +/- 5, and 147 +/- 5 mmHg) and chronic (111 +/- 3.6, 131 +/- 7.4, 130 +/- 8.7, and 130 +/- 7 mmHg) SAD rats. Otherwise, the arterial pressure of control rats remained unchanged to progressive stepwise increase of PIO2 (118 +/- 5, 117 +/- 4, 118 +/- 4, 116 +/- 4 mmHg). These data suggest that the elimination of chemoreceptors in SAD rats produces hypoxemia responsible for hypotensive influences that counteract the pressor effects produced by baroreceptor elimination.