bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulatory effects of endothelin in newborn piglets
Authors: Bradley L. M. , Czaja J. F. , Goldstein R. E.
Published: December 2017

Endothelin, a recently described endothelial cell-derived peptide, produces pulmonary and coronary vasoconstriction in mature animals. We investigated the acute hemodynamic effects of porcine endothelin in 14 anesthetized open-chest new-born piglets during normoxia (Pao2 = 102 +/- 5 mmHg) and hypoxia (fractional inspired O2 concentration = 0.12 X 15 min, Pao2 = 31 +/- 1 mmHg). Six of these animals were pretreated with indomethacin, a cyclooxygenase inhibitor. Low-dose (100 pmol/kg) intravenous bolus injection of endothelin decreased pulmonary vascular resistance index (PVRI) (42 +/- 6 to 16 +/- 4 mmHg.l-1.min.kg, P less than 0.01) and increased coronary blood flow (CBF) (17 +/- 2%, P less than 0.01); cardiac index (CI) and coronary vascular resistance were unaffected. The pulmonary and coronary responses to endothelin were preserved during hypoxia: PVRI fell (160 +/- 22 to 83 +/- 13 mmHg.l-1.min.kg, P less than 0.05) and CBF rose (35 +/- 11%, P less than 0.05). Low-dose endothelin moderately increased mean arterial pressure (61 +/- 3 to 75 +/- 6 mmHg, P less than 0.05) and systemic vascular resistance index (SVRI) (375 +/- 23 to 491 +/- 41 mmHg.l-1.min.kg, P less than 0.01). High-dose (1,000 pmol/kg) endothelin mildly decreased PVRI (51 +/- 7 to 35 +/- 12, NS), moderately increased SVRI (375 +/- 45 to 594 +/- 95 mmHg.l-1.min.kg, P less than 0.05), and markedly diminished CBF (-54 +/- 6%, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Central angiotensinergic system and hypertonic resuscitation from severe hemorrhage
Authors: Velasco I. T. , Baena R. C. , Rocha e Silva M. , Loureiro M. I.
Published: December 2017

Single injections of 4 ml/kg hypertonic NaCl (7.5%) resuscitate dogs from severe blood loss (40-45 ml/kg). Mechanisms involve osmolarity-dependent volume expansion, increased myocardial contractility, and vasodilation. The role of central angiotensinergic pathways in the hemorrhage-hypertonic resuscitation interaction was investigated through experiments performed on male pentobarbital sodium-anesthetized dogs bled to, and held at, 40 mmHg for 30 min. Dogs were treated with 4 ml/kg of 7.5% NaCl or 32 of 0.9% NaCl iv preceded by intracerebroventricular (ICV) injections of 150 micrograms saralasin, 20 micrograms arginine vasopressin inhibitor (AVPI), or 10 micrograms morphine. ICV saralasin and morphine inhibited the full recovery response to hypertonic NaCl, whereas AVPI had no such effect. Saralasin did not inhibit the recovery from hemorrhagic shock produced by large volume isotonic saline reexpansion. These data demonstrate an interaction between the central angiotensin system and small volume hypertonic resuscitation from severe hemorrhagic shock but not between this central system and large volume isotonic reexpansion of circulatory volume. In contrast, the central vasopressinergic system does not appear to be similarly involved.
Effect of wall stretch on coronary hemodynamics in isolated canine interventricular septum
Authors: Resar J. , Livingston J. Z. , Halperin H. R. , Sipkema P. , Krams R. , Yin F. C.
Published: December 2017

The effects of stretch on coronary pressure-flow relations are not well understood. To examine the role of wall stretch per se on coronary hemodynamics, we studied arterially perfused isolated canine interventricular septa in a noncontracting state with vasodilated vessels. We compared the hemodynamic parameters of zero-flow pressure and resistance during passive stretching in the circumferential and the base-to-apex directions alone as well as during simultaneous biaxial stretching in both directions. Even in the unloaded state the zero-flow pressure was positive. Any type of stretching significantly increased the zero-flow pressure and the resistance from their unloaded values. The pressure-flow responses also showed directional dependence. When stretches with matched strains or stresses in each direction were applied sequentially, the resistance increases corresponded to the direction of higher stress. Conversely, the zero-flow pressure response increase corresponded to the direction of greater strain. However, neither response correlated with a measure of global tissue stiffness. Thus there is a complex and tight mechanical interaction between the vessels and the surrounding tissue. These interactions, but not the tissue stiffness, are important determinants of coronary pressure-flow responses during stretch.
Importance of endothelium-derived nitric oxide in porcine coronary resistance arteries
Authors: Tschudi M. , Richard V. , Buhler F. R. , Luscher T. F.
Published: December 2017

Endothelial cells regulate vascular tone through the release of nitric oxide and other relaxing factors. The role of these substances was studied in isolated intramyocardial porcine coronary resistance arteries suspended in myographs for isometric tension recording. The inhibitor of nitric oxide formation NG-monomethyl-L-arginine (L-NMMA; 10(-7)-10(-4)M), but not D-NMMA, caused endothelium-dependent contractions that could be reversed by L-arginine but not by D-arginine. In preparations with endothelium, L-NMMA potentiated the contractions induced by acetylcholine and the relaxations to 3-morpholino-sydnonimine. Under both conditions, the effect of endothelial removal was slightly more pronounced than that of L-NMMA. Bradykinin, serotonin, and the alpha 2-adrenergic agonist clonidine evoked endothelium-dependent relaxations. L-NMMA as well as the inhibitor of guanylate cyclase methylene blue (10(-5) M) prevented the relaxations induced by clonidine, reduced those to serotonin, but hardly affected those to bradykinin. Thus, in porcine coronary resistance arteries, endothelium-derived nitric oxide is continuously produced from L-arginine. Endothelium-dependent relaxations to clonidine are fully mediated and those to serotonin partially mediated by nitric oxide; its release does not involve a Gi protein. An endothelium-derived relaxing factor different from nitric oxide must mediate the relaxations to bradykinin and contribute to those evoked by serotonin.
Adenosine antagonism decreases metabolic but not functional recovery from ischemia
Authors: Angello D. A. , Headrick J. P. , Coddington N. M. , Berne R. M.
Published: December 2017

The effect of adenosine receptor antagonism on function and metabolism was examined in isolated hearts during low flow ischemia and reperfusion. Isovolumic rat hearts perfused at constant flow were subjected to 30 min of ischemia followed by 30 min of reperfusion. Infusion of vehicle or 10 microM 8-phenyltheophylline (8-PT) was initiated 10 min before ischemia and maintained throughout reperfusion. 8-PT infusion had no significant effects on hemodynamic parameters or metabolism preischemia. During ischemia, left ventricular developed pressure declined to approximately 15% of preischemic values in control and 8-PT hearts, and ATP and PCr decreased to approximately 73 and 60% of preischemic values. Inorganic phosphate (Pi) increased to 353 = 41 and 424 +/- 53% of preischemic values in control and 8-PT hearts, respectively. After reperfusion, function recovered to greater than 95% of preischemic levels in control and 8-PT hearts. Unlike control hearts, recovery of metabolites was significantly different during reperfusion in 8-PT hearts (P less than 0.05); ATP, phosphocreatine, and Pi recovered to 82 +/- 8, 71 +/- 8, and 281 +/- 27% of preischemic values, respectively. Venous purine washout was significantly greater (P less than 0.05) during reperfusion in 8-PT hearts (327 +/- 113 nmol) than in control hearts (127 +/- 28 nmol). Blockade of adenosine receptors appears to adversely affect metabolic but not functional recovery in the ischemic-reperfused myocardium.
Vascular factors in isovolumic systemic and pulmonary circuit
Authors: Chen H. I. , Chang K. C. , Hsieh K. S.
Published: December 2017

Experiments were conducted in 12 pentobarbital-anesthetized dogs with sinus denervation and vagotomy. The chest was opened, and the heart was replaced by a roller pump with two perfusion lines. The systemic and pulmonary circulations (SC and PC) were perfused with a constant and adjustable flow (Q). Venous outflows were directly driven by pumps without passing through a reservoir. In each closed circuit, the total blood volume remained constant because inflow and outflow were simultaneously and equally altered. In both SC and PC, arterial pressure (Pa), i.e., systemic arterial and pulmonary arterial pressures (SAP and PAP), was a positive function of Q, and venous pressure (Pv), i.e., right atrial and left atrial pressures (RAP and LAP), was a negative function of Q. The first series of experiments involved three equal step reductions in Q from baseline to zero flow. The venous-to-arterial compliance ratio (Cv/Ca) was calculated from delta Pa/delta Pv and vascular resistance (VR) from (Pa - Pv)/Q. The values of Cv/Ca in SC increased from 9.3 +/- 0.4 to 14.5 +/- 1.1 and 21.9 +/- 1.4 (P less than 0.001) in the three-step Q reduction. VR in the SC was not significantly dependent on Q. In the PC, the Cv/Ca was approximately 2.0 and VR was 0.16 mmHg.ml-1.min.kg, both values being independent of Q. Multiple-step reduction in Q for regression equations was carried out in 8 of the 12 dogs. We found that only the SAP was a linear function of Q (ml.min-1.kg-1): SAP = 18.458 + 0.953Q.(ABSTRACT TRUNCATED AT 250 WORDS)
Central nervous system histamine regulates peripheral sympathetic activity
Authors: Akins V. F. , Bealer S. L.
Published: December 2017

Brain histamine (HA) was depleted in conscious Sprague-Dawley rats by central administration of alpha-fluoromethyl-histidine (alpha-FMH), an irreversible inhibitor of the HA synthesizing enzyme. Isotonic or hypertonic saline was infused intravenously at 10 microliters.100 g-1.min-1 for 30 min and mean arterial pressure (MAP) and heart rate (HR) were monitored. In addition, plasma vasopressin (AVP) and norepinephrine (NE) were measured pre- and postinfusion. Animals pretreated with alpha-FMH showed a delayed and attenuated pressor response and bradycardia during hypertonic saline (HTS) infusion and a significant reduction in plasma NE levels (-29 +/- 8% below control values). However, plasma concentrations of AVP were similar in both groups. Central pretreatment with the H1-antagonist pyrilamine (PYR) also delayed the onset and significantly attenuated the pressor response to HTS infusion, and caused dose-related decreases in plasma NE concentrations (-34 +/- 8, -47 +/- 5, and -52 +/- 7% after 60, 100, and 600 nmol PYR, respectively). These data indicate a role for central HA in peripheral sympathetic activation but not as a mediator of AVP release to a peripheral hyperosmotic stimulus.
Effects of fetal anemia on PO2 difference between uterine venous and umbilical venous blood
Authors: Darby M. J. , Edelstone D. I. , Bass K. , Miller K.
Published: December 2017

In the fetus, the functional equivalent of the alveolar-arterial blood PO2 difference is the uterine venous-umbilical venous blood PO2 difference. Generally, factors that affect one of the venous blood PO2s produce equivalent effects on the other. We previously showed that fetal anemia produces increases in umbilical venous blood PO2. To determine whether this increase was associated either with equivalent increases in uterine venous blood PO2 or with reductions in the uterine venous-umbilical venous PO2 difference, we studied eight chronically catheterized pregnant sheep and fetal lambs. Measurements of O2 gas tensions and O2 saturations, uterine and umbilical blood flows, and uterine, fetal, and placental O2 consumptions were made in animals with normal fetal hematocrits and during reductions in fetal hematocrit of 35% (moderate fetal anemia) or 60% (severe fetal anemia). Fetal anemia produced reductions in the uterine venous-umbilical venous blood PO2 difference; in some cases the PO2 difference was less than 2 mmHg (compared with normal values of 20 mmHg). The development of both moderate and severe fetal anemia had no effect on uterine and umbilical blood flows or placental O2 consumption but did reduce total uterine and fetal O2 consumption. These data indicate that fetal anemia induces changes in placental gas transport. These changes may be due to improvements in gas diffusion, reductions in perfusion mismatching, or reductions in vascular shunting. Our data further indicate that placental O2 consumption rate, which is high in normal pregnant sheep, plays no role in the maintenance of the uterine venous-umbilical venous blood PO2 difference in pregnant sheep.
Theoretical study of pressure-volume relation in left ventricle
Authors: Shoucri R. M.
Published: December 2017

The myocardium is represented as a thick-walled elastic cylinder contracting symmetrically. The concept of body force (force/unit volume) is used to model the force developed by the myocardium in the radial direction during systolic contraction. It is shown that the radial force per unit area developed by the myocardium on its inner surface can be included in the equation describing the pressure-volume relation in the left ventricle. Application of the equations derived to experimental data describing the pressure-volume line in the Suga-Sagawa model is given. The results obtained seem to indicate that the body force developed by the myocardium in a normal ejecting contraction reaches its peak toward the end of the contraction phase and that the peak value is related to the peak isovolumic pressure when a quasistatic approximation of the systolic contraction is considered. Implication of the developed model for future studies in cardiac mechanics is also discussed.
Reactive oxygen metabolite scavengers decrease functional coronary microvascular injury due to ischemia-reperfusion
Authors: Dauber I. M. , Lesnefsky E. J. , VanBenthuysen K. M. , Weil J. V. , Horwitz L. D.
Published: December 2017

The role of reactive oxygen metabolites in ischemia-reperfusion coronary microvascular injury is unclear. To investigate this problem, we tested the effects of the reactive oxygen metabolite scavengers superoxide dismutase (SOD) and dimethylthiourea (DMTU) on ischemia-reperfusion-induced coronary microvascular dysfunction. As an index of vascular function, we assessed microvascular permeability with a double radioisotope protein leak index (PLI) method. Anesthetized dogs underwent 60 min of ischemia via left anterior descending (LAD) occlusion followed by 60 min of reperfusion. Untreated animals (n = 7) received saline. SOD-treated animals (n = 6) received 140 U.kg-1.min-1 (6.6 mg.kg-1.min-1) bovine SOD throughout ischemia and reperfusion. DMTU-treated animals (n = 5) received a 500 mg/kg bolus 30 min before ischemia. At the beginning of reperfusion, radiolabeled autologous protein (113mIn transferrin) and red blood cells (99mTc) were given intravenously for the assessment of permeability. In untreated dogs, ischemia-reperfusion increased the PLI of ischemic (flow less than 20 ml.min-1.100 g-1) myocardium more than threefold compared with that of nonischemic (flow greater than 100 ml.min-1.100 g-1) myocardium (ischemic-to-nonischemic PLI ratio = 3.49 +/- 0.48). SOD reduced the PLI of ischemic myocardium by 45% and DMTU reduced it by 66% (PLI = 9.25 +/- 1.30, 5.04 +/- 1.18, and 3.16 +/- 0.94, untreated, SOD, and DMTU, respectively). The PLI was increased proportional to the regional severity of ischemic blood flow. Both SOD and DMTU reduced the increase in protein leak at all levels of regional ischemic blood flow. Neither SOD nor DMTU increased regional myocardial blood flow to the occluded LAD zone.(ABSTRACT TRUNCATED AT 250 WORDS)
Increased intracellular Na+ and depolarization favor angiotension tachyphylaxis in rabbit aorta
Authors: Frediani-Neto E. , Silva E. G. , Paiva T. B. , Paiva A. C.
Published: December 2017

Tachyphylaxis to both angiotensin II (ANG II) and Sar1-ANG II is observed in normal rabbit aorta rings, but helical strips show tachyphylaxis only to Sar1-ANG II, whereas everted rings are not tachyphylactic to either analogue. In normal rings, a good correlation was observed between intraluminal pH and degree of tachyphylaxis to both analogues, suggesting that rate-limiting access of the agonists to their site of action may enhance tachyphylaxis in this preparation. Membrane potential and intracellular Na+ activity measurements, as well as the relaxation by K+ of norepinephrine-contracted preparations in K(+)-free medium, indicated that helical strips are more depolarized than everted rings due to Na+ leakage into the smooth muscle cells. These results suggest that the differences in the degree of tachyphylaxis induced by angiotensin in different rabbit aorta preparations are due to a less accessible site of action in normal rings and to the higher intracellular Na+ and more depolarized state of helical strips relative to everted rings.
Delayed rectifier outward K+ current is composed of two currents in guinea pig atrial cells
Authors: Sanguinetti M. C. , Jurkiewicz N. K.
Published: December 2017

The delayed rectifier outward K+ current (IK) was studied in isolated guinea pig atrial myocytes using the whole cell voltage-clamp technique. Similar to previous findings in ventricular cells, IK of atrial cells is the composite of two distinct components: IK,r, a rapidly activating current that exhibits strong inward rectification and IK,s, a slowly activating current with only modest rectification. IK,r was defined by its sensitivity to block by Co2+ and the class III antiarrhythmic agent, E-4031. IK,r underlies the prominent outward "hump" (between -30 and +40 mV) in the steady-state current-voltage relationship. Activation of IK,r was not dependent on transient changes in intracellular Ca2+ concentration. Block of Ca2+ current by nisoldipine or nitrendipine did not prevent activation of IK,r. Peak IK,r was not decreased in cells when intracellular Ca2+ was strongly buffered with 1,2-bis(aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. The activation curve for IK,r in atrial cells had a threshold of -40 mV, a half-point of -19 mV, and a slope factor of 5.2 mV. The activation curve for IK,s had a half-point of +24 mV and a slope factor of 15.7 mV. The peak tail currents of fully activated IK,s (21.1 pA/pF) and IK,r (2.53 pA/pF) are about two times that previously measured in guinea pig ventricular cells. This difference in current density may partly explain why action potentials of atrial cells are shorter than those of ventricular cells in guinea pig hearts.
Constrictor action of oxyhemoglobin in monkey and dog basilar arteries in vivo and in vitro
Authors: Toda N. , Kawakami M. , Yoshida K.
Published: December 2017

Angiographic studies on anesthetized dogs and Japanese monkeys showed that oxyhemoglobin (HbO2) injected into the cisterna magna produced a constriction of the basilar artery; the maximal constriction was attained 2-4 h later. Intracisternal injections of autologous blood, prostaglandin (PG) E2 and PGF2 alpha also constricted the artery to a similar extent, although the peak response was obtained much later (approximately 1 wk) with blood and was earlier (approximately 20 min) with PGs. The vasoconstrictor action of HbO2 was almost abolished by treatment for 5 h with aspirin in dogs and monkeys, whereas treatment of dogs with OKY 046, a thromboxane A2 synthesis inhibitor, did not significantly alter the action. In isolated monkey basilar arteries, HbO2 elicited a concentration-related contraction, which was suppressed by treatment with aspirin and by endothelium denudation. The basilar arteries responded to PGE2 and PGF2 alpha with contractions comparable to those caused by elevated external K+. Levels of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha in the nutrient solution bathing dog and monkey cerebral arteries were increased by HbO2; the increment was depressed by endothelium denudation and by treatment with indomethacin. These findings suggest that cerebral artery constriction caused by HbO2 in vivo and in vitro is associated mainly with the release of vasoconstrictor PGs, such as PGE2 and PGF2 alpha. Endothelium appears to play an important role in the release of PGs. Cerebral vasospasm elicited by intracisternal injections of HbO2 may be a useful model for the analysis of mechanisms underlying the provocation of delayed vasospasm after subarachnoid hemorrhage.
Systemic and regional effects of vasopressin and angiotensin in acute left ventricular failure
Authors: Arnolda L. , McGrath B. P. , Johnston C. I.
Published: December 2017

The systemic and regional hemodynamic effects of arginine vasopressin receptor antagonism (AVPA) and angiotensin-converting enzyme inhibition (ACEi) were examined in rabbits with acute left ventricular failure induced by repetitive direct current (DC) shock. Hemodynamic measurements in 24 rabbits 24 h after DC shock compared with 6 sham-operated controls demonstrated a lowered cardiac output (602 +/- 26 vs. 920 +/- 35 ml/min, P less than 0.01), increased left ventricular end-diastolic pressure (LVEDP, 13.6 +/- 1.3 vs. 1.9 +/- 0.5 mmHg, P less than 0.01) and a raised peripheral resistance (9,734 +/- 495 vs. 6,479 +/- 305 dyn.s.cm-5, P less than 0.01). Cerebral blood flow was not altered in rabbits with acute left ventricular failure but intestinal (29 +/- 2 vs. 53 +/- 9 ml/min, P less than 0.01) and renal (82 +/- 6 vs. 130 +/- 8 ml/min, P less than 0.01) blood flows were significantly reduced. No hemodynamic changes were observed after AVPA alone in the acute heart failure group and ACEi alone reduced LVEDP and increased renal vascular conductance. Treatment with both drugs (i.e., AVPA + ACEi) resulted in a significant increase in cardiac output (21%) and a decrease in blood pressure (19%) and peripheral resistance (34%) and restored renal and intestinal blood flows to near normal levels. Thus both vasopressin and angiotensin contribute to the overall increase in peripheral resistance in this model and to the decrease in intestinal and renal blood flow observed. Presumably blockade of one system produced little hemodynamic change because of compensatory increases in the other system.
Oxidative stress inhibits bradykinin-stimulated 45Ca2+ flux in pulmonary vascular endothelial cells
Authors: Elliott S. J. , Schilling W. P.
Published: December 2017

The effects of oxidant stress and altered glutathione reductase activity on agonist-induced flux of Ca2+ were studied in cultured calf pulmonary artery endothelial cells using radioisotopic 45Ca2+. Bradykinin-stimulated uptake of 45Ca2+ was determined after cells were incubated with the membrane-permeant oxidant t-butylhydroperoxide (0.4 mM) for various durations. t-Butylhydroperoxide increased uptake of 45Ca2+ under basal conditions and significantly decreased bradykinin-stimulated uptake in a time-dependent manner through incubation periods of 2 h. Preincubation of cells with 1,3-bis(chloroethyl)-1-nitrosourea markedly reduced bradykinin-stimulated uptake in cells subsequently treated with t-butylhydroperoxide. Bradykinin-stimulated efflux of 45Ca2+ and 86Rb+ was examined in control and oxidant-stressed endothelial cells. t-Butylhydroperoxide initially decreased bradykinin-stimulated efflux of 45Ca2+ but had no effect on 86Rb+ efflux. After more prolonged incubation with the oxidant, stimulated 45Ca2+ efflux was further inhibited, and basal efflux of 86Rb+ was increased to a rate similar to that observed with bradykinin stimulation. Elevated basal 86Rb+ efflux was blocked by tetrabutylammonium chloride, a selective inhibitor of Ca2(+)-dependent K+ channels in endothelial cells. These findings, together with our previously described results using fura-2, suggest that oxidant stress initially inhibits bradykinin-stimulated Ca2+ influx and later inhibits stimulated Ca2+ efflux. Finally, cytosolic free Ca2+ concentration becomes persistently elevated and is associated with elevated basal efflux of K+ via the Ca2(+)-dependent K+ channel.
Xanthine oxidase is not a major source of free radicals in focal cerebral ischemia
Authors: Betz A. L. , Randall J. , Martz D.
Published: December 2017

Xanthine oxidase (XO) has been proposed as an important source of free radicals during ischemia. This enzyme normally exists as a dehydrogenase (XD), but it is converted to XO in some ischemic tissues. Recently, treatment of animals with the XD and XO inhibitor allopurinol or with free radical scavengers before cerebral ischemia has been shown to reduce brain injury. Therefore, we studied conversion of XD to XO in three ischemic and nonischemic brain regions during focal cerebral ischemia resulting from permanent occlusion of the middle cerebral artery (MCAO) in anesthetized rats. In nonischemic brain, 16-22% of the enzyme was in the XO form. After 24 h of ischemia this value was not significantly different (10-15%). Neither the total activity of XO nor that of XD changed, indicating that there was no irreversible conversion of XD to XO. To further explore the possible role of XO, we examined the effect of various doses of allopurinol (5, 20, or 100 mg/kg given 1 h before MCAO or 100 mg/kg given 48, 24, and 1 h before MCAO) on uric acid accumulation, brain edema formation, and cerebral blood flow (CBF) 24 h after MCAO. All but the lowest dose of allopurinol greatly reduced the appearance of uric acid in the ischemic brain; however, only the highest dose of allopurinol had any beneficial effect on brain edema. This reduction in brain edema occurred without a significant improvement in CBF. Thus XO is probably not an important source of free radicals in this model of focal cerebral ischemia.
Loading determinants of isovolumic pressure fall in closed-chest dogs
Authors: Su J. B. , Hittinger L. , Laplace M. , Crozatier B.
Published: December 2017

The respective roles of load level and loading sequence of the left ventricle (LV) are controversial in the in situ heart. They were analyzed under autonomic blockade and sedation in 17 dogs previously instrumented with a pressure micromanometer and ultrasonic crystals measuring LV diameters and wall thickness for computation of LV volume and stress. The time constant of isovolumic pressure fall (T) and end-systolic pressure (ESP) were calculated during the control state, caval occlusion, aortic constriction obtained by inflation of a hydraulic cuff occluder positioned around the aorta, and during the inflation of an intra-aortic balloon. Caval occlusion significantly decreased both ESP (from 124.0 +/- 6.6 to 88.7 +/- 3.7 mmHg; P less than 0.005) and T (from 29.0 +/- 2.2 to 18.8 +/- 2.4 ms; P less than 0.005), which were linearly correlated (mean r = 0.90 +/- 0.03) and inflation of an intra-aortic balloon increased both ESP (from 107.3 +/- 7.1 to 150.6 +/- 10.4 mmHg; P less than 0.005) and T (from 24.6 +/- 2.1 to 32.7 +/- 2.3 ms; P less than 0.005). Both interventions did not modify the loading sequence (analyzed by the evolution of systolic wall stress vs. time). In contrast, aortic constriction delayed to midsystole the time to which wall stress reached its peak and, for matched ESP with intra-aortic balloon inflation, T was not significantly different from control. We conclude that both the level of afterload and the loading sequence of LV are the determinants of T when contractility is not modified.
Interactions between nitroglycerin and endothelium in vascular smooth muscle relaxation
Authors: Dinerman J. L. , Lawson D. L. , Mehta J. L.
Published: December 2017

To evaluate the role of endothelium in nitroglycerin (NTG)-mediated vascular relaxation, epinephrine-contracted rat thoracic aortic segments with and without intact endothelium were exposed to NTG (10(-10) to 10(-5) M). Aortic segments with intact (endo+, n = 15) and denuded endothelium (endo-, n = 9) exhibited typical NTG-induced relaxation. However, the mean effective concentration of NTG was lower for endo- than for endo+ segments (P less than 0.001). To determine if this phenomenon related to nitric oxide (NO) generation by endothelium, six endo+ segments were treated with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO production. These endo+ segments exhibited greater (P less than 0.001) relaxation in response to NTG than the untreated endo+ segments. Oxyhemoglobin, an inhibitor of guanylate cyclase activation, greatly diminished NTG-mediated relaxation of all aortic segments. To determine if the enhanced NTG-mediated relaxation of endo- segments was unique to the guanosine 3',5'-cyclic monophosphate-dependent vasodilator NTG, other endo+ and endo- segments were exposed to adenosine 3',5'-cyclic monophosphate-dependent vasodilator papaverine (10(-8) to 10(-4) M), and no difference in EC50 was noted between endo+ and endo- segments. Thus endothelium attenuates NTG-mediated vasorelaxation, and this attenuation is abolished by inhibition of endothelial NO production with L-NMMA. These observations indicate that endothelium is a dynamic modulator of vascular smooth muscle relaxant effects of NTG. This modulation appears to result from a competitive interaction between endothelial NO and NTG.
Left ventricular contractility is depressed in IgE-mediated anaphylactic shock in dogs
Authors: Correa E. , Mink S. , Unruh H. , Kepron W.
Published: December 2017

To determine whether myocardial dysfunction contributes to vascular collapse in anaphylactic shock, we examined left ventricular (LV) contractility, coronary blood flow, and myocardial lactate metabolism during antigen challenge in eight dogs that were sensitized to ragweed pollen extract (anaphylaxis group). Findings in the anaphylaxis group were contrasted to those in another group of dogs in which mean blood pressure was decreased to the same extent by arteriolar vasodilation with nitroprusside. The animals were examined under nonhypoxic conditions while anesthetized and ventilated. LV mechanics were examined with subendocardial crystals placed primarily along the anterior-posterior minor axis of the LV. During antigen challenge, a depression in LV contractility was observed in the anaphylaxis group as assessed by fractional dimensional shortening, stroke volume, and the slope of the end-systolic pressure-dimension relationship. During anaphylaxis, moreover, coronary vasodilation rather than coronary vasoconstriction was observed, and evidence of myocardial ischemia as assessed by altered myocardial lactate metabolism was not found. Our results indicate that depressed LV contractility occurs in anaphylactic shock. The results further suggest that the mechanism may be due to a direct effect of mediators of anaphylaxis on the myocardium to produce systolic dysfunction.
Pharmacological evidence for two types of myocardial sarcoplasmic reticulum Ca2+ release
Authors: Lynch C.
Published: December 2017

Contractions of guinea pig papillary muscles were studied at 37 degrees C under a variety of conditions and stimulation rates that markedly alter the pattern of tension development. When rested-state contractions (RSCs) were enhanced by treatments that increase intracellular adenosine 3',5'-cyclic monophosphate (0.1-1 microM isoproterenol, 1-10 microM forskolin), a markedly enhanced late peak tension developed after a 100-ms delay. Such late peak tension was selectively depressed by local anesthetics (200-400 microM procaine, 4-10 microM tetracaine, or 0.5-1 mM ethyl aminobenzoate). In contrast, 0.1-1 microM ryanodine had little effect on late peak tension, whereas 5 mM caffeine reduced the delay before tension development. Inotropic interventions such as increased external Ca2+ concentration or the Ca2+ channel agonist BAY K 8644 did not elicit such distinct late peaking RSCs. Rapid initial tension development observed under a variety of situations (short cycle lengths, stimulation rates of 0.25 Hz plus isoproterenol, decreased external Na+ concentration) was markedly depressed by 0.01-1 microM ryanodine and by caffeine, whereas local anesthetics had little effect. These results suggest two pharmacologically distinct types of sarcoplasmic reticulum Ca2+ release: 1) Ca2+ that accumulates during prior depolarizations is released immediately upon depolarization and decreased by ryanodine and caffeine; 2) extracellular Ca2+ that enters the myocyte is accumulated and released after an initial delay and is selectively depressed by low concentrations of local anesthetics.
Myocardial protection is lost before contractile function recovers from ischemic preconditioning
Authors: Murry C. E. , Richard V. J. , Jennings R. B. , Reimer K. A.
Published: December 2017

Preconditioning myocardium with brief episodes of ischemia reduces energy demand and delays cell death during a subsequent ischemic episode. We hypothesized that postischemic contractile dysfunction after the brief ischemic episodes ("stunning") causes this reduced energy demand. If this hypothesis is correct, then cardioprotection should persist as long as mechanical function still is depressed at the onset of sustained ischemia. To analyze the temporal relationship between preconditioning and stunning, infarct size was compared in two groups of open-chest anesthetized dogs that were preconditioned with a 15-min coronary occlusion followed by a sustained 40-min occlusion. One group received 5 min of reperfusion and the second group received 120 min of reperfusion between occlusions. Nonpreconditioned controls received a single 40-min occlusion. A 15-min occlusion caused severe stunning, which did not improve during 2 h of reperfusion. In the 5-min reflow group, preconditioning resulted in dramatically smaller infarcts, averaging 2.2 +/- 0.9% of the area at risk vs. 26.5 +/- 4.2% in controls (P less than 0.01), confirmed by a marked shift in the inverse relationship between collateral blood flow and infarct size. Despite persistently severe stunning in the 120-min reflow group, infarct size was intermediate, averaging 12.3 +/- 2.7% (P less than 0.05 vs. 5-min reflow; P less than 0.01 vs. control), and the infarct vs. flow regression had returned toward control. Thus the cardioprotective effect of preconditioning was attenuated when the intervening reperfusion time was extended, even though severe contractile dysfunction persisted. We conclude that myocardial stunning, per se, is insufficient to cause preconditioning.
Contrasting effects of vasopressin and angiotensin II on rabbit aortic baroreceptors
Authors: Munch P. A. , Longhurst J. C.
Published: December 2017

Arginine vasopressin (AVP) reportedly enhances, whereas angiotensin II (ANG II) attenuates, baroreflex control of the circulation. Here we examine whether these responses can be attributed, in part, to local actions on myelinated baroreceptor (BR) afferents, either directly or via changes in vascular tone. An in vitro rabbit aortic arch/aortic nerve preparation was used to study regularly discharging presumably myelinated BRs under controlled static and pulsatile pressures. At constant suprathreshold pressures, AVP (10(-13) M to 10(-6) M) had no effect on arch diameter or BR frequency, whereas equimolar concentrations of ANG II evoked dose-dependent vasoconstriction and associated BR inhibition. Differences were not caused by limited diffusion to BR endings lying outside the media, since similar results were obtained with either luminal or adventitial applications. AVP also had no effect on diameter or discharge in arches preconstricted with norepinephrine, whereas acetylcholine (ACh) relaxed the arch and thereby increased BR activity. These results eliminate possible AVP-induced endothelium-dependent vasodilation or potentiation of adrenergic vasoconstriction that would not be evident in isolated arches lacking tone. Finally, AVP did not sensitize BRs to changes in pressure, since ramp-evoked pressure-discharge curves remained constant and pulsatile discharge in response to sine-wave pressure inputs was unaltered. ANG II, however, shifted pressure-discharge curves to higher pressures and, with pulsatile inputs at constant mean pressure, reduced peak and average discharge firing rates. In conclusion, AVP has no apparent peripheral effect on aortic myelinated BRs in rabbits that could contribute to amplification of the baroreflex when AVP levels are elevated. In contrast, ANG II can inhibit BR firing as a consequence of local vasoconstriction, which may contribute to attenuation of the reflex when ANG II levels are elevated.
Adenosine formation and energy status during hypoperfusion and 2-deoxyglucose infusion
Authors: He M. X. , Gorman M. W. , Romig G. D. , Meyer R. A. , Sparks H. V.
Published: December 2017

The relationship between adenosine (Ado) formation and cytosolic energy status was studied in isolated guinea pig hearts during hypoperfusion plus norepinephrine infusion (0.6 nmol/min) and in isolated rat hearts during 2-deoxyglucose (2-DG) infusion. 31P nuclear magnetic resonance (31P-NMR) was used to measure phosphate concentrations, and both phosphorylation potential (expressed as [ATP]/[ADP][Pi]) and energy charge [expressed as (([ATP] + 1/2[ADP])/([ATP] + [ADP] + [AMP]))] were calculated as indexes of cytosolic energy status. Both progressive flow reductions and increasing length of exposure to 2-DG led to progressive decreases in energy charge and phosphorylation potential. In both cases, steady-state Ado release first increased then declined despite a continued fall in energy status. Inosine release followed a similar pattern. This biphasic pattern of Ado release vs. energy charge is similar to the pattern seen in in vitro studies of cytosolic 5'-nucleotidase, supporting the hypothesis that Ado formation in vivo is regulated by the influence of energy status on this enzyme. However, Ado release in vivo peaked at an energy charge much higher (0.997) than that observed in vitro (0.60-0.86). It is therefore probable that the inhibition of Ado formation in the perfused heart occurs via factor(s) in addition to energy charge.
Diastolic coronary resistance and capacitance are independent of the duration of diastole
Authors: Judd R. M. , Redberg D. A. , Mates R. E.
Published: December 2017

Systolic myocardial contraction may produce changes in coronary resistance and capacitance that persist throughout a normal diastole. In addition, coronary resistance and capacitance as determined in the arrested heart may not accurately describe normal diastolic behavior. To evaluate these possibilities, an identification method capable of characterizing the input impedance of the coronary circulation in as little as 150 ms was developed. Using this method, coronary dynamics were measured during early and late diastoles in the beating heart with tone intact as well as during adenosine-induced maximal vasodilation. Coronary dynamics were also measured in the arrested heart during maximal vasodilation. With vasomotor tone intact, the parameters of a lumped model of the coronary circulation showed no variation from early to late diastole. During maximal vasodilation, model parameters also showed no variation from early to late diastole. Parameters in the arrested heart were not statistically different from those of the beating heart during maximal vasodilation. However, model parameters determined during maximal vasodilation were significantly different from those determined with tone intact. These results suggest that although coronary resistance and capacitance are dependent on vasomotor tone, they remain constant throughout diastole and remain similar in the arrested heart.
Evaluation of phospholipid peroxidation as malondialdehyde during myocardial ischemia and reperfusion injury
Authors: Ceconi C. , Cargnoni A. , Pasini E. , Condorelli E. , Curello S. , Ferrari R.
Published: December 2017

Peroxidation of membrane phospholipid polyunsaturated fatty acids is considered a major mechanism of the damage occurring on reperfusion of the myocardium after a prolonged period of ischemia. The evidence in support of this mechanism of damage is based on tissue malondialdehyde quantitation by the thiobarbituric acid test (TBA test). In an attempt to verify this topic, we have subjected isolated and Langendorff-perfused rabbit hearts to a period of 60 min of severe ischemia plus 30 min of reperfusion. At appropriate time points, malondialdehyde was determined in the tissue by means of TBA test and directly by reversed-phase, high-pressure liquid chromatography (HPLC). We have found no correlation between the two compared assays. During reperfusion, there was the formation of non-lipid-related, malondialdehyde-like, TBA-reactive substance that leads to overestimation of the extent of lipid peroxidation. On the contrary, by direct HPLC quantitation, there was a decrease of tissue malondialdehyde during ischemia and during the early phases of reperfusion. Our results demonstrate that TBA test is not a reliable index of lipid peroxidation in organ systems.
Increase in sympathetic activity with age. I. Role of impairment of arterial baroreflexes
Authors: Hajduczok G. , Chapleau M. W. , Johnson S. L. , Abboud F. M.
Published: December 2017

The purpose of this study was to evaluate changes in arterial baroreflex function with aging. Mean arterial pressure (MAP) obtained in the awake state was 110 +/- 7 mmHg in the young animals (1 yr; n = 5) and 128 +/- 6 mmHg in the old beagles (11 yr; n = 11) (P less than 0.05). In response to bolus administration of varying doses of phenylephrine and nitroglycerin in the conscious state, the slope relating heart rate (HR) to MAP was attenuated significantly in the old animals compared with the young (-0.87 +/- 0.30 vs. -2.35 +/- 0.44 beats.min-1.mmHg-1; P less than 0.05). After atropine, the baroreflex control of HR was abolished in both groups. After anesthesia and sectioning of the aortic depressor nerves, and with isolated carotid sinus pressures (CSP) held at 50 mmHg, absolute renal sympathetic nerve activity (RSNA) was significantly greater in the old (368 +/- 40 Hz) vs. the young animals (41 +/- 9 Hz). In the old, the gains of baroreflex inhibition of MAP (0.78 +/- 0.09) and normalized RSNA (0.38 +/- 0.14%/mmHg) during increases in CSP were decreased significantly compared with the young (MAP, 1.16 +/- 0.17 mmHg, and RSNA, 0.72 +/- 0.06%/mmHg). In a subgroup of old normotensive animals (n = 5), the baroreflex gain of RSNA was still attenuated (0.43 +/- 0.11%/mmHg) compared with the young. The reflex reduction in absolute RSNA as a function of baseline RSNA was also impaired in old vs. young beagles.(ABSTRACT TRUNCATED AT 250 WORDS)
Oxidant-mediated, CD18-dependent microvascular dysfunction induced by complement-activated granulocytes
Authors: Carden D. L. , Smith J. K. , Korthuis R. J.
Published: December 2017

To determine the mechanisms whereby complement-activated granulocytes induce microvascular dysfunction in skeletal muscle, we examined the effect of antineutrophil serum (ANS), IB4 (a monoclonal antibody that inhibits CD18-dependent neutrophil adherence), xanthine oxidase inhibition or inactivation, deferoxamine, and catalase on the increase in canine gracilis muscle microvascular permeability induced by intravascular administration of zymosan-activated plasma (ZAP). Changes in vascular permeability were assessed by measurement of the solvent drag reflection coefficient (sigma) for total plasma proteins, and the extent of neutrophil infiltration was estimated by assessing muscle myeloperoxidase activity. ZAP infusion was associated with a marked increase in vascular permeability compared with control muscles that received no treatment or to muscles treated with zymosan heat-inactivated plasma (ZIP) (sigma = 0.51 +/- 0.04, 0.89 +/- 0.02, and 0.90 +/- 0.01, respectively). Estimates of sigma in animals rendered neutropenic with ANS, or treated with IB4, deferoxamine, or catalase before ZAP infusion were not significantly different from values obtained in control or ZIP-treated muscles (sigma = 0.96 +/- 0.02, 0.88 +/- 0.03, 0.85 +/- 0.02, and 0.79 +/- 0.01, respectively). However, xanthine oxidase inactivation or inhibition provided no protection from this ZAP-induced microvascular dysfunction (sigma = 0.58 +/- 0.02 and 0.58 +/- 0.01, respectively). In addition, neutropenia and inhibition of neutrophil adherence also prevented ZAP-induced increases in vascular resistance and tissue neutrophil infiltration.(ABSTRACT TRUNCATED AT 250 WORDS)
Opposing effects of diacetyl monoxime on contractility and calcium transients in isolated myocardium
Authors: Marijic J. , Buljubasic N. , Stowe D. F. , Turner L. A. , Kampine J. P. , Bosnjak Z. J.
Published: December 2017

Isolated, perfused guinea pig hearts were used to determine the effects of diacetyl monoxime (DAM) on atrial rate, atrioventricular conduction time (AVCT), and left ventricular peak systolic pressure (LVSP). Contractile force and calcium transients were also monitored in isolated papillary muscles injected with aequorin in the absence and presence of ryanodine (RYA). In the isolated heart, 0.2-5 mM DAM caused significant dose-dependent decreases in LVSP (up to 51%) without change in atrial rate and AVCT. DAM (10 mM) produced a small slowing of atrial rate, no change in AVCT, and a 76% decrease in LVSP; 20 and 30 mM DAM further reduced LVSP, decreased atrial rate 38%, and produced AV dissociation. In isolated, paced papillary muscles, 2, 10, and 30 mM DAM decreased contractile force 27, 58, and 87%, respectively, while calcium transients increased by -9, 38, and 225%, respectively. All cardiac effects of DAM were readily reversible. RYA (1 microM) alone and with DAM (30 mM) decreased contractile force by 30 and 99%, respectively and decreased calcium transients by 59 and 74%, respectively. This study shows that low concentrations of DAM have little effect on electrical activity but greatly depress contractility and modify intracellular handling of calcium.
Endothelium in functional aortic changes of coarctation hypertension
Authors: Bell D. R. , Bohr D. F.
Published: December 2017

Eleven coarctation hypertensive (CH), twelve sham control (C), and seven one-kidney, one-clip (1K,1C) rats were used to examine the role of pressure and the endothelium in vascular sensitivity changes to acetylcholine (ACh), serotonin (5-HT), and norepinephrine (NE) in chronic arterial hypertension. Terminal mean carotid artery pressures were CH = 156 +/- 5 mmHg, C = 99 +/- 3 mmHg, and 1K,1C = 159 +/- 5 mmHg. Femoral artery pressures were CH = 100 +/- 3 mmHg, C = 98 +/- 4 mmHg, and 1K,1C = 154 +/- 4 mmHg, respectively. Isometric tension recordings were made from helically cut strips of thoracic and abdominal aortas, with and without functional endothelium, from the three groups of rats. Sensitivity to relaxation by acetylcholine, expressed as -log of 50% effective dose, was significantly depressed in thoracic aortas from CH and 1K,1C rats and abdominal aortas from 1K,1C rats but not from abdominal aortas of CH rats. A similar relationship between the groups was seen for 5-HT contractions. Sensitivity to NE was enhanced in thoracic and abdominal aortas of hypertensive rats. Inactivation of aortic endothelia abolished ACh responses, did not alter 5-HT relationships between the three groups, and abolished the differences in sensitivity to NE in thoracic aortas. The data suggest that pressure and the endothelium may play a role in vascular sensitivity changes in hypertension.