bluuebunny/crossref_metadata_2025 huggingface dataset:
Wall tension and myocardial dysfunction after ischemia and reperfusion
Authors: Downing S. E.
Published: December 2017

Cell viability is maintained during prolonged ischemia (ISCH) in isolated heart systems because mechanical function is nil (acute hibernation). By contrast, a noncontracting ischemic segment in an in vivo heart exhibits irreversible damage after < or = 30 min. To explore this difference, isolated rabbit hearts were buffer perfused and exposed to elevations of ventricular balloon pressure (BP) during ISCH to mimic systolic stresses of a dyskinetic (DYSK) segment. Relationships of magnitude and duration of stress to recovery of systolic function and metabolism were assessed. After 30 min of reperfusion (R30) in hearts subjected to 90 min of ISCH [10% coronary flow (CF)] and BP = 0, peak systolic pressure (PSP) returned to 69% of control. With BP set at 120 mmHg, recovery was to only 24%. With BP = 80, PSP at R30 was 46%. Extent of recovery was inversely affected by the duration of elevated pressure. Tissue ATP was reduced from 18.5 to 3.7 and glycogen from 164 to 28 mumol/g in the BP = 120 group. CF and myocardial O2 consumption were reduced to 50% at R30; there was a threefold increase in wall stiffness. These data suggest that mechanical stress of DYSK contributes significantly to metabolic and functional deterioration of ischemic myocardium.
Changes in myocardial contraction patterns in response to regional ischemia and sympathetic nerve stimulation
Authors: Birkeland S. , Westby J. , Faerestrand S. , Grong K.
Published: December 2017

We studied the effect of inferior cardiac nerve stimulation on global and regional left ventricular function before and after circumflex coronary arterial (CFX) occlusion in 12 pentobarbital-anesthetized cats. Regional function was evaluated by orthogonal sonomicrometry in the anterior midwall of the left ventricle and by two-dimensional short-axis echocardiography. CFX occlusion provoked hypokinesis in the nonischemic free wall adjacent to the dyskinetic ischemic region (17.6 +/- 2.3 vs. 34.6 +/- 2.2% preocclusion wall thickening; P < 0.01) and gradually improved systolic wall thickening toward the contralateral remote region, where the maximal hyperkinetic response was measured (52.9 +/- 4.4 vs. 32.5 +/- 3.3% preocclusion wall thickening; P < 0.001). In the anterior wall, remote region, hyperkinesis was predominant in longitudinal segments (8.1 +/- 0.8 vs. 2.3 +/- 0.6% preocclusion ejection shortening; P < 0.001) and slight in circumferential segments (11.0 +/- 0.7 vs. 9.1 +/- 0.6% preocclusion ejection shortening; P < 0.01). The postocclusion systolic wall thickening and segment-shortening pattern were not modified by sympathetic nerve stimulation, which increased cardiac output less after coronary occlusion, although contractility (dP/dt) increased markedly. In conclusion, the myocardial contraction pattern in ischemic and nonischemic regions after CFX occlusion is not much modified by sympathetic cardiac nerve stimulation.
Plasmin potentiates induction of nitric oxide synthesis by interleukin-1 beta in vascular smooth muscle cells
Authors: Durante W. , Schini V. B. , Catovsky S. , Kroll M. H. , Vanhoutte P. M. , Schafer A. I.
Published: December 2017

Experiments were performed to examine the effect of the major fibrinolytic protease, plasmin, on the production of nitric oxide from interleukin-1 beta (IL-1 beta)-treated cultured human and rat aortic smooth muscle cells. Incubation of vascular smooth muscle cells with IL-1 beta resulted in significant accumulation of nitrite and nitrate in the culture media. Plasmin, either added exogenously or generated by the reaction of tissue plasminogen activator with plasminogen, potentiated the IL-1 beta-mediated release of nitrite and nitrate from smooth muscle cells in a concentration-dependent manner, without affecting the production of nitrite and nitrate from cells untreated with IL-1 beta. This potentiating effect was abolished when plasmin was incubated with the protease inhibitor, alpha 2-antiplasmin. The perfusates from columns containing IL-1 beta-treated smooth muscle cells relaxed detector blood vessels without endothelium, and the addition of IL-1 beta-treated smooth muscle cells to suspensions of indomethacin-treated platelets inhibited their aggregation. Untreated smooth muscle cells or cells treated with plasmin alone did not have such effects. However, the simultaneous treatment of smooth muscle cells with IL-1 beta and plasmin markedly enhanced both the relaxing activities of the perfusates and the inhibition of platelet aggregation. Treatment of smooth muscle cells with NG-nitro-L-arginine inhibited the cytokine-mediated effects as well as the potentiating effect of plasmin. These results demonstrate that the plasmin can enhance the production of nitric oxide by IL-1 beta-treated vascular smooth muscle cells.
Blockade of endothelium-dependent responses in conscious rats by cyclosporin A: effect of L-arginine
Authors: Gallego M. J. , Lopez Farre A. , Riesco A. , Monton M. , Grandes S. M. , Barat A. , Hernando L. , Casado S. , Caramelo C. A.
Published: December 2017

This study was undertaken to examine the effect of the major immunosuppressive drug, cyclosporin A (CyA), on endothelial function. Conscious Wistar rats, treated with CyA (25 mg.kg-1 x day-1 im for 15 days), developed an inhibition of the endothelium-dependent acetylcholine (ACh)-mediated vasodilation, diuresis, natriuresis, and guanosine 3',5'-cyclic monophosphate excretion. The response to two endothelium-independent agents, i.e., sodium nitroprusside and atrial natriuretic peptide was preserved in similarly treated rats. The toxic effects of CyA were acutely overcome by the administration of the amino acid L-arginine (L-Arg), a source of substrate for nitric oxide. Moreover, the simultaneous administration of L-Arg (200 mg/kg ip for 15 days) significantly prevented the functional effects of CyA toxicity. The present data suggest that, in early stages of CyA toxicity, the predominant functional alteration occurs at the endothelial level. The reversibility of such alteration by L-Arg opens the possibility for further strategies aimed to reduce the harmful effects of CyA.
Circulatory models in assessment of cardiac enzyme release in dogs
Authors: van Kreel B. K. , van der Veen F. H. , Willems G. M. , Hermens W. T.
Published: December 2017

Cardiac ischemia causes interstitial leakage of cellular enzymes followed by release of these enzymes into plasma. Quantitative interpretation of these data requires a specific circulatory model, and the performance of such models was investigated. Plasma activities of cardiac enzymes were measured for increasingly abrupt forms of ischemic heart injury in the dog: 1) permanent ligation of the left anterior descending coronary artery (LAD); 2) reperfusion after 2 h of ligation of the LAD; and 3) calcium-free perfusion of the LAD during 10 min (calcium-paradox injury). Release into plasma of a rapidly (41%/h) and a slowly (2.2%/h) catabolized enzyme was calculated from the plasma activities, using a detailed circulatory model with compartments for heart, plasma, muscle, skin, and viscera. The time course of cellular enzyme leakage into interstitial space in the heart was calculated from release into plasma and a range of reported values for transendothelial permeability. Simplification to one- and two-compartment models introduced, respectively, 10 and 2% error in calculated cumulative release. Considering the other sources of error, this implies adequate performance of the two-compartment model. Protein washout from the heart is strongly influenced by expansion of interstitial protein space with dead myocyte volume and depends on the microheterogeneity of necrotic tissue areas. Accelerated release of enzymes into plasma after reperfusion reflects accelerated cellular leakage rather than enhanced washout.
Heart rate perturbation in the stage 17-27 chick embryo: effect on stroke volume and aortic flow
Authors: Cuneo B. , Hughes S. , Benson D. W.
Published: December 2017

Heart rate (HR), stroke volume (SV), and aortic flow increase linearly between developmental stages 17 and 27, as the embryonic chick heart progresses from a bent tube to a rudimentary four-chambered structure and cardiac mass increases fourfold. We hypothesized that HR perturbation, expressed as percent of intrinsic HR (%HR), would have a developmentally dependent effect on flow and SV. HR was transiently perturbed to 40–250% of intrinsic rate with a 1-mm cooled or heated steel probe applied to the sinus venosus of 81 embryos. Aortic blood velocity, cross-sectional area, and HR were used to calculate flow and SV. At each stage, flow was maximal at intrinsic HR. The %HR vs. SV relationship was linear, inverse, and developmentally dependent. In spite of a tremendous change in ventricular shape, mass, and volume, HR control during development of the preinnervated heart maximizes blood flow to the developing embryo.
Mechanisms of antifibrillatory effect of acidic reperfusion: role of perfusate bicarbonate concentration
Authors: Ibuki C. , Hearse D. J. , Avkiran M.
Published: December 2017

Transient (2 min) acidic (pH 6.6) reperfusion with low [HCO3-] solution suppresses reperfusion-induced ventricular fibrillation (VF) in the isolated rat heart. Using this preparation, we tested whether the effect was mediated by the high [H+] or the low [HCO3-] of perfusate. Left and right coronary beds were independently perfused with HCO3(-)-containing (25.0 mmol/l) solution at pH 7.4. Regional ischemia was then induced by stopping flow to the left coronary bed for 10 min. Hearts were subsequently assigned to four groups (n = 12 hearts/group), and the left coronary bed was reperfused with either HCO3(-)-containing (25.0 or 4.0 mmol/l) or HCO3(-)-free (5.0 mmol/l HEPES) solution, at pH 7.4 throughout (control reperfusion) or at pH 6.6 for the first 2 min and at pH 7.4 from 2 to 5 min (acidic reperfusion). Regardless of the buffer, controls exhibited a high (92 and 100%) incidence of VF; this was reduced to 42% in both of the acidic reperfusion groups (P < 0.05). There were no intergroup differences in heart rate, coronary flow, or size of ischemic zone. Thus high [H+], rather than low [HCO3-], appears to mediate the antifibrillatory effect of transient acidic reperfusion.
Effects of oxygen and exogenous L-arginine on EDRF activity in fetal pulmonary circulation
Authors: McQueston J. A. , Cornfield D. N. , McMurtry I. F. , Abman S. H.
Published: December 2017

To determine whether L-arginine, the precursor of endothelium-derived relaxing factor (EDRF), increases vasodilator activity in the fetal pulmonary circulation, we studied its effects on basal pulmonary vascular tone and on pulmonary vasodilation stimulated by oxygen and acetylcholine (ACh) in chronically prepared late-gestation fetal lambs. L-Arginine infusion (30–300 mg over 10 min) into the left pulmonary artery (LPA) increased blood flow (18–57%) without changing pulmonary artery pressure. To determine whether O2-induced vasodilation involves EDRF and is augmented by L-arginine treatment, we infused L-arginine or NG-nitro-L-arginine (L-NNA), an inhibitor of EDRF synthesis, while increasing fetal PO2 6 Torr by delivering 100% O2 to the ewe for 120 min. In controls, LPA blood flow progressively increased from 106 +/- 13 ml/min (baseline) to 257 +/- 34 ml/min (peak) at 40 min of increased PO2 (P < 0.05, baseline vs. peak) but steadily returned toward baseline during the next hour. Treatment with L-NNA markedly attenuated O2-induced pulmonary vasodilation (P < 0.05 vs. control). L-Arginine infusion did not augment or sustain the O2-induced vasodilator response. We also examined whether L-arginine could sustain pulmonary vasodilation to ACh, another EDRF-dependent stimulus, and found that the EDRF substrate neither potentiated nor sustained the ACh response. We conclude that: in the fetal lung 1) exogenous L-arginine is a fetal pulmonary vasodilator, 2) increased PO2 augments EDRF activity in the fetal lung, and 3) supplemental L-arginine does not sustain either O2- or ACh-induced vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of neurotensin and neuropeptide Y on coronary circulation and myocardial function in dogs
Authors: Ertl G. , Bauer B. , Becker H. H. , Rose G.
Published: December 2017

This study analyzed the effects of the neuropeptides, neurotensin, and human and porcine analogue, neuropeptide Y, in anesthetized open-chest dogs. The left anterior descending coronary artery was cannulated and perfused at constant pressure via a blood reservoir. Flow to the coronary cannula was measured by an electromagnetic flowmeter, and regional segment lengths were measured by sonomicrometer crystals. Neurotensin injected into the coronary cannula resulted in a dose-dependent increase of coronary flow; neuropeptide Y resulted in a decrease of coronary flow. Because these changes in flow were not explained by systemic hemodynamic effects or alterations in regional myocardial function, they were considered to be coronary dilatation or constriction. Coronary dilatation by neurotensin was not prevented by alpha- or beta-adrenoceptor blockade but was completely abolished by indomethacin or by lowering coronary perfusion pressure to 35 mmHg when depressed systolic segment shortening indicated myocardial ischemia. Coronary constriction by neuropeptides Y persisted at coronary perfusion pressure of 35 mmHg and was only attenuated by indomethacin. We conclude that in contrast to systemic effects, coronary vasodilatation by neurotensin is mediated by a prostanoid product of cyclooxygenase. Preactivation of the prostaglandin system may explain why neurotensin lost its coronary dilator effect during myocardial ischemia. Neuropeptide Y may elicit coronary constriction in addition to mechanic reduction of coronary flow resembling severe coronary stenosis.
Cerebral blood flow responsivity to CO2 in anesthetized chronically diabetic dogs
Authors: Sieber F. E. , Brown P. R. , Wu Y. , Koehler R. C. , Traystman R. J.
Published: December 2017

The effect of diabetes mellitus on the cerebrovascular response to CO2 is unclear. We examined the effects of diabetes on cerebral blood flow (CBF) and cerebral oxygen uptake (CMRO2) during CO2 alterations. Four groups of dogs were studied: nondiabetic, normoglycemic controls; non-diabetic acute hyperglycemia; diabetic (pancreatectomy) with high-dose insulin treatment to maintain blood glucose between 4.0 and 6.0 mM; and diabetic with low-dose insulin treatment to maintain blood glucose at 13.2 +/- 0.4 mM. Six weeks after either sham surgery or pancreatectomy, dogs were anesthetized with fentanyl (50 micrograms/kg) plus pentobarbital (10 mg/kg), and microsphere determinations of CBF were made during normo-, hypo-, and hypercapnia. On the day of the study, arterial glucose levels in the control, acute hyperglycemia, and high- and low-dose insulin diabetic groups were 4.0 +/- 0.3, 14.9 +/- 2.5, 3.3 +/- 0.8, and 13.3 +/- 0.7 mM, respectively, at control. The corresponding baseline CMRO2 levels were 2.8 +/- 0.2, 3.0 +/- 0.2, 4.1 +/- 0.4, and 4.0 +/- 0.3 ml O2.100 g-1 x min,1, and the values in both diabetic groups were higher than control. Normocapnic CBF in the acute hyperglycemia, high-dose insulin, and low-dose insulin groups was elevated from control (54 +/- 3, 50 +/- 3, 51 +/- 3 vs. 36 +/- 1 ml x 100 g-1 x min-1) and cerebrovascular resistance was lower (2.24 +/- 0.15, 2.51 +/- 0.14, 2.38 +/- 0.21 vs. 3.35 +/- 0.18 mmHg.ml-1 x 100 g.min). CBF responses to both hypercapnia and hypocapnia were similar among groups. Thus both acute hyperglycemia and diabetes decrease cerebrovascular resistance and increase CBF.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibition of spinal afferent nerve-mediated gastric hyperemia by nicotine: role of ganglionic blockade
Authors: Leung F. W.
Published: December 2017

The hypothesis that intravenous nicotine modulates gastric spinal afferent nerve function by its ganglionic-blocking property is tested. Stimulation of the gastric spinal afferent nerves in anesthetized rats is accomplished by intragastric capsaicin irrigation. Gastric blood flow is monitored by laser-Doppler flowmetry. The increase in gastric blood flow during intragastric capsaicin irrigation is significantly reduced by 4 and 40 micrograms.kg-1.min-1 of intravenous nicotine. The inhibition appears to be specific for the spinal afferent nerves as the increase in gastric blood flow induced by electrical stimulation of the vagal afferent nerves is unaltered by these doses of intravenous nicotine. A ganglionic-blocking dose (10 mg/kg) of intraperitoneal hexamethonium also significantly attenuates the gastric vasodilatory effect of intragastric capsaicin. Intravenous nicotine (40 micrograms.kg-1.min-1) combined with intraperitoneal hexamethonium (10 mg/kg) completely abolishes the gastric vasodilatory effect of intragastric capsaicin. These data suggest that intravenous nicotine offers a specific inhibition of the gastric spinal afferent nerve-mediated hyperemia, possibly as a consequence of its ganglionic-blocking property.
Enhancement of endothelial cAMP accumulation by adenine nucleotides: role of methylxanthine-sensitive sites
Authors: Cote S. , Van Sande J. , Boeynaems J. M.
Published: December 2017

ATP is a well-known inducer of prostacyclin and nitric oxide release from vascular endothelial cells. These responses are mediated by P2 receptors coupled to a phospholipase C. We have investigated the influence of ATP on the control of adenosine 3',5'-cyclic monophosphate (cAMP) in bovine aortic endothelial cells. ATP produced a slight increase in the cAMP content of unstimulated endothelial cells. A more impressive response to ATP (5-fold) was observed in forskolin-stimulated cells. The rank orders of potency of various ATP analogues were strikingly different for the increase in cAMP and the accumulation of inositol phosphates. The action of ATP was unaffected by indomethacin. Protein kinase C downregulation produced only a partial inhibition of the ATP response. The effect of phorbol 12-myristate 13-acetate and bradykinin on the forskolin-induced accumulation of cAMP was much smaller than that of ATP. Neither adenosine deaminase nor AMP deaminase decreased the response to ATP, which thus cannot result from the ATP degradation into adenosine. However, 8-(p-sulfophenyl)theophylline inhibited the responses to both ATP and adenosine. In conclusion, ATP enhances the accumulation of cAMP in endothelial cells. This action appears to be the sum of two components: a minor one resulting from kinase C activation and a major one mediated either by a direct interaction of ATP with A2 receptors, or by putative methylxanthine-sensitive P2 receptors.
Measurement of blood pressure and heart rate by telemetry in conscious, unrestrained marmosets
Authors: Schnell C. R. , Wood J. M.
Published: December 2017

A system is described for the continuous measurement of blood pressure, heart rate, and motor activity by telemetry in conscious marmosets freely moving in their home cages. Consistent diurnal variations in these parameters were observed under standard conditions, although these parameters were sensitive to changes in the environment. Blood pressure values were similar to those measured by nontelemetric methods in conscious, restrained marmosets. However, heart rate was lower, indicating that telemetry is less stressful. The suitability of this system for assessing the effects of blood pressure-lowering drugs was evaluated. An acute or a prolonged treatment with a converting enzyme inhibitor of marmosets maintained on a low-sodium diet induced a fall in blood pressure as previously observed using nontelemetric methods. With telemetry, however, more accurate information on the duration of response and the effects of the treatment on the diurnal rhythms was obtained. These observations demonstrate the advantages of telemetry for evaluating the hemodynamic effects of drug treatments under physiological conditions.
Purification and regulation of an AMP-specific cytosolic 5'-nucleotidase from dog heart
Authors: Darvish A. , Metting P. J.
Published: December 2017

The major enzyme responsible for adenosine production during myocardial hypoxia or ischemia is 5'-nucleotidase. We purified an AMP-specific 5'-nucleotidase to homogeneity from the 150,000-g supernatant of dog heart homogenate using phosphocellulose, DEAE-cellulose, and ADP-agarose affinity chromatography. Sodium dodecyl sulfate-poly-acrylamide gel electrophoresis of the purified enzyme yielded a single protein band of 43 kDa. The molecular mass of the holoenzyme, determined by gel filtration and sucrose density-gradient centrifugation, was approximately 166 kDa, suggesting a tetrameric structure. Dog heart cytosolic 5'-nucleotidase was active at physiological pH (6.8-7.8) and demonstrated a preference for AMP over IMP as substrate. The enzyme exhibited sigmoidal saturation kinetics, with half-maximal activity at 2.6 mM AMP in the absence of ADP. ADP (0-250 microM) activated cytosolic 5'-nucleotidase by increasing maximal velocity and affinity for AMP. The enzyme was inhibited by 4 mM ATP, but 5'-nucleotidase activity increased as [ATP] was reduced. Mg2+ was required for activity, with maximal activation at approximately 3.5 mM free Mg2+. These data suggest that the regulation of AMP-specific cytosolic 5'-nucleotidase by adenine nucleotides and free Mg2+ may be important in the production of adenosine during conditions promoting ATP hydrolysis, such as myocardial hypoxia or ischemia.
Polymorphonuclear leukocyte-derived O2-reactive species activate primed platelets in human whole blood
Authors: Pratico D. , Iuliano L. , Alessandri C. , Camastra C. , Violi F.
Published: December 2017

The activation of human platelets by polymorphonuclear leukocytes (PMN) was investigated in human whole blood challenged with "priming" concentrations of arachidonic acid or collagen in the presence or absence of N-formyl-Met-Leu-Phe (FMLP), a selective activator of PMN. With the use of arachidonic acid or collagen alone at priming concentrations or FMLP alone, no platelet response was observed. In contrast, FMLP in combination with arachidonic acid or collagen caused irreversible platelet aggregation with thromboxane A2 production. Platelet response to FMLP-activated PMN was enhanced by superoxide dismutase and blocked by catalase or the NADPH oxidase inhibitor diphenyliodonium, suggesting a role for the O2-.-H2O2 system in this cellular interaction. This was corroborated by experiments with exogenously added H2O2, which mimicked FMLP effects in the activation of primed platelets in whole blood. The present investigation indicates that platelets primed with minute amounts of arachidonic acid or collagen can be activated, in human whole blood, by oxygen-reactive species released by PMN.
Response of collateral-dependent myocardium to vasopressin release during prolonged intense exercise
Authors: Symons J. D. , Longhurst J. C. , Stebbins C. L.
Published: December 2017

We hypothesized that vasopressin concentrations during exercise attenuate the increase in collateral-dependent blood flow leading to left ventricular dysfunction in Ameroid-occluded miniswine. An Ameroid occluder was placed around the proximal left circumflex coronary artery (LCX) of 19 miniswine. Ten weeks later V1 receptor blockade with the use of [d(CH2)5Tyr-(Me)]arginine vasopressin (10-12 micrograms/kg iv) increased resting transmural flow (radioactive microspheres) in the LCX region, indicating the presence of V1 receptors. Neither injection of lysine vasopressin (125 pmol/kg) after V1 receptor blockade nor injection of two specific V2 receptor agonists caused changes in mean arterial pressure, heart rate, or left anterior descending coronary arterial flow velocity, indicating that V2 receptors mediate no appreciable vasodilation in the swine coronary circulation. Next the ratio of collateral to noncollateral flow and regional systolic wall thickening (sonomicrometer dimension gauges) were measured at rest and after 20 min of prolonged, intense treadmill exercise (85-90% of heart rate reserve) in the presence and absence of V1 receptor antagonism. This degree of exertion increased plasma lysine vasopressin from 6.2 +/- 1.0 at rest to 21.0 +/- 7.0 pg/ml (P < 0.05) during the unblocked run. However, the decrease in transmural blood flow ratio (collateral to noncollateral flow) from rest was similar during exercise before and after V1 receptor blockade (0.78 +/- 0.07 and 0.80 +/- 0.05, respectively; P < 0.05 vs. rest). Likewise, percent systolic wall thickening in the collateral-dependent region decreased from rest to exercise in the absence and presence of V1 receptor antagonism (35.9 +/- 4.5 and 39.5 +/- 3.8%, respectively; P < 0.05 vs. rest).(ABSTRACT TRUNCATED AT 250 WORDS)
Lipid peroxidation contributes to cardiac deficits after ischemia and reperfusion of the small bowel
Authors: Horton J. W. , White D. J.
Published: December 2017

Our previous studies showed that intestinal ischemia-reperfusion (IR) impairs cardiac contractile function. The present study examined the contribution of oxygen free radicals and lipid peroxidation of cardiac cell membrane to cardiac dysfunction after intestinal IR in a rat model of superior mesenteric artery (SMA) occlusion (atraumatic clip for 20 min) and collateral arcade ligation. Controls were sham operated (group 1, n = 25). In group 2, 30 rats with SMA occlusion were killed 3-4 h after reperfusion without treatment. Aminosteroid (U-74389F), a pharmacological agent known to inhibit lipid peroxidation of membranes, was given 1 min before occlusion of the SMA (group 3, n = 19). All rats were killed 3-4 h after reperfusion of the ischemic intestine, and the hearts were harvested for in vitro assessment of cardiac function (Langendorff preparation). Cardiac contractile depression occurred in the untreated group as indicated by a fall in left ventricular pressure (from 76 +/- 3 to 64 +/- 3 mmHg, P = 0.01), maximum +dP/dt (from 1,830 +/- 60 to 1,577 +/- 64 mmHg/s, P = 0.05), and maximum -dP/dt (from 1,260 +/- 50 to 950 +/- 60 mmHg/s, P = 0.005). Lipid peroxidation of cardiac membranes occurred after untreated IR as indicated by the rise in cardiac malondialdehyde levels (MDA) (from 0.203 +/- 0.046 to 0.501 +/- 0.044 nM/mg protein, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of myocardial fiber orientation on the electrical induction of ventricular fibrillation
Authors: Chen P. S. , Cha Y. M. , Peters B. B. , Chen L. S.
Published: December 2017

Although many studies have documented the importance of myocardial fiber orientation in the generation and maintenance of reentrant arrhythmia, its role in the induction of reentry by a single strong premature stimulus is held to be minimal. To study the importance of fiber orientation on the mechanisms of ventricular vulnerability to single strong premature electrical stimulation, computerized mapping studies using 56 closely (2. 5–5 mm) spaced epicardial bipolar electrodes were performed on six open-chest dogs to determine the patterns of activation after the application of a single strong premature stimulus. In an additional three dogs, both epicardial and endocardial mapping studies were performed with closely spaced electrodes. The baseline driving stimulus (S1) and the premature stimulus (S2) were given to the same or different sites on the right ventricular epicardium. When the line connecting the S1 and S2 (the electrical axis of stimulation) was roughly parallel to the fiber orientation, the vast majority of the early sites were found to lie between the S1 and S2 sites, with none of the early sites occurring on the side of the S2 site opposite to the S1 site. At the onset of ventricular fibrillation, figure-eight reentry was easily demonstrated. In comparison, when the S1 and S2 were given to the same site, or when the electrical axis of stimulation was roughly perpendicular to the fiber orientation, the early sites could occur on all sides of the S2 site. In these instances, a figure-eight reentry was not present at the onset of ventricular fibrillation, although this pattern could develop after the first few beats. These findings indicate that myocardial fiber orientation is an important factor in determining the patterns of activation during the electrical induction of ventricular fibrillation.
Role of cation gradients in hypercontracture of myocytes during simulated ischemia and reperfusion
Authors: Nishida M. , Borzak S. , Kraemer B. , Navas J. P. , Kelly R. A. , Smith T. W. , Marsh J. D.
Published: December 2017

We examined the relationship between transsarcolemmal cation gradients and hypercontracture of cardiac myocytes in ischemia and reperfusion using adult rat ventricular myocytes superfused with buffer mimicking normal or ischemic extracellular fluid. Contractile performance of electrically stimulated cells was recorded by an optical video system simultaneously with measurements of intracellular Ca2+ concentration ([Ca2+]i) using fura-2 or intracellular pH (pHi) using 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. While cells were exposed to simulated ischemia buffer, the transsarcolemmal H+ gradient was abolished, [Ca2+]i transient stopped, and twitch contraction of myocytes ceased. Upon reperfusion with normal buffer, H+ gradient was quickly restored, Ca2+ transients restarted with transient increase in systolic Ca2+, and twitch contraction restarted with development of hypercontracture, which continued after [Ca2+]i returned to preischemic level even in the presence of near-normal concentrations of high-energy phosphates. When the transsarcolemmal proton, Na+, and Ca2+ gradients were altered so that Na+ entry via Na(+)-H+ exchange and Ca2+ entry via Ca(2+)-Na+ exchange were made less favorable, the transient systolic overshoot of Ca2+ at reperfusion and development of hypercontracture was largely avoided. These results suggest that Na+ and then Ca2+ entry via the Na(+)-H+ and Na(+)-Ca2+ exchangers, respectively, probably contribute to the increase in [Ca2+]i and hypercontracture of myocytes at time of reperfusion in this model.
Effective distributed compliance of the canine descending aorta estimated by modified T-tube model
Authors: Burattini R. , Campbell K. B.
Published: December 2017

To estimate descending thoracic aortic compliance in anesthetized open-chest dogs, a modified T-tube arterial model was used. This model consists of two uniform and lossless elastic tubes, one representing arteries going toward the head and upper limbs and the other (body tube) representing descending aortic circulation to the trunk and lower limbs. Each tube terminates with a generalized first-order low-pass filter load. Pressure and flow in the ascending aorta and flow in the upper descending aorta were measured and used to estimate model parameters. Using the estimated model parameters, we calculated the pressure waveshape at the termination of the body tube. Comparison of this model-predicted pressure with pressure measured in the abdominal aorta near the origin of renal arteries suggested that the end of the body tube (effective reflecting site of the body circulation) corresponds to this major branching site of the abdominal aorta. To calculate the length of the body tube, we used aortic pulse wave velocity estimated from the measurements of pressure in ascending and abdominal aorta. Calculated body tube length averaged 30.3 +/- 2.8 cm and approximated the measured length (30.6 +/- 3.0 cm) of the aorta from the arch to the region of the origin of renal arteries. Compliance of the body tube averaged 123 +/- 20 x 10(-6) g-1.cm4.s2 and was interpreted as the descending thoracic aortic compliance. The ratio of this compliance to the body tube length gave an estimate of the effective distributed compliance, i.e., the compliance per unit length that would be observed in the absence of tapering. This ratio averaged 4.10 +/- 0.86 x 10(-6) g-1.cm3.s2 and fell in between the values of local aortic compliance independently estimated along the descending thoracic aorta from measurements of pressure and diameter. Thus tube compliance resulted in a physically identifiable property. This property was contrasted with the ill-defined effective compliances of the terminal loads.
Distributed-in-space product formation in vivo: enzymic kinetics
Authors: Goresky C. A. , Bach G. G. , Schwab A. J.
Published: December 2017

Distributed-in-space Michaelis-Menten enzymic conversion of precursor substrate to product within an organ is explored when all formed product is released into the bloodstream. In the nonlinear saturating enzymic case, length-wise precursor concentration profiles are found to vary from a falling exponential to a slowly declining linear profile, with rise in input concentration. The vascular profile for product rises in complimentary fashion; the sum of precursor and product is constant along the length. Symmetric permeability barriers produce stepdowns in precursor concentration from blood to tissue and, for product, converse stepdowns from tissue to blood are produced. Tracer precursor, introduced as an impulse input within this steady state, is converted to product with details of its distribution varying with the number of barriers for precursor. During this conversion, reversible tracer precursor association with enzyme leads to an enzymic space effect perceived as a saturating additional compartment, largest at tracer bulk levels, and decreasing with increase in underlying bulk concentration. While tracer product is not delayed by enzyme association, its outflow profile varies with the amount and location of enzyme, the enzymic rate constants, and the barriers for product between enzyme and the blood.
Effects of aging on cerebral vascular responses to serotonin in rats
Authors: Hajdu M. A. , McElmurry R. T. , Heistad D. D. , Baumbach G. L.
Published: December 2017

The purpose of this study was to examine effects of aging on responses of large cerebral arteries to serotonin. We measured cerebral microvascular pressure (with a micropipette and servo-null method), diameter of pial arterioles, and cerebral blood flow (microspheres) in adult (12- to 14-mo-old, n = 15) and aged (24- to 27-mo-old, n = 14) Wistar rats. Responses to intra-atrial infusion of serotonin (5 and 50 micrograms.kg-1.min-1) were examined. Infusion of the low dose of serotonin decreased mean arterial pressure and pial arteriolar pressure in adult and aged rats to similar levels. Cerebral blood flow was not reduced in adult or aged rats during infusion of the low dose of serotonin. The high dose of serotonin did not affect mean arterial pressure but reduced pial arteriolar pressure [from 46 +/- 4 to 23 +/- 2 (SE) in adult rats and from 52 +/- 3 to 18 +/- 4 mmHg in aged rats]. The high dose of serotonin increased large-artery resistance from 0.9 +/- 0.1 to 1.6 +/- 0.2 in adult rats and from 0.9 +/- 0.1 to 2.7 +/- 0.6 mmHg.ml-1.min.100 g in aged rats. Cerebral blood flow was reduced significantly in aged rats (from 59 +/- 3 to 41 +/- 6 ml.min-1.100 g-1), but not in adult rats, during infusion of the high dose of serotonin. We conclude that aging augments constrictor responses of large cerebral arteries to intravascular serotonin, which results in a reduction of cerebral blood flow in aged but not adult rats.
Relationship between shortening load, contractility, and myocardial energetics in intact dog
Authors: Dell'Italia L. J. , Evanochko W. T. , Blackwell G. G. , Pearce D. J. , Pohost G. M.
Published: December 2017

A canine model was developed to estimate left ventricular wall stress, volumes, contractility, and high-energy phosphate metabolites without the need for major surgery. A percutaneously inserted catheter-tip manometer was used to record high-fidelity left ventricular pressure while gradient echo cinemagnetic resonance (cine-MR) imaging alternated with in vivo 31P-nuclear magnetic resonance (NMR) spectroscopy during pharmacological maneuvers to increase cardiac work. Left ventricular circumferential wall stress, volumes, maximum rate of pressure development (dP/dtmax), and the ratio of phosphocreatine (PCr) to gamma-ATP (PCr/gamma-ATP) were recorded sequentially during control 1, dobutamine infusion, control 2, angiotensin infusion, and control 3 in five anesthetized, closed-chest dogs. PCr/gamma-ATP did not change significantly during controls 1-3, angiotensin, and dobutamine infusion. Left ventricular peak positive dP/dt (+dP/dtmax) increased significantly during dobutamine (3,338 +/- 831 mmHg/s, P < 0.001) but was unchanged during angiotensin (1,818 +/- 317 mmHg/s) and controls 1-3 (1,915 +/- 434 vs. 1,808 +/- 478 vs. 1,859 +/- 414 mmHg/s). However, dobutamine decreased the total systolic stress integral (area under the wall stress-time relationship) and end-diastolic and end-systolic volumes, whereas angiotensin increased these parameters compared with control conditions. The unchanged PCr/gamma-ATP is in accord with the results from other open-chest surface coil 31P-NMR experiments in the normal heart. Our assessment of left ventricular functional parameters provides new information that complements these more invasive studies in which heart rate-pressure product was measured during increases in cardiac work.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine mimics ischemic preconditioning via a glibenclamide-sensitive mechanism in dogs
Authors: Yao Z. , Gross G. J.
Published: December 2017

The major objectives of the present study were to examine the ability of acetylcholine (ACh) to mimic ischemic preconditioning in dogs and to determine the role of cardiac ATP-sensitive potassium (KATP) channels in mediating its effects. Barbital-anesthetized open-chest dogs were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 4 h of reperfusion. Preconditioning was elicited by 10 min of LAD occlusion followed by 10 min of reperfusion before the 60-min occlusion period. ACh (10 micrograms/min) or an equivalent volume of saline were infused into the LAD for 10 min followed by a 10-min drug-free period before the 60-min ischemic insult. In another group, the specific KATP channel blocker glibenclamide (0.3 mg/kg iv) was given 15 min before ACh administration. Transmural myocardial blood flow was measured at 30 min of occlusion, and infarct size (IS) was determined by triphenyltetrazolium staining and expressed as a percentage of the anatomic area at risk (AAR). There were no significant differences in hemodynamics, collateral blood flow, or AAR between groups. Preconditioning produced a marked reduction (P < 0.05) in IS (5.3 +/- 3.0 vs. 23.7 +/- 5.9% in the controls). ACh, similar to preconditioning, resulted in a dramatic decrease in IS (10.0 +/- 2.9%), whereas glibenclamide completely abolished its protective effects (20.9 +/- 4.8%). These results are the first to indicate that ACh mimics ischemic preconditioning via a cardiac KATP channel-sensitive mechanism in dogs.
Contribution of prostaglandins to exercise-induced vasodilation in humans
Authors: Wilson J. R. , Kapoor S. C.
Published: December 2017

It has been postulated that endothelial release of prostaglandins contributes to exercise-induced vasodilation of skeletal muscle arterioles. To test this hypothesis, 12 normal subjects underwent brachial arterial and venous catheter insertion and instrumentation of their forearm to measure plethysmographic forearm blood flow. Forearm blood flow and arterial and venous 6-ketoprostaglandin F1 alpha (PGF1 alpha) and prostaglandin E2 (PGE2) were then measured during two levels of wrist flexion exercise (0.2 and 0.4 W). In nine of the subjects, exercise was repeated after intra-arterial infusion of indomethacin (0.3 mg/100 ml forearm vol). Exercise increased forearm blood flow (2.0 +/- 0.2 to 12.1 +/- 1.1 ml.min-1.100 ml-1) and forearm release of PGF1 alpha (162 +/- 28 to 766 +/- 193 pg.min-1.100 ml-1) and PGE2 (26 +/- 6 to 125 +/- 46 pg.min-1.100 ml-1) (all P < 0.05). Indomethacin virtually abolished forearm prostaglandin release and reduced forearm blood flow at rest (2.2 +/- 0.2 to 1.7 +/- 0.2 ml.min-1.100 ml-1), at 0.2 W (6.3 +/- 0.7 to 5.4 +/- 0.7 ml.min-1.100 ml-1), and at 0.4 W (12.2 +/- 1.5 to 10.3 +/- 1.3 ml.min-1.100 ml-1) (all P < 0.02). These data suggest that release of vasodilatory prostaglandins contributes to exercise-induced arteriolar vasodilation and hyperemia in skeletal muscle.
Nitric oxide attenuates cardiac myocyte contraction
Authors: Brady A. J. , Warren J. B. , Poole-Wilson P. A. , Williams T. J. , Harding S. E.
Published: December 2017

Cardiac muscle fibers have microvessels in close proximity, the distance from the nearest capillary being no greater than 8 microns. We performed experiments on isolated, electrically stimulated, contracting guinea pig cardiac myocytes to test whether NO from endothelium or nitrovasodilators or directly superfused in solution might affect myocyte contractility. In endothelium-myocyte coculture experiments, 10(-7) M bradykinin reduced myocyte shortening by 11 +/- 3.5%. This effect was abolished in the presence of NG-nitro-L-arginine methyl ester and was unaffected by indomethacin. Sodium nitroprusside, but not organic nitrovasodilators, reduced myocyte contraction amplitude by 23% at 3 x 10(-5) M. This effect was reversed by methylene blue. Superfusion with NO solution had an effect similar to sodium nitroprusside, as did exposure to 8-bromoguanosine 3',5'-cyclic monophosphate. Thus the present study shows that cardiac myocyte contraction is attenuated by NO, which appears to act via production of guanosine 3',5'-cyclic monophosphate within the myocytes. Because cardiac myocytes in vivo are in such close proximity to endothelium, the effects of endothelial products on cardiac myocyte contractility may be important in myocardial function.
Effect of low-density lipoproteins, mevinolin, and G proteins on Ca2+ response in cultured chick atrial cells
Authors: Tan W. , Barnett J. V. , Pietrobon D. , Hehn G. , Greiser C. , Marsh J. D. , Galper J. B.
Published: December 2017

Growth of cells from atria of embryonic chick hearts 14 days in ovo in medium supplemented with lipoprotein-depleted serum (LPDS) results in an increase in total cell cholesterol, enhanced parasympathetic responsiveness (7), and decreased sympathetic responsiveness (1). These effects were reversed by the hydroxymethyl glutaryl CoA reductase inhibitor, mevinolin. In these studies, comparison of cell growth in medium supplemented with fetal calf serum (FCS) and LPDS demonstrated that, after growth with LPDS, the ability of Ca2+ and the Ca2+ channel agonist, BAY K 8644, to enhance the amplitude of contraction decreased by 25 and 50%, respectively. These effects of growth in LPDS were reversed by incubation with mevinolin. LPDS had no effect on either Ca2+ channel number as measured by (+)-[5-methyl-3H]PN200-110 binding or Ca2+ current density as measured by the whole cell patch method. Treatment of cells grown in LPDS with pertussis toxin, which inactivates alpha o and alpha i, returned the contractile response to 10(-7) M BAY K 8644 to control levels. Pertussis toxin had no effect on the contractile response or adenosine 3',5'-cyclic monophosphate levels in control cells grown in FCS alone. These data suggest that alterations in the relative levels of alpha o and alpha s in cells grown in LPDS may play a role in regulating the contractile response to Ca2+ channel agonists and to exogenous Ca2+.
Polyethylene glycol-conjugated superoxide dismutase in focal cerebral ischemia-reperfusion
Authors: He Y. Y. , Hsu C. Y. , Ezrin A. M. , Miller M. S.
Published: December 2017

Generation of free radicals during reperfusion after organ ischemia has been implicated in the pathogenesis of ischemic injury. We have previously shown that a combination of intravenous polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) and catalase (PEG-CAT), at a dose of 10,000 U/kg each, is effective in reducing infarct size in a focal cerebral ischemia model in the rat. It is not clear whether PEG-SOD alone is sufficient to reduce ischemic brain injury. In this study we determined the therapeutic efficacy of PEG-SOD and its dose-response curve. In a range of 1,000-30,000 U/kg, PEG-SOD exhibited a U-shaped dose-response curve. Only 10,000 U/kg significantly reduced infarct size [control 121 +/- 12 mm3 (mean +/- SE), n = 35; PEG-SOD 95 +/- 10 mm3, n = 36, P < 0.05]. PEG-SOD at the doses tested did not have significant acute hemodynamic effects but had a tendency to improve postischemic hypotension. This beneficial effect of PEG-SOD on blood pressure did not appear to fully account for the treatment effect of PEG-SOD on infarct size. The narrow therapeutic dose range of PEG-SOD in this study and similar findings of SOD in other investigations may contribute to the inconsistent protective effects of SOD preparations in ischemia-reperfusion injury in the literature.
Sodium hyperosmolarity of intestinal lymph causes arteriolar vasodilation in part mediated by EDRF
Authors: Steenbergen J. M. , Bohlen H. G.
Published: December 2017

This study evaluated 1) the effect of increased submucosal lymph osmolarity on the regulation of first-order (1A) and second-order (2A) intestinal arterioles and 2) the role of endothelium-derived relaxing factor (EDRF) in hypertonic-induced vasodilation. Increasing the submucosal lymph osmolarity from 280 to 400 mosM, in increments of 30 mosM, resulted in a dose-dependent dilation of 1A and 2A. A submucosal lymph tonicity of 340 mosM, as occurs during glucose and oleic acid absorption, caused dilation of 1A (118%) and 2A (124%) equivalent to that during absorptive hyperemia. The dilation caused by 400 mosM mannitol (137%) was similar to that with 340 mosM NaCl (131%) and approximately 70% of that with 400 mosM NaCl (152%). After EDRF blockade, the responses to sodium hypertonicity decreased by about one-half; blockade reduced mannitol-induced dilation by 22%. These results indicate that sodium hypertonicity, as occurs during absorption, can play a major role in absorptive hyperemia, and about one-half of the dilation is related to a sodium-coupled release of EDRF.
Myogenic tone is coupled to phospholipase C and G protein activation in small cerebral arteries
Authors: Osol G. , Laher I. , Kelley M.
Published: December 2017

The cellular transduction mechanisms underlying the response of blood vessels to mechanical forces such as pressure or stretch are largely unknown. In this report we test the hypothesis that myogenic tone in the cerebral circulation is coupled to activation of phospholipase C (PLC) and G proteins. Rat posterior cerebral arteries (luminal diam 189 +/- 4 microns) were cannulated in an arteriograph and allowed to develop myogenic tone at 75 mmHg (122 +/- 6 microns; P < 0.01). Exposure to U-73122, an inhibitor of PLC, produced concentration-dependent vasodilation, with near-maximal (> 90%) inhibition at concentrations > 3 microM (50% inhibitory concentration = 0.8 +/- 0.04 microM). The action of U-73122 was confirmed by demonstrating that constrictor responses to serotonin (PLC mediated) could be significantly attenuated or abolished at concentrations (0.5–1 microM) that were ineffective in antagonizing potassium depolarization or indolactam-induced constrictions (both PLC independent). Incubation in pertussis toxin (100 ng/ml, 2–2.5 h), an inhibitor of some G protein subtypes, reduced myogenic tone by 74 +/- 12%, with luminal diameters increasing from 129 +/- 7 to 160 +/- 7 microns. Conversely, nonspecific G protein activation using AlF-4 (NaF+AlCl3, 0.5-5 mM) significantly increased myogenic tone by 86 +/- 9%, reducing luminal diameters from 132 +/- 6 to 88 +/- 8 microns (P < 0.01). Together, these findings suggest that 1) PLC is activated in arteries that possess myogenic tone, 2) pharmacological inhibition of PLC results in a virtual loss of pressure-induced constriction, and 3) G proteins may modulate mechanotransduction through pathways superimposed on basal myogenic tone.