bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional wall motion and strain analysis across stages of Fontan reconstruction by magnetic resonance tagging
Authors: Fogel M. A. , Gupta K. B. , Weinberg P. M. , Hoffman E. A.
Published: December 2017

To determine whether systolic regional wall deformation and motion, which may be used as an index of mechanical function, change with surgical intervention in patients with a functional single ventricle, a noninvasive magnetic resonance tagging technique was used to examine 33 such patients at all stages of Fontan reconstruction. The systolic motion of the intersection points was tracked to determine regional twist and radial shortening. Finite strain analysis was applied to the grid lines, and principal E1 strains were derived. The results were as follows. 1) Fontan and prebidirectional cavopulmonary anastomosis (hemiFontan) groups had the highest compressive strains, and regional heterogeneity of strain was least in the Fontan group. 2) Fontan patients had endocardial/epicardial strain different from the other surgical subgroups as well as the normal left ventricle, while the pre- and post-hemiFontan groups had basal/apical short-axis strain different from Fontan patients and normal subjects. 3) Functional single left ventricles had a different strain distribution across wall regions and surgical subgroup from functional single right ventricles. 4) Contrary to the normal human adult studied by the same method, which twists uniformly counterclockwise, 31 of 33 single ventricles, regardless of ventricular morphology or surgical subgroup, twisted counterclockwise in one region, clockwise in another, and met at a "transition zone" of no twist, which had the highest strains of all regions. 5) Radial contraction was greatest in the superior walls and least at the inferior walls of single-ventricle patients regardless of morphology. In the Fontan group, the inferior walls moved paradoxically. In conclusion, markedly different strain characteristics are noted at each stage of Fontan reconstruction, across various wall regions, and between ventricular morphological groups. Differences in regional wall motion were demonstrated in functional single ventricles throughout Fontan reconstruction regardless of morphology, and differences in associated strains and radial contraction were noted across various wall regions and surgical subgroups. These may play an important role in the energetics of the heart and the long-term viability of the single ventricle.
Permissive role of NO in alpha 2-adrenoceptor-mediated dilations in rat cerebral arteries
Authors: Bryan R. M. , Steenberg M. L. , Eichler M. Y. , Johnson T. D. , Swafford M. W. , Suresh M. S.
Published: December 2017

Dilations produced with UK-14304, a selective alpha 2-adrenoceptor agonist, in rat middle cerebral arteries (MCAs) were blocked after removal of the endothelium or inhibition of nitric oxide synthase (NOS). After endothelium removal or inhibition of NOS, the addition of subthreshold doses of an exogenous nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine, restored the dilations produced by UK-14304. In a similar manner the guanosine 3',5'-cyclic monophosphate (cGMP) analogues 8-bromoguanosine 3',5'-cyclic monophosphate and N2,2'-O-dibutyrylguanosine 3',5'-cyclic monophosphate restored the dilations of MCAs after endothelial removal. Because NO cannot be synthesized and released in MCAs after inhibition of NOS, it cannot be directly responsible for the dilation. The basal release of NO from the endothelium acts permissively in the vasodilation by maintaining adequate levels of cGMP. Removal of this basal release of NO by removal of endothelium or inhibition of NOS abolishes the alpha 2-adrenoceptor-mediated dilation.
Cardiorespiratory transfer during sleep: a study in healthy young men
Authors: Van de Borne P. , Biston P. , Paiva M. , Nguyen H. , Linkowski P. , Degaute J. P.
Published: December 2017

This study tested the concept that changes in breathing parameters account for modifications in respiratory-related blood pressure (BP) and R-R interval (RRI) variability during nocturnal sleep. BP (Finapres), electrocardiogram, respiration (Respitrace), and polygraphic sleep recordings were recorded continuously in 13 healthy men aged 18-37 yr. The transfer characteristics identified by coherence and gain measures between the calibrated thoraco-abdominal motion and the respiratory-related BP and RRI variability evidenced a consistent increase during transitions from wake to light sleep and from light to deep sleep but returned to waking levels during rapid-eye-movement sleep (P < 0.0001). These changes were related to the specific modifications occurring in the respiratory rate, tidal volume, and ribcage-to-abdominal motion ratio during the different sleep stages (0.28 < r < 0.39; P < 0.0001). This study demonstrates 1) that modifications in the breathing pattern account for 8-15% of the variance in the cardiorespiratory transfer, and 2) that respiratory modulation of vagal activity is not the main mechanism controlling the magnitude of the respiratory-related BP and RRI variability during sleep.
Impaired arginine metabolism and NO synthesis in coronary endothelial cells of the spontaneously diabetic BB rat
Authors: Wu G. , Meininger C. J.
Published: December 2017

Arginine metabolism via nitric oxide (NO) synthase and other pathways was studied in coronary endothelial cells (EC) from the spontaneously diabetic BB rat, an animal model of human type I diabetes mellitus (IDDM). EC were prepared from insulin-treated diabetic BB (BBd) and non-diabetes-prone BB (BBn) rats. Basal NO synthesis was studied in EC cultured for 48 h in medium containing 0.4 mM L-arginine. At the end of the culture period, the medium was analyzed for nitrite and nitrate (two major end stable oxidation products of NO), and the cells were used to determine arginine uptake and metabolism and the activities of some arginine-degrading enzymes. For studies of arginine metabolism, cells were incubated at 37 degrees C for 1 h in Krebs-Henseleit bicarbonate buffer (pH 7.4) containing 1 mM L(-)[1-14C]arginine or L(-)[1-14C]ornithine. The rates of production of nitrite plus nitrate by BBd EC were only 15% of those of BBn cells. This impaired NO synthesis in BBd EC was not due to alterations in arginine uptake, NO synthase activity, or intracellular arginine concentrations but might have resulted from a limited intracellular availability of cofactors of NO synthase. In addition to the arginine-NO pathway, arginine was found to be metabolized to urea, ornithine, and, to a much lesser extent, CO2 via arginase and ornithine aminotransferase. The activities of arginase and the formation of ornithine and urea from arginine were decreased by 90% in BBd compared with BBn cells. These results, coupled with the reduced NO synthesis, indicate metabolic defects in arginine metabolism in BBd EC.(ABSTRACT TRUNCATED AT 250 WORDS)
Different properties of the atrial G protein-gated K+ channels activated by extracellular ATP and adenosine
Authors: Fu C. , Pleumsamran A. , Oh U. , Kim D.
Published: December 2017

Extracellular ATP (ATPo) and adenosine activate G protein-gated inwardly rectifying K+ currents in atrial cells. Earlier studies have suggested that the two agonists may use separate pathways to activate the K+ current. Therefore, we examined whether the K+ channels activated by the two agonists have different properties under identical ionic conditions. In cell-attached patches, K+ channels activated by 100 microM ATP in the pipette had a single-channel conductance and mean open time of 32.0 +/- 0.2 pS and 0.5 +/- 0.1 ms, respectively, compared with 31.3 +/- 0.3 pS and 0.9 +/- 0.1 ms for the K+ channels activated by adenosine (140 mM KCl). With ATPo as the agonist, the K+ channel activity in cell-attached patches was approximately threefold lower than that in inside-out patches with 100 microM GTP in the bath. Applying ATP to the cytoplasmic side of the membrane (ATPi) produced a biphasic concentration-dependent effect on channel activity: an increase at low [mean affinity constant (K0.5) = 190 microM] and a decrease at high (K0.5 = 1.3 mM) concentrations. In contrast, with adenosine as the agonist, K+ channel activity in cell-attached patches was approximately fourfold greater than that in inside-out patches with 100 microM GTP in the bath. In inside-out patches, ATPi only augmented the K+ channel activity (K0.5 = 32 microM). These results show that although both ATPo and adenosine activate kinetically similar K+ channels in atrial cells, the channels are regulated differently by intracellular nucleotides.
Prolonged leukocyte transit time in coronary microcirculation of endotoxemic pigs
Authors: Goddard C. M. , Allard M. F. , Hogg J. C. , Herbertson M. J. , Walley K. R.
Published: December 2017

We quantified the timing and extent of leukocyte retention by the coronary microcirculation in a pig model of hyperdynamic sepsis in three ways. First, the transmyocardial leukocyte gradient was determined as coronary blood flow (calibrated ultrasonic flow probe) multiplied by the difference between leukocyte counts in the aorta and coronary sinus. Measurements were taken at 1-min intervals for 30 min and then at 3-min intervals for 45 min in anesthetized pigs exposed to either endotoxin (50 micrograms/kg iv over 30 min) (n = 7) or vehicle (n = 7). Second, postmortem morphometric analysis was used to quantitate the number and location of retained myocardial leukocytes. Finally, myocardial capillary transit time of leukocytes was calculated from the above measures. In the endotoxin group 2.1 +/- 0.8 x 10(9) leukocytes/100 g wet wt were retained in the coronary circulation, primarily in capillaries. This resulted in 111 +/- 37 (P < 0.05) times as many leukocytes in the coronary microcirculation than predicted from the arterial leukocyte concentration. Myocardial capillary transit time of leukocytes was prolonged to 39.1 +/- 20.6 s (P < 0.05) in the endotoxin group versus 5.0 +/- 1.4 s in the control group. We conclude that, after endotoxin infusion in a pig model of hyperdynamic sepsis, myocardial leukocyte transit is slowed, leading to the retention of large numbers of leukocytes in the coronary microcirculation.
Laser-Doppler perfusion imaging of microvascular blood flow in rabbit tenuissimus muscle
Authors: Linden M. , Sirsjo A. , Lindbom L. , Nilsson G. , Gidlof A.
Published: December 2017

To evaluate a newly developed high-resolution laser-Doppler perfusion imager (HR-LDPI) for analysis of local tissue perfusion, blood flow measurements in the rabbit tenuissimus muscle were carried out in combination with intravital microscopic observation. The principle of the LDPI method is based on a low-power laser beam scan of the exposed tissue from which a two-dimensional color-coded perfusion map is created through computerized signal analysis. The perfusion of the tenuissimus muscle prepared for microscopic observation was analyzed in a 5 mm x 8 mm area as the muscle was exposed to atmospheric oxygen tension (Po2; 20 kPa), a low Po2 (approximately 3 kPa), and after vasodilatation induced by topical application of prostaglandin E2 (PGE2). In selected areas free from larger vessels, a significantly lower perfusion average reading was demonstrated under high Po2 conditions compared with low Po2 conditions (P < 0.05, n = 5 animals), and application of PGE2 gave rise to an average reading significantly higher than that at low Po2 (P < 0.01, n = 6 animals). The results were in good agreement with the flow changes observed microscopically, and the architecture of the microvascular network, as depicted by in vivo micrographs, was clearly recognizable in the perfusion images. In conclusion, blood flow changes in the rabbit tenuissimus muscle induced by various stimuli were quantitated with the HR-LDPI method and could be spatially resolved in great detail, illustrating the potential of using HR-LDPI for analysis of local blood flow and to reveal spatial perfusion heterogeneity in tissues.
Multiple growth factors are released from mechanically injured vascular smooth muscle cells
Authors: Crowley S. T. , Ray C. J. , Nawaz D. , Majack R. A. , Horwitz L. D.
Published: December 2017

Local release of mitogenic and chemotactic signals during angioplasty-induced vascular injury may initiate restenosis. We investigated whether mechanical injury to vascular smooth muscle cells (VSMC) results in the release of biologically active peptide growth factors. Monolayers of bovine SMC cultures were mechanically injured by cell scraping. Conditioned medium (CM) from control and injured SMC cultures was collected, and the mitogenic activity was measured by [3H]thymidine incorporation in recipient SMC cultures. Mitogenic activity from injured CM was detected within 15 min after injury. When the CM from injured cells was removed 15 min after injury and replaced with serum-free media, there was no detectable mitogenic activity in the replacement CM assessed 1-6 days postinjury. Suramin, a nonspecific peptide growth factor antagonist, significantly inhibited the mitogenic activity of injured CM. Basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF A chain), and epidermal growth factor (EGF) were detected in CM from injured cells by immunoblot analysis. The mitogenic activity of injured CM was significantly inhibited with neutralizing antibodies to bFGF (34%), PDGF-AA (32%), PDGF-BB (25%), and EGF (25%). A neutralizing antibody to transforming growth factor (TGF)-beta had no effect. In conclusion, bFGF, PDGF, and EGF are immediately released from mechanically injured VSMC. VSMC likely contain preformed, biologically active growth factors that are efficiently released from the cell cytoplasm following mechanical injury. Conditioned medium from injured VSMC is highly mitogenic, and this activity is probably due to multiple growth factors interacting synergistically.
Complexity and "chaos" in blood pressure after baroreceptor denervation of conscious dogs
Authors: Wagner C. D. , Mrowka R. , Nafz B. , Persson P. B.
Published: December 2017

To investigate how arterial baroreceptors affect the dynamic properties of short-term blood pressure control, we determined Lyapunov exponents and correlation dimensions of blood pressure. Two groups of conscious dogs were studied: a control group (n = 7) and a group subjected to total sinoaortic and cardiopulmonary baroreceptor denervation (n = 7). As a measure of variability, standard deviation was determined and power spectra were calculated. In the lower frequency range (f < 0.1 Hz) power density was inversely related to frequency in both groups, indicating "1/f noise." Estimating the correlation dimension via the Grassberger-Procaccia algorithm as a quantification of complexity revealed a decrease after baroreceptor denervation (1.74 +/- 0.2 vs. 3.05 +/- 0.23 control; P < 0.05). Determination of the largest Lyapunov exponents lambda 1, which indicates the sensitive dependence on initial conditions, a hallmark of chaos, also yielded a diminution after denervation (lambda 1 = 0.74 +/- 0.08 vs. 1.85 +/- 0.18, P < 0.01). The results were cross-checked with surrogate data statistics. The null hypothesis, that there is no nonlinear structure in arterial blood pressure time series, was rejected. This shows that after baroreceptor denervation, blood pressure control is less complex and less sensitive to initial conditions ("chaos"). In contrast, variability (standard deviation) is increased (22.2 +/- 3.1 denervation vs. 8.3 +/- 1.4 control; P < 0.05). It is concluded that under physiological conditions, arterial and cardiopulmonary baroreceptors reduce variability of blood pressure, however, at the cost of blood pressure being less predictable. Thus the regulation is more sensitive depending on initial conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
Anandamide and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin
Authors: Ellis E. F. , Moore S. F. , Willoughby K. A.
Published: December 2017

Anandamide (AN, arachidonyl ethanolamide) has been isolated from the brain and shown to be an endogenous ligand for the delta 9-tetrahydrocannabinol (delta 9-THC) receptor. The purpose of these studies was to determine whether AN or delta 9-THC can affect the cerebral circulation. With the use of the closed cranial window AN and delta 9-THC (10(-13)-10(-3) M) were topically applied to rabbit cerebral arterioles and effects on diameter were measured with a microscope. AN and delta 9-THC similarly induced a dose-dependent dilation starting at concentrations as low as 10(-12) M. Maximum dilation for AN was 25% and that for delta 9-THC 22%. Topical coapplication of indomethacin, a cyclooxygenase inhibitor, completely blocked dilation, whereas the free radical scavengers superoxide dismutase and catalase or the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) had no effect on AN-induced dilation. The cerebrospinal fluid level of prostaglandin E2 increased only in response to 10(-7) M and greater AN and was not affected by delta 9-THC. [3H]AN superfused through the cranial window was 20% converted to arachidonic acid. These results show that AN and delta 9-THC can modulate cerebral arterioles, likely by stimulating release and metabolism of endogenous arachidonic acid. Whether dilation is due to vasodilator eicosanoids, or other vasoactive agents whose synthesis or release is cyclooxygenase dependent, is uncertain.
Differential regulation of G protein expression in rat hearts exposed to chronic hypoxia
Authors: Kacimi R. , Moalic J. M. , Aldashev A. , Vatner D. E. , Richalet J. P. , Crozatier B.
Published: December 2017

Chronic hypoxia impairs adrenergic responsiveness. A modulation of Gs and/or G1 protein alpha-subunits may be associated with the downregulation of the beta-adrenergic receptors previously found in chronic hypoxia. G protein gene expression and protein level and function in rat hearts exposed to a 30-day hypobaric chronic hypoxia were compared with control rat hearts. No change was observed in G alpha s mRNA levels in either right or left ventricles. In right ventricles, mRNA levels of G alpha i-2 increased by 40% (P < 0.05), but not in left ventricles. In both left and right ventricles, chronic hypoxia did not modify G alpha i-2 and G alpha s protein amounts, but significantly decreased functional activity of G alpha s. In conclusion, gene expression, protein levels of G alpha s and G alpha i-2, and activity of G alpha s do not change in parallel fashion with chronic hypoxia. In chronic hypoxic right ventricles, although the mRNA level of G alpha i-2 is increased, the protein level is unchanged. One potential mechanism of desensitization to catecholamines in chronic hypoxia appears to involve a decreased functional activity of G alpha s in spite of normal mRNA and protein levels
Effect of L-NAME on pressure-flow relationships in isolated rabbit lungs: role of red blood cells
Authors: Sprague R. S. , Stephenson A. H. , Dimmitt R. A. , Weintraub N. L. , Branch C. A. , McMurdo L. , Lonigro A. J. , Weintraub N. A.
Published: December 2017

Nitric oxide (NO) is produced by and relaxes pulmonary arteries and veins; however, a role for NO as a participant in the control of pulmonary vascular resistance (PVR) remains to be defined. Here we investigated the hypothesis that for NO to serve as a determinant of PVR in the rabbit requires the presence of blood. In isolated blood-perfused rabbit lungs, NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) increased PVR and the slope of the pressure-flow relationship. These effects of L-NAME were prevented by pretreatment with L-arginine. In contrast, in lungs perfused with a physiological salt solution, L-NAME had no effect on PVR or the pressure-flow relationship. The addition of washed red blood cells (RBCs) to physiological salt solution, but not the addition of plasma and platelets, restored the response to L-NAME. This effect of RBCs was not reproduced by increasing perfusate viscosity with dextran. These results suggest that, in the rabbit lung, NO is a determinant of PVR in the presence of blood. Moreover, that aspect of blood that permits the generation of NO appears to be related to the RBC and not to perfusate viscosity.
Muscle blood flow during exercise in sedentary and trained hypothyroid rats
Authors: McAllister R. M. , Delp M. D. , Thayer K. A. , Laughlin M. H.
Published: December 2017

Hypothyroidism is characterized by exercise intolerance. We hypothesized that active muscle blood flow during in vivo exercise is inadequate in the hypothyroid state. Additionally, we hypothesized that endurance exercise training would restore normal blood flow during acute exercise. To test these hypotheses, rats were made hypothyroid (Hypo) over 3-4 mo with propylthiouracil. A subset of Hypo rats was trained (THypo) on a treadmill at 30 m/min (15% grade) for 60 min/day 5 days/wk over 10-15 wk. Hypothyroidism was evidenced by approximately 80% reductions in plasma triiodothyronine levels in Hypo and THypo and by 40-50% reductions in citrate synthase activities in high oxidative muscles in Hypo compared with euthyroid (Eut) rats. Training efficacy was indicated by increased (25-100%) citrate synthase activities in muscles of THypo vs. Hypo. Regional blood flows were determined by the radiolabeled microsphere method before exercise and at 1-2 min of treadmill running at 15 m/min (0% grade). Preexercise muscle blood flows were generally similar among groups. During exercise, however, flows were lower in Hypo than in Eut for high oxidative muscles such as the red section of vastus lateralis [277 +/- 24 and 153 +/- 13 (SE) ml.min-1.100 g-1 for Eut and Hypo, respectively; P < 0.01] and vastus intermedius (317 +/- 32 and 187 +/- 20 ml.min-1.100 g-1 for Eut and Hypo, respectively; P < 0.01) muscles. Training (THypo) did not normalize these flows (168 +/- 24 and 181 +/- 24 ml.min-1.100 g-1 for red section of vastus lateralis and vastus intermedius muscles, respectively). Blood flows to low oxidative muscle, such as the white section of vastus lateralis muscle, were similar among groups (21 +/- 5, 25 +/- 4, and 34 +/- 7 ml.min-1.100 g-1 for Eut, Hypo, and THypo, respectively; P = NS). These findings indicate that hypothyroidism is associated with reduced blood flow to skeletal muscle during exercise, suggesting that impaired delivery of nutrients to and/or removal of metabolites from skeletal muscle contributes to the poor exercise tolerance characteristic of hypothyroidism.
cAMP enhances inducible nitric oxide synthase mRNA stability in cardiac myocytes
Authors: Oddis C. V. , Simmons R. L. , Hattler B. G. , Finkel M. S.
Published: December 2017

The effects of adenosine 3',5'-cyclic monophosphate (cAMP) on cardiac myocyte nitric oxide (NO) production were studied. Maximal nitrite (NO2(-)) production by cultured neonatal rat cardiac myocytes was achieved with 500 U/ml interleukin-1 beta (IL-1 beta) for 48 h (4.6 +/- 0.3 nmol/1.25 x 10(5) cells; n = 12). Cardiac myocytes exposed to 500 U/ml IL-1 beta for 48 h stained positively for inducible nitric oxide synthase (iNOS) by immunohistochemistry. Forskolin (FSK; adenylate cyclase stimulator) or dibutyryl cAMP (DBcAMP; membrane-permeable cAMP analogue) administration alone had no effect on NO2(-) production. The addition of FSK or DBcAMP to IL-1 beta significantly increased NO2-) levels vs. IL-1 beta alone (9.7 +/- 0.6 and 10.9 +/- 0.8 vs. 4.6 +/- 0.3 nmol/1.25 x 10(5) cells per 48 h, respectively; P < 0.01; n = 12). Semiquantitative reverse transcriptase-polymerase chain reaction revealed increased iNOS mRNA in myocytes treated with FSK+IL-1 beta or DBcAMP+IL-1 beta vs. those treated with IL-1 beta alone. The addition of FSK or DBcAMP to IL-1 beta increased iNOS mRNA half-life over IL-1 beta treatment alone (10.6, 11.7 vs. 2.4 h, respectively). Cardiac myocytes do not express iNOS in response to cAMP alone. Rather, cAMP enhances iNOS mRNA stability following cytokine exposure.
Hemorrhage alters plasma and cardiac enkephalins and catecholamines in anesthetized dogs
Authors: Mateo Z. , Napier L. , Gaugl J. F. , Barron B. A. , Caffrey J. L.
Published: December 2017

Intrinsic cardiac enkephalins participate in circulatory regulation either through the modification of vagal control or vasomotor sympathetic control. We extracted, chromatographed, and assayed plasma and myocardial enkephalins from anesthetized dogs under control conditions and during hemorrhagic hypotension (2 h at 40 mmHg). Blood samples were collected at intervals during the experiment. Blood gases were stable, pH declined to 7.1, and heart rate rose. Plasma catecholamines increased and remained high throughout hypotension. Catecholamine and enkephalin immunoreactivities (ir) were unchanged in time controls. Plasma methionine-enkephalin (ME) and peptide F increased twofold and methionine-enkephalin-arginine-phenylalanine (MEAP) and peptide B increased 10- to 30-fold during hypotension. Plasma proenkephalin (ProEnk) and other large enkephalins were unchanged during hypotension. Myocardial norepinephrine was greater in the atria and both atrial and ventricular contents were decreased after hypotension. ProEnk and peptide B accounted for > 60% of the cardiac enkephalins, and their ventricular concentrations were three to four times atrial concentrations. Myocardial MEAP concentrations were 15-25 times the ME concentrations in the same tissue extracts. Hypotension increased myocardial peptide B and ProEnk, and ME, MEAP, and peptide F were unchanged. The data demonstrate a preferential processing to or retention of MEAP rather than ME-ir enkephalins in the heart. The data also indicate that myocardial MEAP-ir enkephalins respond to changes in the circulatory environment and appear in the plasma during hemorrhagic hypotension.
Select dietary fatty acids attenuate cardiopulmonary dysfunction during acute lung injury in pigs
Authors: Murray M. J. , Kumar M. , Gregory T. J. , Banks P. L. , Tazelaar H. D. , DeMichele S. J.
Published: December 2017

We examined the effect of substituting linoleic acid (LA) with eicosapentaenoic acid (EPA) and gamma-linolenic acid (gamma-LA), precursors of trienoic and monoenoic eicosanoids, respectively, on acute lung injury (ALI). Three groups (n = 8/group) of pigs were fed enteral diets containing LA (diet A), EPA (diet B), or EPA+gamma-LA (diet C) for 8 days. ALI was then induced with a 0.1 mg/kg bolus of Escherichia coli endotoxin followed by a continuous infusion for 4 h (0.075 mg.kg-1.h-1). Pulmonary arterial and capillary wedge pressures, cardiac index (CI), arterial blood gases, arterial O2 content, and plasma thromboxane B2 (TxB2) were measured. Arterial PO2 decreased at 20 min in animals fed diet A. This change was attenuated with diets B and C. The EPA- and EPA + gamma-LA-enriched diets attenuated the fall in O2 delivery at 20 min, an improvement that was sustained throughout the 4-h study period with the EPA+gamma-LA-enriched diet only. This improvement in O2 delivery was due not only to the improved arterial PO2, but also to the maintenance of CI at 20 min in animals fed diets B and C and throughout the 4-h study period in animals fed diet C. At 4 h, TxB2 increased 10-fold over baseline in animals fed diet A, whereas in animals fed diets B and C the increase was only 3-fold. These decreased TxB2 levels in animals fed diets B and C correlate with an attenuation in the increase in pulmonary vascular resistance that was observed at 20 min after endotoxin infusion in animals fed diet A. These data suggest that specialized enteral diets enriched in EPA+gamma-LA improve gas exchange and O2 delivery, presumably in part through a modification of TxB2 production with a decrease in pulmonary vascular resistance and an increase in CI, during ALI.
Increased spillover and reduced clearance both contribute to rise in plasma catecholamines after birth in lambs
Authors: Smolich J. J. , Cox H. S. , Eisenhofer G. , Esler M. D.
Published: December 2017

We studied the relationship between changes in norepinephrine (NE) and epinephrine (Epi) levels, total body spillover, and total body clearance at birth. Near-term fetal lambs were chronically instrumented under general anesthesia with arterial, venous, and left atrial catheters. One week later, NE and Epi kinetics (isotope dilution methodology) and systemic blood flows (radioactive microspheres) were measured in fetuses and then in the same animals 1 and 4 h after cesarean section delivery. Comparing fetal and 1-h lambs 1) systemic output fell by 33% (P < 0.005); 2) systemic plasma NE increased by 144% (P < 0.005), and plasma Epi increased sevenfold (P < 0.005); 3) total body NE spillover rose by 63% (P < 0.01) and Epi spillover by fivefold (P < 0.005); and 4) total body NE clearance decreased by 34% (P < 0.005) and Epi clearance by 37% (P < 0.005). Systemic blood flow and kinetic data were similar in 1- and 4-h lambs and were therefore pooled to define the interrelationship among perinatal changes in NE and Epi plasma levels, spillover, and clearance. Between fetal and newborn lambs, plasma NE rose by 1,375 +/- 207 pg/ml, of which 604 +/- 119 pg/ml (approximately 44%) resulted from increased NE total body spillover and 771 +/- 160 pg/ml from reduced NE total body clearance. In the same interval, plasma Epi rose by 292 +/- 30 pg/ml, of which 123 +/- 18 pg/ml (approximately 42%) was due to Epi total body spillover and 169 +/- 19 pg/ml to reduced Epi total body clearance. These findings indicate that 1) sympathoadrenal activity increases with birth, and 2) increased total body spillover and reduced total body clearance contribute a similar portion of the plasma NE and Epi surge at birth.
Pulsatile perfusion system for ex vivo investigation of biochemical pathways in intact vascular tissue
Authors: Labadie R. F. , Antaki J. F. , Williams J. L. , Katyal S. , Ligush J. , Watkins S. C. , Pham S. M. , Borovetz H. S.
Published: December 2017

We have constructed and performed initial validation of an innovative perfusion system that allows exposure of intact segments of vascular tissue to realistic physiological and hemodynamic environments ex vivo. Computer-controlled opening and closing of an in-line gate valve allows generation of arterial pressure waveforms. The control algorithm predicted resultant pressure waveforms with a high degree of accuracy (Pearson correlation coefficient > 0.97). To document vascular homeostasis ex vivo, vasomotor bioassays and morphological studies were performed. The bioassays consisted of injecting epinephrine (2 x 10(-3) mg/ml) into the perfusion system followed by acetylcholine (100 microM) while concurrently measuring vessel diameter with a laser micrometer, significant vasomotion was measured for canine carotid arteries (n = 4) bioassayed after 1, 24, and 48 h of perfusion (P < 0.03). Additionally, human saphenous vein segments were perfused for 24 h (n = 4) and viewed with laser confocal scanning microscopy and transmission electron microscopy; photomicrographs show typical vascular morphology. We conclude that the vascular perfusion system described herein is well suited for investigating the response of intact vascular tissue to hemodynamic variables.
Platelet dense-granule centralization and the persistence of ADP secretion
Authors: Fogelson A. L. , Wang N. T.
Published: December 2017

After activation of a human platelet, its adenosine diphosphate (ADP)-containing dense granules are moved toward the platelet's center and release their ADP into the channels of the open canalicular system (OCS). Mathematical modeling is used to investigate a possible role of this centralization in prolonging the duration of ADP secretion compared with direct release at the platelet's plasma membrane. A key parameter is the degree to which the diffusion of ADP through the narrow and tortuous channels of the OCS is slower than ADP diffusion in plasma. For small but physiologically plausible values of this parameter and with use of literature-based values for the amount and concentration of dense-granule, ADP, the platelet serves as a continuing source of ADP; the concentration of ADP in the immediate environment of the platelet remains high enough to activate nearby platelets for 5-13 s, many times longer than if ADP were released directly at the plasma membrane.
Baroreflex gain: characterization using autoregressive moving average analysis
Authors: Patton D. J. , Triedman J. K. , Perrott M. H. , Vidian A. A. , Saul J. P.
Published: December 2017

To study heart rate baroreflex gain, autoregressive moving average (ARMA) analysis, a multivariate method that allows evaluation of the dynamic ("beat-to-beat") interactions between changes in biological signals, was used to evaluate the relationships between R-R interval and arterial blood pressure (BP) during random-interval breathing. Parameters obtained by ARMA analysis of spontaneous fluctuations in BP and R-R interval in 17 volunteers were used to model the response of R-R interval to a transient 1-mmHg increase in BP; the resulting impulse-response and step-response curves were compared with baroreflex gain measured using bolus injections of phenylephrine (PE) and sodium nitroprusside (SNP). Impulse-response curves for the systolic BP-R-R relationship showed an early (0-1 s) sharp maximum of 5.5 +/- 4.2 ms/mmHg, which was smaller in magnitude but linearly correlated with baroreflex gain derived from SNP (14.5 +/- 9.7 ms/mmHg; r = 0.80, P < 0.002) and PE (31.6 +/- 26.7 ms/mmHg; r = 0.53, P < 0.05) injections. A similar relationship was also found between the one-beat ARMA step response and SNP injection (r = 0.70, P = 0.01). The integrated step response of the BP-R-R relationship over 6 s was 6.4 +/- 4.1 ms/mmHg, with no correlation to baroreflex gain determined by SNP (r = 0.33, P = 0.20) or PE (r = -0.15, P = 0.57). In conclusion, quantification of baroreflex gain consistent with other techniques may be achieved by ARMA analysis without perturbing mean BP. Correlation of baroreflex gain obtained by bolus injection to early measures of baroreflex gain obtained from the ARMA maximum impulse and early step responses, but not the late step response, suggests that the ARMA method may provide additional information regarding the frequency dependent effects of BP on R-R-interval.
Myocardial morphometric changes related to decreased contractility after endotoxin
Authors: Goddard C. M. , Allard M. F. , Hogg J. C. , Walley K. R.
Published: December 2017

Decreased ventricular contractility during sepsis lasts much longer than the half-lives of inflammatory mediators that have been suggested to be myocardial depressant factors. Our hypothesis is that blood-borne factors may also cause myocardial structural changes, including damage and death of myocytes, associated with decreased ventricular contractility. We tested this hypothesis in an isolated rabbit heart perfused by a support rabbit. Support rabbits received 1 mg/kg endotoxin i.v. over 30 min (endotoxin group, n = 7) or vehicle (control group, n = 6). The slope of the end-systolic pressure-volume relationship, Emax, was used to measure contractility of the isolated heart. Five hours after endotoxin infusion, Emax decreased by 17 +/- 7% (P < 0.03) compared with 0 +/- 2% in the control group. Quantitative morphometric analysis of isolated hearts from the endotoxin group demonstrated an increased volume fraction of myocardial capillaries occupied by leukocytes (15.7 +/- 3.5 vs. 3.0 +/- 0.7% in the control group, P < 0.05), structurally abnormal myocytes (7.6 +/- 3.6 vs. 0.8 +/- 0.4%, P < 0.05), and interstitial edema (23.2 +/- 5.2 vs. 14.3 +/- 2.1%, P < 0.05). We conclude that blood-borne factors cause myocardial structural changes that may contribute to decreased ventricular contractility and may explain the prolonged decrease in ventricular contractility during sepsis.
Soluble forms of 5'-nucleotidase in rat and human heart
Authors: Skladanowski A. C. , Smolenski R. T. , Tavenier M. , de Jong J. W. , Yacoub M. H. , Seymour A. M.
Published: December 2017

Intracellular AMP hydrolysis probably produces sufficient adenosine in ischemic heart to exert physiological activity. Because data on adenosine-producing systems in human heart are scarce, we measured 1) formation of adenosine (catabolites) in ischemic human heart slices and 2) cytoplasmic 5'-nucleotidase activity in human left ventricle. We also measured the latter in rat ventricle and cardiomyocytes. During the first 5 min of incubation, adenosine production in slices (n = 5) equaled 26 +/- 10 (SD) nmol.min-1.g wet wt-1, and total AMP content was 0.81 +/- 0.46 mM. Cytoplasmic IMP-preferring 5'-nucleotidase activity in homogenates of human heart (N-II, 167 +/- 78 mU/g, n = 23) was significantly higher than that of the AMP-preferring one (N-I, 107 +/- 61 mU/g, n = 24). Both isozymes were two to three times more active in rat heart than in human heart. Rat cardiomyocytes contained comparable amounts of the two 5'-nucleotidases. Kinetics of N-I isolated from explanted human heart displayed features similar to the enzyme from animal heart, with a Michaelis constant of 1.5 mM under maximally stimulated conditions. This form can provide the amount of adenosine found in ischemic slices. In conclusion, human heart shows lower cytosolic 5'-nucleotidase activities than rat heart. Nevertheless, cytosolic 5'-nucleotidase activity in human heart can easily account for adenosine formation during ischemia.
Altered Ca2+ handling in ventricular myocytes isolated from diabetic rats
Authors: Lagadic-Gossmann D. , Buckler K. J. , Le Prigent K. , Feuvray D.
Published: December 2017

It has been suggested that alterations in intracellular Ca2+ homeostasis may be responsible for the development of diabetic cardiomyopathy. We have studied the effects of streptozotocin-induced diabetes on intracellular Ca2+ concentration ([Ca2+]i) in enzymically isolated rat ventricular myocytes. [Ca2+]i was measured using indo 1 or fluo 3. Both diastolic and peak systolic [Ca2+]i were reduced in diabetic compared with normal myocytes (by 52 and 43%, respectively). The decay phase of the systolic [Ca2+]i transient was slower in the diabetic myocyte compared with normal (time constant = 89.6 +/- 3.4 ms, n = 23, normal vs. 105.2 +/- 4.05 ms, n = 20, diabetic; P < 0.01). This led to a significant prolongation of the [Ca2+]i transient duration in the diabetic myocyte. In both normal and diabetic myocytes, increasing the frequency of electrical stimulation decreased peak systolic [Ca2+]i.The relationship between stimulation frequency and normalized peak systolic [Ca2+]i was the same for both normal and diabetic myocytes. We also found that the caffeine-induced Ca2+ release [used as an index of sarcoplasmic reticulum (SR) Ca2+ content] was significantly reduced in diabetic myocytes. These data indicate that SR Ca2+ content is decreased by diabetes. In the presence of thapsigargin (2.5 microM, an inhibitor of SR Ca(2+)-adenosinetriphosphatase), the magnitude and time course of stimulus-evoked [Ca2+]i transients were identical in both groups of myocytes, suggesting that Ca2+ influx and/or efflux across the plasma membrane is not significantly affected in diabetes. We conclude that 1) diabetes is associated with significant alterations in [Ca2+]i homeostasis and 2) the decrease in systolic [Ca2+]i and lengthening of the systolic [Ca2+]i transient result primarily from dysfunction of the SR.
Dorsal aortic impedance in stage 24 chick embryo following acute changes in circulating blood volume
Authors: Yoshigi M. , Hu N. , Keller B. B.
Published: December 2017

The effects of acute changes in circulating blood volume on embryonic vascular hemodynamics were evaluated with the use of input impedance. We simultaneously measured dorsal aortic pressure with a servo-null system and flow velocity with a 20-MHz pulsed Doppler system in n = 90 stage 24 chick embryos. We withdrew or infused 1,3, or 5 microliters of blood via a second-order vitelline vein (n = 10 per group). In addition, we withdrew and then infused or infused and then withdrew 3 microliters (n = 5 per group). Characteristic impedance, peripheral resistance, arterial compliance and elastance, and hydraulic power as well as basic hemodynamic parameters were evaluated on the basis of the three-element windkessel model. In response to withdrawal, mean and pulse pressure, mean flow, arterial compliance, and hydraulic power decreased, whereas peripheral resistance and arterial elastance increased in a dose-dependent manner. Results in response to infusion were converse in effect. Characteristic impedance was unchanged by volume alternations. Oscillatory fraction of hydraulic power was higher than mature circulation and remained relatively constant during interventions, which indicates well-regulated energy efficiency for vascular growth in the embryonic circulation. A hysteresis relevant to altered peripheral resistance was present after multiple interventions. Embryonic vasculature is sensitive to circulating blood volume and preserve blood pressure at the expense of blood flow. In the absence of autonomic innervation, embryonic vascular tone may be regulated by mechanical properties of the vessel (the law of Laplace) and/or vasoactive substances.
PKC inhibitors prevent endothelial dysfunction after myocardial ischemia-reperfusion in rats
Authors: Numaguchi K. , Shimokawa H. , Nakaike R. , Egashira K. , Takeshita A.
Published: December 2017

The intracellular mechanism for endothelial dysfunction after myocardial ischemia-reperfusion remains to be elucidated. It has been reported that activation of protein kinase C (PKC) occurs after myocardial ischemia-reperfusion and that the activation impairs endothelium-dependent relaxation. Thus we examined the role of PKC activation in the ischemia-reperfusion-induced endothelial dysfunction. Isolated rat hearts perfused with a constant flow were subjected to global ischemia for 15 min followed by reperfusion for 20 min. Coronary vascular responses to the endothelium-dependent vasodilators acetylcholine (ACh) and bradykinin (BK) and the endothelium-independent vasodilator sodium nitroprusside (SNP) were examined before and after the ischemia-reperfusion. Endothelium-dependent relaxations to ACh and BK were impaired after the ischemia-reperfusion, whereas endothelium-independent relaxations to SNP were unaffected. Pretreatment with a PKC inhibitor, staurosporine, H7, or calphostin C, prevented the impairments. Phorbol 12-myristate 13-acetate, a PKC-activating phorbol ester, attenuated the relaxations to ACh and BK but not those to SNP. These results suggest that PKC activation may be involved in part in the ischemia-reperfusion-induced endothelial dysfunction.
Innate protection of baboon myocardium: effects of coronary artery occlusion and reperfusion
Authors: Shen Y. T. , Fallon J. T. , Iwase M. , Vatner S. F.
Published: December 2017

To determine whether the extent of myocardial infarction differs in conscious baboons and pigs, both devoid of performed collaterals, the effects of 40 and 90 min of coronary artery (CA) occlusion (O) both followed by 4-7 days of CA reperfusion (R) were examined in both species. CAO reduced subendocardial and subepicardial blood flows similarly, almost to zero, in baboons and pigs for the entire CAO period. At 24 h of CAR, subendocardial blood flow had almost returned to pre-CAO control levels in baboons but remained significantly depressed in pigs. The major difference in hemodynamics during CAO and CAR was in left ventricular end-diastolic pressure, which rose by 6 +/- 1 mmHg in pigs over the initial 24-h reperfusion period but did not change significantly in baboons. These data on recovery of subendocardial blood flow and left ventricular end-diastolic pressure suggest larger infarcts in pigs than in baboons. Indeed, infarct size expressed as a function of area at risk (IF/AAR) was significantly greater (P <0.05) in pigs (53 +/- 4.9%) than in baboons (17 +/- 2.9%) with 90 min of CAO and 4-7 days of CAR. With 40 min of CAO and 4-7 days of CAR, IF/AAR was 46 +/- 3.6% in pigs, whereas in baboons the IF/AAR was minimal, i.e., 2 +/- 0.6%. Thus pigs and baboons were characterized by minimal coronary collateral circulation, but infarct size was significantly less in conscious baboons than in conscious pigs. Potentially, these differences could be explained, in part, by natural protective mechanisms and/or less reperfusion injury in primates. These results in primates may also help explain the salutary effects of CAR in patients at intervals longer than have been demonstrated to be beneficial in other experimental animals.
Bradykinin pathway is involved in acute hemodynamic effects of enalaprilat in dogs with heart failure
Authors: Barbe F. , Su J. B. , Guyene T. T. , Crozatier B. , Menard J. , Hittinger L.
Published: December 2017

To determine the role of the renin-angiotensin system and the bradykinin pathway in the mechanism of action of angiotensin-converting enzyme inhibitors in heart failure, the acute effects of enalaprilat (1 mg/kg) were compared with those of a renin inhibitor (ciprokiren, 1 mg/kg i.v.) in 10 chronically instrumented conscious dogs with heart failure induced by right ventricular pacing (3 wk, 240 beats/min). The effects of enalaprilat and ciprokiren on bradykinin infusion (3, 10, and 30 micrograms/min) and the effects of enalaprilat in the presence of the bradykinin B2 receptor antagonist Hoe-140 (10 micrograms/kg i.v.) were also examined. Both inhibitors significantly decreased mean aortic pressure and increased cardiac output. However, enalaprilat induced significantly greater hemodynamic effects than ciprokiren (mean aortic pressure, -13 +/- 3 vs. -6 +/- 1 mmHg; cardiac output, 0.4 +/- 0.1 vs. 0.15 +/- 0.1 l/min). Bradykinin infusion led to dose-dependent decreases in mean aortic pressure and increases in cardiac output that were not modified by pretreatment with ciprokiren but were potentiated 10-fold by enalaprilat. Hoe-140 significantly reduced the hemodynamic effects of enalaprilat. Thus endogenous bradykinin is involved in the acute hemodynamic effects of enalaprilat in experimental heart failure.
Effect of subarachnoid hemorrhage on dilatation of rat basilar artery in vivo
Authors: Sobey C. G. , Heistad D. D. , Faraci F. M.
Published: December 2017

Cerebral vasodilator responses are often impaired following subarachnoid hemorrhage (SAH). Because depolarization of vascular muscle may occur after SAH, we tested in vivo the hypothesis that SAH may augment dilatation in response to hyperpolarization due to activation of K+ channels. Anesthetized rats were studied two days after injection of saline or autologous blood into the cisterna magna. Diameter of the basilar artery in vivo was 224 +/- 5 microns (mean +/- SE) in saline-treated rats and 201 +/- 6 microns in SAH rats (P < 0.05). In control rats, acetylcholine (ACh), sodium nitroprusside (SNP), aprikalim and calcitonin gene-related peptide (CGRP; both activators of ATP-sensitive K+ channels), papaverine, 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP), and brain natriuretic peptide (BNP; an activator of particulate guanylate cyclase) produced concentration-dependent dilatation. In SAH rats, vasodilatation was impaired in response to ACh and SNP. In contrast, vasodilator responses to aprikalim and CGRP were augmented in SAH, rats (by two- to fourfold). Vasodilator responses to 8-BrcGMP, papaverine, and BNP were similar in both groups. Thus responses mediated by activation of soluble guanylate cyclase are selectively impaired by SAH, but responses to guanosine 3',5'-cyclic monophosphate are normal. Vasodilator responses to activation of ATP-sensitive K+ channels are augmented by SAH.