bluuebunny/crossref_metadata_2025 huggingface dataset:
Focal topographic changes in inflammatory microcirculation associated with lymphocyte slowing and transmigration
Authors: West Charles A. , He Chufa , Su Mei , Secomb Timothy W. , Konerding Moritz A. , Young Alan J. , Mentzer Steven J.
Published: December 2017

Microcirculation is the primary mechanism for delivering lymphocytes to inflammatory tissues. Blood flow within microvessels ensures a supply of lymphocytes at the blood-endothelial interface. Whether the structure of the inflammatory microcirculation facilitates lymphocyte transmigration is less clear. To illuminate the microcirculatory changes associated with lymphocyte transmigration, we used intravital videomicroscopy to examine the dermal microcirculation after application of the epicutaneous antigen oxazolone. Intravascular injection of fluorescein-labeled dextran demonstrated focal topographic changes in the microcirculation. These focal changes had the appearance of loops or hairpin turns in the oxazolone-stimulated skin. Changes were maximal at 96 h and coincided with peak lymphocyte recruitment. To determine whether these changes were associated with lymphocyte transmigration, lymphocytes obtained from efferent lymph of draining lymph nodes at 96 h were fluorescently labeled and reinjected into inflammatory microcirculation. Epifuorescence intravital video microscopy demonstrated focal areas were associated with lymphocyte slowing and occasional transmigration. In contrast, focal loops and lymphocyte slowing were rarely observed in the contralateral control microcirculation. Results suggest that structural adaptations in inflammatory microcirculation represented by focal topographic changes may contribute to regulation of tissue entry by recirculating lymphocytes.
Effects of ANG II on bradykinin receptor gene expression in cardiomyocytes and vascular smooth muscle cells
Authors: Kintsurashvili Ekaterina , Duka Irena , Gavras Irene , Johns Conrado , Farmakiotis Dimitrios , Gavras Haralambos
Published: December 2017

Bradykinin has vasodilatory and tissue-protective effects exerted via its B2type receptor, whereas the B1receptor is constitutively absent but inducible by inflammation and toxins. In previous studies, we found that B2receptor gene knockout mice exhibit overexpression of the B1receptor, which assumes a vasodilatory function and is further upgraded in renovascular hypertension. The present study was designed to explore the effects of excess angiotensin II (ANG II) on B1receptor and B2receptor gene expression in mouse cardiomyocytes and rat vascular smooth muscle cells (VSMC) in vivo (after a 3-day infusion of 30 ng/min ANG II in 11 wild-type and in 13 genetically engineered mice with deleted B2receptor gene) and in vitro (ANG II added in rat VSMC culture in the presence or absence of AT1or AT2receptor antagonist). Expression of B1and B2receptor mRNA was assessed by reverse transcriptase-polymerase chain reaction. ANG II infusion caused upregulation by 30% of the already significantly overexpressed B1receptors in cardiomyocytes of the B2receptor gene knockout mice, but in the wild-type mice it upregulated only the B2receptor mRNA by 47%. The addition of ANG II in VSMC culture produced a time-dependent induction of B1and upregulation of B2receptor gene expression, maximal at 3 h (by fivefold), declining almost to baseline by 24 h. The addition of losartan completely blocked this effect, whereas the AT2blocker PD-123319 made no difference, indicating that this is an AT1-mediated effect of ANG II. The data indicate that excess ANG II in subpressor doses in vivo upregulates expression of the B2receptor, but in its absence, the already overexpressed B1receptor is further upregulated, evidently assuming a counterregulatory response; in vitro, it transiently upregulates both bradykinin receptors.
Effects of augmented delivery of pyruvate on myocardial high-energy phosphate metabolism at high workstate
Authors: Ochiai Koichi , Zhang Jianyi , Gong Guangrong , Zhang Yi , Liu Jingbo , Ye Yun , Wu Xiaoyun , Liu Haiying , Murakami Yo , Bache Robert J. , Ugurbil Kamil , From Arthur H. L.
Published: December 2017

This study was performed to determine whether the fall in myocardial high-energy phosphates (HEP) that occurs during high workstates can be ascribed to either inadequate glycolytic pyruvate generation and conversion to acyl-CoA or limitation of long-chain fatty acid transport into the mitochondria. This was tested by using infusions of either pyruvate or butyrate in anesthetized dogs. Pyruvate was used because it bypasses the glycolytic sequence of reactions, activates pyruvate dehydrogenase, and increases mitochondrial NADH concentration ([NADHm]) in isolated myocardium, whereas butyrate enters the mitochondria without need for transport by the rate-limiting, palmitoyl-carnitine transporter. Increasing blood pyruvate from 0.16 ± 0.016 mM to >3 mM did not alter baseline HEP levels determined with31P nuclear magnetic resonance, but caused an increase in the rate-pressure product and a modest increase in myocardial oxygen consumption (MV˙o2). Infusion of dobutamine + dopamine (each 20 μg · kg−1· min−1iv) increased MV˙o2and caused decreases of myocardial phosphocreatine (PCr)/ATP. Pyruvate partially reversed the decrease of HEP levels produced by catecholamine stimulation, whereas butyrate had no effect. Neither pyruvate nor butyrate caused an increase of MV˙o2during catecholamine infusion. Deoxymyoglobin was not detected by1H magnetic resonance spectroscopyy in any group. The data demonstrate that carbon substrate availability to the mitochondria is not the only cause of the reduction of PCr/ATP that occurs at high workstates. Supplemental pyruvate (but not butyrate) attenuated the reduction of PCr/ATP during the high workstates; this may have resulted from direct effects on intermediary metabolism or from other effects such as the free radical scavenging activity of pyruvate.
Enhanced sympathoexcitatory and pressor responses to central Na+ in Dahl salt-sensitive vs. -resistant rats
Authors: Huang Bing S. , Wang Hao , Leenen Frans H. H.
Published: December 2017

An enhanced responsiveness to increases in cerebrospinal fluid (CSF) Na+ by high salt intake may contribute to salt-sensitive hypertension in Dahl salt-sensitive (S) rats. To test this hypothesis, sympathetic and pressor responses to acute and chronic increases in CSF Na+were evaluated. In conscious young (5–6 wk old) and adult (10–11 wk old) Dahl S and salt-resistant (R) rats as well as weight-matched Wistar rats, hemodynamic [blood pressure (BP) and heart rate (HR)] and sympathetic [renal sympathetic nerve activity (RSNA)] responses to 10-min intracerebroventricular infusions of artificial CSF (aCSF) and Na+-rich aCSF (containing 0.2–0.45 M Na+) were evaluated. Intracerebroventricular Na+-rich aCSF increased BP, RSNA, and HR in a dose-related manner. The extent of these increases was significantly larger in Dahl S versus Dahl R or Wistar rats and young versus adult Dahl S rats. In a second set of experiments, young Dahl S and R rats received a chronic intracerebroventricular infusion of aCSF or Na+-rich (0.8 M) aCSF (5 μl/h) for 14 days, with the use of osmotic minipumps. On day 14 in conscious rats, CSF was sampled and BP, HR, and RSNA were recorded at rest and in response to air stress, intracerebroventricular α2-adrenoceptor agonist guanabenz, intracerebroventricular ouabain, and intravenous phenylephrine and nitroprusside to estimate baroreflex function. The infusion of Na+-rich aCSF versus aCSF increased CSF Na+ concentration to the same extent but caused severe versus mild hypertension in Dahl S and Dahl R rats, respectively. After central Na+ loading, hypothalamus “ouabain” significantly increased in Dahl S and only tended to increase in Dahl R rats. Moreover, sympathoexcitatory and pressor responses to intracerebroventricular exogenous ouabain were attenuated by Na+-rich aCSF to a greater extent in Dahl S versus Dahl R rats. Responses to air-jet stress or intracerebroventricular guanabenz were enhanced by Na+-rich aCSF in both strains, but the extent of enhancement was significantly larger in Dahl S versus Dahl R. Na+-rich aCSF impaired arterial baroreflex control of RSNA more markedly in Dahl S versus R rats. These findings indicate that genetic control of mechanisms linking CSF Na+ with brain “ouabain” is altered in Dahl S rats toward sympathetic hyperactivity and hypertension.
Chronic estrogen depletion alters adenosine diphosphate-induced pial arteriolar dilation in female rats
Authors: Xu H. L. , Santizo R. A. , Koenig H. M. , Pelligrino D. A.
Published: December 2017

We examined pial arteriolar reactivity to a partially endothelial nitric oxide synthase (eNOS)-dependent vasodilator ADP as a function of chronic estrogen status. The eNOS-dependent portion of the ADP response was ascertained by comparing ADP-induced pial arteriolar dilations before and after suffusion of a NOS inhibitor, N ω-nitro-l-arginine (l-NNA; 1 mM) in intact, ovariectomized (Ovx), and 17β-estradiol (E2)-treated Ovx females. We also examined whether ovariectomy altered the participation of other factors in the ADP response. Those factors were the following: 1) the prostanoid indomethacin (Indo); 2) the Ca2+-dependent K+ (KCa) channel, iberiotoxin (IbTX); 3) the ATP-regulated K+(KATP) channel glibenclamide (Glib); 4) the KCa-regulating epoxygenase pathway miconazole (Mic); and 5) the adenosine receptor 8-sulfophenyltheophylline (8-SPT). In intact females, the eNOS-dependent (l-NNA sensitive) portion of the ADP response represented ∼50% of the total. The ADP response was retained in the Ovx rats but l-NNA sensitivity disappeared. On E2 replacement, the initial pattern was restored. ADP reactivity was unaffected by Indo, Glib, Mic, and 8-SPT. IbTX was associated with 50–80% reductions in the response to ADP in the intact group that was nonadditive with l-NNA, and 60–100% reductions in the Ovx group. The present findings suggest that estrogen influences the mechanisms responsible for ADP-induced vasodilation. The continued sensitivity to IbTX in Ovx rats, despite the loss of a NO contribution, is suggestive of a conversion to a hyperpolarizing factor dependency in the absence of E2.
Pregnancy and estradiol decrease GTPase activity in the guinea pig uterine artery
Authors: Buhimschi Irina A. , Hall Gentzon , Thompson Loren P. , Weiner Carl P.
Published: December 2017

The mechanisms by which pregnancy redistributes cardiac output in an organ-specific manner are poorly understood. We propose that it is consequential to estrogen-mediated alterations in G protein-mediated signal transduction. Aortas and uterine (UAs) and mesenteric arteries (MAs) were obtained from late-pregnant, nonpregnant, or ovariectomized guinea pigs chronically treated with 17β-estradiol. High-affinity GTPase activity was assayed enzymatically. The cGMP generated in response to the endothelium-dependent agonist ACh was measured in UAs incubated with or without cholera toxin (CTX, which inhibits Gsα). Pregnancy significantly decreased UA but not aorta or MA GTPase activity. 17β-Estradiol decreased UA GTPase activity compared with untreated ovariectomized animals. ACh increased cGMP in pregnant but not nonpregnant UAs. Pretreatment of nonpregnant UAs with CTX increased ACh-induced cGMP levels similar to pregnancy. Thus pregnancy and estradiol decrease the GTPase activity of a CTX-sensitive G protein in UAs, increasing receptor-dependent cGMP release. This alteration in receptor-mediated G protein coupling in UAs may contribute to the characteristic cardiovascular adaptation to pregnancy.
Ca2+influx mediates enhanced α2-adrenergic contraction in aortas from rats treated with NOS inhibitor
Authors: Mukundan Harshini , Kanagy Nancy L.
Published: December 2017

Previously, we reported that aortic segments from rats made hypertensive with the nitric oxide synthase inhibitor Nω-nitro-l-arginine (l-NNA) exhibit enhanced contractile sensitivity to both α2-adrenergic receptor (α2-AR) stimulation and to KCl-induced depolarization. We hypothesized that increased contractile responses to these agents was due to a change in the common effector L-type voltage-dependent calcium channel (VDCC). In aortic segments from control and l-NNA-treated rats, contraction to the α2-AR agonist UK-14304 stimulated Ca2+influx but released intracellular Ca2+only in control arteries. UK-14304-induced contraction was blocked by the VDCC antagonist nifedipine in both control and l-NNA aortas but contraction of aortas from l-NNA-treated rats was blocked by lower concentrations. Calcium imaging studies in fura 2-loaded freshly isolated aortic vascular smooth muscle cells also demonstrated UK-14304-stimulated Ca2+influx sensitive to nifedipine only in cells from l-NNA-treated rats. We conclude that α2-AR contraction in the rat aorta is mediated primarily by Ca2+influx and that l-NNA-induced hypertension increases the dependence of this contraction on VDCCs.
Natriuretic peptides like NO facilitate cardiac vagal neurotransmission and bradycardia via a cGMP pathway
Authors: Herring Neil , Zaman Junaid A. B. , Paterson David J.
Published: December 2017

We tested the hypothesis that natriuretic peptide receptors (NPRs) that are coupled to cGMP production act in a similar way to nitric oxide (NO) by enhancing acetylcholine release and vagal-induced bradycardia. The effects of enzyme inhibitors and channel blockers on the action of atrial natriuretic peptide (ANP), brain-derived natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) were evaluated in isolated guinea pig atrial-right vagal nerve preparations. RT-PCR confirmed the presence NPR B and A receptor mRNA in guinea pig sinoatrial node tissue. BNP and CNP significantly ( P < 0.05) enhanced the heart rate (HR) response to vagal nerve stimulation. CNP had no effect on the HR response to carbamylcholine and facilitated the release of [3H]acetylcholine during atrial field stimulation. The particulate guanylyl cyclase-coupled receptor antagonist HS-142–1, the phosphodiesterase 3 inhibitor milrinone, the protein kinase A inhibitor H89, and the N-type calcium channel blocker ω-conotoxin all blocked the effect of CNP on vagal-induced bradycardia. Like NO, BNP and CNP facilitate vagal neurotransmission and bradycardia. This may occur via a cGMP-PDE3-dependent pathway increasing cAMP-PKA-dependent phosphorylation of presynaptic N-type calcium channels.
Endothelial NO and prostanoid involvement in newborn and juvenile pig pial arteriolar vasomotor responses
Authors: Willis Adam P. , Leffler Charles W.
Published: December 2017

Specific cerebrovascular dilatory responses in newborn piglets are entirely prostanoid dependent, but require both nitric oxide (NO) and prostanoids in juveniles. We examined endothelial dependency and mechanisms of NO- and prostanoid-mediated cerebrovascular responses in anesthetized newborn and juvenile pigs implanted with closed cranial windows. Light/dye endothelial injury inhibited newborn and juvenile hypercapnic and bradykinin (BK) responses and inhibited dilation to acetylcholine in juveniles. Iloprost and NO act permissively in restoring light/dye inhibited newborn and juvenile responses, respectively. Differences in sensitivity to iloprost and sodium nitroprusside were not observed. Juvenile (not newborn) hypercapnic and BK cerebrovascular responses were sensitive to soluble guanylyl cyclase inhibition. Pial arteriolar diameter and cortical production of prostacyclin, cAMP, and cGMP in response to BK were measured under control conditions, after treatment with indomethacin and/or N ω-nitro-l-arginine methyl ester (l-NAME). Indomethacin inhibited BK responses in newborns. Juvenile responses were inhibited by l-NAME, and mildly by indomethacin. Cortical 6-keto-PGF1α, cAMP, and cGMP increased in response to BK in both age groups. Newborn cerebrovascular responses are largely NO independent, but NO becomes more important with maturation.
Aβ-peptides enhance vasoconstriction in cerebral circulation
Authors: Niwa Kiyoshi , Porter Valerie A. , Kazama Ken , Cornfield David , Carlson George A. , Iadecola Costantino
Published: December 2017

Amyloid-β (Aβ)-peptides are involved in the pathophysiology of Alzheimer's dementia. We studied the effects of Aβ on selected constrictor responses of cerebral circulation. Mice were anesthetized (by using urethane-chloralose) and equipped with a cranial window. Arterial pressure and blood gases were monitored and controlled. Cerebral blood flow (CBF) was monitored by a laser Doppler probe. Topical superfusion with Aβ1–40 (0.1–10 μM), but not with the reverse peptide Aβ40–1, reduced resting CBF (−29 ± 4% at 5 μM; P < 0.05) and augmented the reduction in CBF produced by the thromboxane analog U-46619 (+45 ± 3% at 5 μM; P < 0.05). Aβ1–40 or Aβ1–42 did not affect the reduction in CBF produced by hypocapnia. The reduction in resting CBF and the enhancement of vasoconstriction were reversed by treatment with the free radical scavengers superoxide dismutase or manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin. Substitution of the methionine residue in position 35 with norleucine, a mutation that abolishes the ability of Aβ to produce free radicals, abolished its vascular effects. Nanomolar concentrations of Aβ1–40 constricted isolated pressurized middle cerebral artery segments with intrinsic tone (−16 ± 3% at 100 nM; P < 0.05). We conclude that Aβ acts directly on cerebral arteries to produce vasoconstriction and to enhance selected constrictor responses. The evidence supports the idea that Aβ-induced production of reactive oxygen species plays a role in this effect. The vascular actions of Aβ may contribute to the deleterious effects resulting from accumulation of this peptide in Alzheimer's dementia.
Afferent baroreceptor discharge in pregnant rats
Authors: Laiprasert J. D. , Hamlin R. L. , Heesch C. M.
Published: December 2017

The baroreflex function curve is shifted to lower operating pressures, efferent sympathoexcitatory responses are attenuated, and sympathoinhibitory responses are potentiated in pregnant compared with virgin rats. It has been proposed that during pregnancy, elevated levels of 3α-hydroxy-dihydroprogesterone (3α-OH-DHP), a major metabolite of progesterone, may contribute to this difference, because acute intravenous administration of 3α-OH-DHP to virgin female rats mimics the effects of pregnancy on the baroreflex. To determine whether changes in the afferent limb might contribute to these baroreflex responses, the effects of pregnancy and 3α-OH-DHP on aortic depressor nerve activity were assessed in the current study. Baroreceptor discharge curves were obtained in Inactin-anesthetized rats by recording aortic nerve activity during ramp increases and decreases in mean arterial pressure (MAP) [intravenous phenylephrine and nitroprusside infusion] before [(control, C) 15 min (E1), and 30 min (E2) after 3α-OH-DHP (220 μg/kg bolus + 22 μg · kg−1 · min−1 infusion iv)]. Baseline blood pressure was significantly lower in pregnant (109 ± 4.4 mmHg) compared with virgin (122 ± 2.8 mmHg) rats. The only significant difference in the baroreceptor discharge curves was a decrease in curve midpoint in pregnant rats (virgin = 140 ± 2.7 vs. pregnant = 124 ± 3.6 mmHg). 3α-OH-DHP had no effect on afferent baroreceptor discharge curves in either virgin or pregnant groups. These results suggest that pressure-dependent baroreceptor resetting may contribute to a shift in the baroreflex curve to lower operating pressures, but cannot completely explain differences in baroreflex function between virgin and pregnant animals.
Brief murine myocardial I/R induces chemokines in a TNF-α-independent manner: role of oxygen radicals
Authors: Nossuli Tareck O. , Frangogiannis Nikolaos G. , Knuefermann Pascal , Lakshminarayanan Venkatesh , Dewald Oliver , Evans Alida J. , Peschon Jacques , Mann Douglas L. , Michael Lloyd H. , Entman Mark L.
Published: December 2017

Early chemokine induction in the area at risk of an ischemic-reperfused (I/R) myocardium is first seen in the venular endothelium. Reperfusion is associated with several induction mechanisms including increased extracellular tumor necrosis factor (TNF)-α, reactive oxygen intermediate (ROI) species formation, and adhesion of leukocytes to the venular endothelium. To test the hypothesis that chemokine induction in cardiac venules can occur by ROIs in a TNF-α-independent manner, and in the absence of leukocyte accumulation, we utilized wild-type (WT) and TNF-α double-receptor knockout mice (DKO) in a closed-chest mouse model of myocardial ischemia (15 min) and reperfusion (3 h), in which there is no infarction. We demonstrate that a single brief period of I/R induces significant upregulation of the chemokines macrophage inflammatory protein (MIP) -1α, -1β, and -2 at both the mRNA and protein levels. This induction was independent of TNF-α, whereas levels of these chemokines were increased in both WT and DKO mice. Chemokine induction was seen predominantly in the endothelium of small veins and was accompanied by nuclear translocation of nuclear factor-κB and c-Jun (AP-1) in venular endothelium. Intravenous infusion of the oxygen radical scavenger N-2-mercaptopropionyl glycine (MPG) initiated 15 min before ischemia and maintained throughout reperfusion obviated chemokine induction, but MPG administration after reperfusion had begun had no effect. The results suggest that ROI generation in the reperfused myocardium rapidly induces C-C and C-X-C chemokines in the venular endothelium in the absence of infarction or irreversible cellular injury.
Role of reactive oxygen species in IL-1β-stimulated sustained ERK activation and MMP-9 induction
Authors: Gurjar Milind V. , Deleon Jason , Sharma Ram V. , Bhalla Ramesh C.
Published: December 2017

We have recently demonstrated that interleukin-1β (IL-1β) stimulates matrix metalloproteinase-9 (MMP-9) induction. In this study we have investigated the roles of superoxide and extracellular signal-regulated kinase (ERK) activation in MMP-9 induction following exposure to IL-1β. IL-1β stimulated biphasic ERK activation in vascular smooth muscle (VSM) cells, a transient activation that reached a maximum at 15 min and declined to baseline levels within 1 h, and a second phase of sustained ERK activation lasting up to 8 h. To determine the role of ERK in IL-1β-stimulated MMP-9 induction, we treated cells with the specific ERK pathway inhibitor PD-98059 at different time intervals after IL-1β stimulation. Addition of PD-98059 up to 4 h after IL-1β stimulation significantly inhibited MMP-9 induction, suggesting a role for sustained ERK activation in MMP-9 induction. IL-1β treatment stimulated superoxide production in VSM cells that was inhibited by pretreatment of cells with the superoxide scavenger N-acetyl-l-cysteine (NAC) and also by overexpression of the human manganese superoxide dismutase (MnSOD) gene. Treatment of VSM cells with NAC selectively inhibited the sustained phase of ERK activation without influencing the transient phase, suggesting a role for reactive oxygen species in sustained ERK activation. In addition, both NAC treatment and MnSOD overexpression significantly inhibited IL-1β-stimulated MMP-9 induction ( P < 0.05). The results demonstrate that IL-1β-dependent MMP-9 induction is mediated by superoxide-stimulated ERK activation.
Myocardial metabolism of exogenous FDP is consistent with transport by a dicarboxylate transporter
Authors: Hardin Christopher D. , Lazzarino Giuseppe , Tavazzi Barbara , Di Pierro Donato , Roberts Tina M. , Giardina Bruno , Rovetto Michael J.
Published: December 2017

The extent to and the mechanism by which fructose-1,6-bisphosphate (FDP) crosses cell membranes are unknown. We hypothesized that its transport is either via band 3 or a dicarboxylate transporter. The question was addressed in isolated Langendorff rat hearts perfused under normoxic conditions. Groups of hearts received the following metabolic substrates (in mM): 5 FDP; 5 FDP + either 5, 10, or 20 fumarate; 10 FDP and either 5, 10, or 20 fumarate; or 5 FDP + 2 4,4′-dinitrostilbene-2,2′-disulfonate (DNDS), a band 3 inhibitor. FDP uptake and metabolism were measured as production of [13C]lactate from [13C]FDP or14CO2and [14C]lactate from uniformly labeled [14C]FDP in sample perfusates. During 30 min of perfusion, FDP metabolism was 12.4 ± 2.6 and 31.2 ± 3.0 μmol for 5 and 10 mM FDP, respectively. Addition of 20 mM fumarate reduced FDP metabolism over a 30-min perfusion period to 3.1 ± 0.6 and 6.3 ± 0.5 μmol for 5 and 10 mM FDP groups, respectively. DNDS did not affect FDP utilization. These data are consistent with transport of FDP by a dicarboxylate transport system.
Respiratory alkalosis does not alter NOx concentrations in human plasma and erythrocytes
Authors: Ishibashi Takaharu , Kubota Kaname , Himeno Mariko , Matsubara Taku , Hori Tomoyuki , Ozaki Kazuyuki , Yamozoe Masaru , Aizawa Yoshifusa , Yoshida Junko , Nishio Matomo
Published: December 2017

To test the hypothesis that NOx (NO[Formula: see text] and NO[Formula: see text], metabolites of NO) accumulates in red blood cells (RBC) in response to changes in Pco 2 and bicarbonate (HCO[Formula: see text]) concentration in blood, we examined the effect of changes in Pco 2 and HCO[Formula: see text] induced by hyperventilation in healthy adults on partitioning of NOx in whole blood. NOx in hemolysate was measured by a high-performance liquid chromatography-Griess system equipped with a C18 reverse phase column to trap hemoglobin, which enables determination of whole blood NOx concentration and calculation of NOx concentration in RBC with high accuracy and reproducibility. NOx concentration in RBC was lower than that in plasma, and equilibrium between plasma and RBC was achieved rapidly after addition of NO[Formula: see text]. Changes in Pco 2 and HCO[Formula: see text] by hyperventilation failed to influence NOx concentrations in both plasma and RBC. Plasma NOx concentrations correlated with whole blood NOx and RBC NOx concentrations. Our results indicate that changes in Pco 2 or HCO[Formula: see text] induced by hyperventilation do not influence NOx compartmentalization in plasma and RBC.
Activated polymorphonuclear cells increase sickle red blood cell retention in lung: role of phospholipids
Authors: Haynes Johnson , Obiako Boniface
Published: December 2017

This study investigates the role of the activated polymorphonuclear cell (APMN) products on sickle red blood cell (SRBC) retention/adherence in the pulmonary circulation. Isolated rat lungs were perfused with51Cr-labeled normal RBCs (NRBC) or SRBCs (10% hematocrit) suspensions ± PMNs. Specific activities of lung and perfusate were measured and retention (the number of SRBC/g lung) was calculated. SRBC retention was 3.5 times greater than NRBC retention. PMN activation was required to increase SRBC retention. Supernatants from APMN increased SRBC retention, which suggested soluble products such as oxidants, PAF, and/or leukotriene (LTB4) are involved. Heat inactivation of PMN NADPH oxidase had no effect on retention. Whereas neither platelet-activating factor (PAF) nor LTB4(secreted by APMN) increased SRBC retention, PAF+LTB4did. The PAF antagonist, WEB-2170, attenuated SRBC retention mediated by PAF+LTB4and APMNs. Similarly, zileuton (5-lipoxygenase inhibitor) attenuated APMN-mediated SRBC retention. We conclude the concomitant release of PAF and LTB4from APMN is involved in the initiation of microvascular occlusion by SRBCs in the perfused rat lung.
Sympathetic nonnoradrenergic cutaneous vasoconstriction in women is associated with reproductive hormone status
Authors: Stephens Dan P. , Bennett Lee Ann T. , Aoki Ken , Kosiba Wojciech A. , Charkoudian Nisha , Johnson John M.
Published: December 2017

We tested whether a nonnoradrenergic component of reflex vasoconstriction of skin blood flow (SkBF) is sensitive to female reproductive hormones. Six women taking oral contraceptives underwent whole-body cooling during high-hormone (HH) and low-hormone (LH) phases of oral contraceptive use. SkBF was monitored by laser Doppler flowmetry (LDF) at sites treated by intradermal injection of yohimbine-propranolol (5 mM and 1 mM; YOPR) to block the effects of norepinephrine (NE) or at saline (Sal) control sites. Mean arterial pressure (MAP) was measured with the use of the Penaz method. Cutaneous vascular conductance (CVC = LDF/mean arterial pressure) was expressed as a percentage of baseline. Whole body skin temperature was decreased from 34 to 31°C in HH and LH. In both HH and LH, CVC at Sal-treated sites was reduced during cooling (CVC = 53.1 ± 8.6% and 54.4 ± 4.2%, both P < 0.05). In HH, CVC at YOPR sites was reduced during cooling (78.8 ± 3.6%, P < 0.05). In contrast, CVC at YOPR sites was not reduced significantly during cooling in LH (CVC = 95.9 ± 2.8%, P > 0.05). Across phases, CVC at YOPR sites during cooling was significantly different ( P < 0.05). After cooling, the effects of NE at YOPR sites were completely blocked. These data indicate that a nonnoradrenergic mechanism of reflex cutaneous vasoconstriction is present in women and is associated with reproductive hormone status.
Oxidant species trigger late preconditioning against myocardial stunning in conscious rabbits
Authors: Tang Xian-Liang , Takano Hitoshi , Rizvi Ali , Turrens Julio F. , Qiu Yumin , Wu Wen-Jian , Zhang Qin , Bolli Roberto
Published: December 2017

Conscious rabbits underwent six 4-min occlusion and 4-min reperfusion cycles for 3 consecutive days ( day 1, 2, and 3); on day 1, rabbits received intravenous vehicle [preconditioning (PC)] ( group I, n = 6), superoxide dismutase (SOD; group II, n = 5), catalase ( group III, n = 6), or the hydroxyl radical (· OH) and peroxynitrite (ONOO−) scavenger N-2-mercaptopropionyl glycine (MPG [group IV], n = 6). In the PC group, the recovery of systolic wall thickening (WTh) after the sixth reperfusion was markedly improved on days 2 and 3 compared with day 1 and the total deficit of WTh was correspondingly reduced, indicating a late PC effect against myocardial stunning. Neither SOD nor catalase had any significant effect on the severity of stunning on day 1 or on the development of late PC on days 2 and 3, despite high plasma levels. In contrast, MPG markedly attenuated the severity of stunning on day 1 and prevented the development of late PC on day 2. Two additional groups of rabbits received an intracoronary infusion of vehicle ( group V, n = 4) or the reactive oxygen species (ROS) generating solution [cumene hydroperoxide (CuOOH, group VI, n = 7)] on day 0, and were then subjected to the six occlusion/reperfusion cycles on days 1, 2, and 3. In group VI, infusion of CuOOH elicited a late PC effect 24 h later (on day 1). Taken together, these results demonstrate that oxidant species play an essential role in triggering the development of late PC against stunning in conscious rabbits. The fact that late PC was blocked by MPG and mimicked by CuOOH implicate ONOO−and/or ·OH as the oxygen species responsible for the initiation of this phenomenon. In addition, the finding that exogenous ROS (CuOOH) reproduced the phenotype of late PC indicates that ROS are not only necessary but also sufficient to trigger this defensive adaptation of the heart to stress.
Targeted disruption of the gene for natriuretic peptide receptor-A worsens hypoxia-induced cardiac hypertrophy
Authors: Klinger James R. , Warburton Rod R. , Pietras Linda , Oliver Paula , Fox Jennifer , Smithies Oliver , Hill Nicholas S.
Published: December 2017

Targeted disruption of the gene for natriuretic peptide receptor-A (NPR-A) worsens pulmonary hypertension and right ventricular hypertrophy during hypoxia, but its effect on left ventricular mass and systemic pressures is not known. We examined the effect of 3 wk of hypobaric hypoxia (0.5 atm) on right and left ventricular pressure and mass in mice with 2 (wild type), 1, or 0 copies of Npr1, the gene that encodes for NPR-A in mice. Under normoxic conditions, right ventricular peak pressure (RVPP) was greater in 0 than in 2 copy mice, but there were no genotype-related differences in carotid artery PP (CAPP). The left ventricular free wall weight-to-body weight (LV/body wt) ratio was greater in 0 than in 2 copy mice and there was a trend toward a greater right ventricular weight-to-body weight (RV/body wt) ratio. Three weeks of hypoxia increased RVPP and RV/body wt in all genotypes. The increase in RVPP was similar in all genotypes (11–14 mmHg), but the hypoxia-induced increase in RV/body wt was more than twice as great in 0 copy mice than in 2 copy mice (1.11 ± 0.06 to 2.65 ± 0.46 vs. 0.96 ± 0.04 to 1.4 ± 0.09, P < 0.05). Chronic hypoxia had no effect on CAPP in any genotype and did not effect LV/body wt in 1 or 2 copy mice, but increased LV/body wt 41% in 0 copy mice. We conclude that absent expression of NPR-A worsens right ventricular hypertrophy and causes left ventricular hypertrophy during exposure to chronic hypoxia without increasing pulmonary or systemic arterial pressure responses.
Continual recordings of cardiac sympathetic nerve activity in conscious sheep
Authors: Jardine David L. , Charles Christopher J. , Melton Ian C. , May Clive N. , Forrester Melanie D. , Frampton Christopher M. , Bennett Sinclair I. , Ikram Hamid
Published: December 2017

Cardiac sympathetic nerve activity (CSNA) is of major importance in the etiology of heart disease but is impossible to measure directly in humans. Ovine and human cardiovascular systems are similar; therefore, we have developed a method for the daily recording of CSNA in conscious sheep. After thoracotomy, electrodes were glued into the left thoracic cardiac nerve and CSNA, blood pressure (BP), and heart rate were recorded daily. Satisfactory recordings ≥7 days of CSNA were obtained in 11 of 28 sheep (40%), mean recording time 10.6 days, range 7-47. During the first week, CSNA decreased gradually from 78 ± 8 at baseline to 60 ± 7 bursts/min on day 5( P = 0.02) or from 76 ± 9 to 57 ± 7 bursts/100 beats on day 7 ( P = 0.04). Similarly, BP decreased from 103 ± 4 to 94 ± 4 mmHg ( P = 0.03). Low-frequency heart rate variability decreased from 0.12 ± 0.02 to 0.06 ± 0.02 ms2on day 6 ( P = 0.004) but was not correlated to CSNA. In conclusion, CSNA that can be continually recorded in conscious sheep decreases during the first week postsurgery and, thereafter, stabilizes. This model should provide valuable insights in future investigations of cardiac disease.
Forebrain renin-angiotensin system has a tonic excitatory influence on renal sympathetic nerve activity
Authors: Wei Shun-Guang , Felder Robert B.
Published: December 2017

All elements of the renin-angiotensin system (RAS) are present in the forebrain, particularly in circumventricular organs surrounding the third cerebral ventricle. We tested the hypothesis that forebrain angiotensin-converting enzyme (ACE) has a tonic excitatory influence on sympathetic drive. Neurally intact and sinoaortic-denervated pentobarbital-anesthetized rats were treated with forebrain-directed intracarotid artery (ICA) versus intravenous injections of angiotensin I (ANG I) and of the ACE inhibitor captopril. In intact rats, ICA ANG I elicited a rise in arterial pressure and a concomitant reduction in renal sympathetic nerve activity (RSNA; ICA captopril elicited the opposite responses). In barodenervated rats, ICA ANG I increased and ICA captopril decreased arterial pressure and RSNA in parallel; intravenous ANG I had no effect on RSNA. The findings suggest that the intrinsic forebrain RAS has a tonic excitatory influence on sympathetic drive that is overshadowed in normal rats by baroreflex mechanisms, but may assume a more prominent role in pathophysiological states (e.g., heart failure) in which baroreflex mechanisms are impaired and RAS activity is augmented.
Effect of aldosterone and of plasma extracts on a rat heart-lung preparation
Authors: Ballard Kathryn , Lefer Allan , Sayers George
Published: December 2017

Heart-lungs from intact rats were perfused with blood from intact rats (intact-intact preparations) or with blood from adrenalectomized rats (intact-adrenalectomized preparations). Left ventricular work index (LVWI) was employed to evaluate performance of the heart-lung and calculated as the product of cardiac output and mean arterial blood pressure. In confirmation of a previous report from this laboratory, LVWI was less for intact-adrenalectomized preparations than for intact-intact preparations. Aldosterone, added to perfusion blood from adrenalectomized rats to make a concentration of 2 x 10–3, 8 x 10–3 or 3.2 x 10–2 µg/100 ml, increased LVWI of the intact-adrenalectomized preparation to that of the intact-intact preparation. Extracts of plasma from intact rats, which may be expected to contain corticosteroids, were also capable of increasing LVWI of the intact-adrenalectomized preparation. Extracts of plasma from adrenalectomized rats were inactive.
Tissue slice water and electrolyte metabolism of adult cats during cold exposure
Authors: Boatman Joseph B. , Pisarcik Patricia A. , Rabinovitz Marvin J.
Published: December 2017

Liver, kidney and thyroid slices were taken from adult cats exposed to 0°C from 2 hours to 15 days, and incubated under oxygenation in Krebs-Ringer phosphate buffer media for 30 minutes at 38°C. Pre- and postincubation wet weight/dry weight and Na24 exchanges were measured. I131 exchange was measured in thyroid slices. At 1–12 hours of cold exposure kidney cortex, liver and thyroid exhibited increased uptake of water from the media, declining at 4–6 days of cold exposure below control values. By 8–12 days these values returned to control levels or above. Na24 uptake by kidney and liver slices and I131 uptake by thyroid was inversely proportional to values found for water uptake. I131 uptake by thyroid declined with time of cold exposure; by 8–12 days, I131 uptake from the media had significantly increased, reaching 45% above control values on the 15th day. It was concluded cold exposure placed severe and immediate metabolic demands upon the tissues, resulting in impaired tissue electrolyte and water equilibrium.
Splanchnic baroreceptors in the dog
Authors: Selkurt Ewald E. , Rothe Carl F.
Published: December 2017

The hemodynamic effects of systemic blood pressure of varying intraluminal pressure in the celiac and superior mesenteric arteries through a range of 20–210 mm Hg were examined in dogs. Responses were compared to a smaller series of cats. Systemic arterial pressure in the dogs rose and fell only about 10% from the mean through this range of decrease and increase, respectively, in the splanchnic arteries. By comparison, comparable decrements of pressure in the celiac and mesenteric arteries of cats gave marked increases in pressure averaging 74%. It was found that the sino-aortic reflexes held the splanchnic mechanism in check in the dog for with sinus denervation the response was significantly increased. Evidence indicated that the responses could be explained on a hydrodynamic basis and that splanchnic baroreceptor reflex activity in the dog is slight.
Modulatory influence on cerebral cortical optic response from the carotid sinus area
Authors: Koella Werner P. , Smythies John R. , Levy Charles K. , Czicman John S.
Published: December 2017

We have previously shown that serotonin injected intracarotidly exerts its effect on the cerebral evoked response through at least three receptor fields: the carotid sinus (factor X), the brain stem (Y) and the specific sensory synapses (Z). To demonstrate factor X directly, Dial-anesthetized cats were prepared for recording of the cortical visual response. The normally innervated carotid sinus area was isolated from the circulation and cannulated for perfusion with Ringer's solution. Depending upon the dose, serotonin added to the perfusion fluid induced enhancement or reduction of the amplitude of the evoked response. With doses ranging from 0.019 to 10.0 µg a dose-response curve similar to the one calculated in the previous series was found. Also, the time course of the changes in potential amplitude was similar to the one in the previous series. In order to match in this way the results of the present and the previous series a correcting factor of approximately 32 had to be introduced; for example the effect produced by 10.0 µg in the previous series was similar to the one induced by 0.3125 µg in the present series. This divergence is plausibly explained on the basis of the different perfusion rate used in the two series.
Tolerance of irradiated animals to prolonged hypoxia
Authors: Newsom Bernard D. , Kimeldorf Donald J.
Published: December 2017

Rats were maintained at a simulated altitude of 15,000 feet for 30 days following exposure to x-ray doses in the 30-day ld10–90 range. Nonirradiated rats maintained concurrently tolerated this level of altitude without apparent distress. The effect of prolonged altitude exposure on the irradiated animals was equivalent to a 100 r decrease in the x-ray dose necessary to produce a 50% mortality response at 30 days. Mice as well as rats exhibited a greater mortality response to a given x-ray dose if maintained at altitude during the postirradiation period. Red blood cell volume, hemoglobin and hematocrit values were determined at intervals during 30 days of exposure to 15,000 feet simulated altitude following 450 r or 0 r, and were compared to those for similar groups maintained at sea level. The blood picture of irradiated animals during the 1st 20 days at altitude more closely resembled irradiated animals maintained at sea level than the altitude controls. These data suggest that the increased mortality of animals maintained at altitude following radiation exposure is the result of a reduced blood cell volume and an inadequate erythropoietic response during exposure to hypoxia.
Effects of ouabain on Ca45 entry in quiescent and electrically driven rabbit atria
Authors: Sekul Antonio A. , Holland William C.
Published: December 2017

The effects of ouabain (4 x 10–8 to 1 x 10–6 m) on the rates of Ca45 entry into quiescent and electrically driven rabbit atria have been compared. Ouabain had no effect on Ca45 entry on quiescent preparations but increased the uptake in those electrically driven. The calculated entry per impulse was estimated to be 0.0027 pmole/cm2 in controls and 0.0129 pmole/cm2 in ouabain-treated preparations. It is concluded that digitalis glycosides only affect calcium exchange that accompanies the process of activation.
Effect of spinal cord transection on hyperlipemia induced by Tween 80
Authors: Correll James W. , Simpson Charles W.
Published: December 2017

Higher serum total lipid concentrations normally found in female rabbits indicate a sex-linked difference in homeostatic regulation of serum lipids. Following intravenous administration of Tween 80 an immediate increase in the serum total lipid concentration resulted from the addition of Tween and was similar in all experiments. A secondary increase in serum lipids of endogenous origin became maximum 6 hours after injection and differed in normal rabbits depending on sex. Transection of the spinal cord at the 5th thoracic level or above greatly reduced the secondary increase in both sexes, while transection at the 10th thoracic level or below did not change the response in females but reduced it in males. Complete adrenalectomy did not reduce the secondary increase in either sex. The findings indicate that the central nervous system, with peripheral connections between the 5th and 10th thoracic levels of the spinal cord, is important in the genesis of hyperlipemia induced by the surface-active agent, Tween 80. A function of testicular tissue dependent on innervation is also suggested.
Effects of bile acids on fecal excretion of end products of cholesterol metabolism
Authors: Beher William T. , Baker Gizella D. , Anthony William L.
Published: December 2017

The influence of bile acids on liver cholesterol mobilization and on the excretion of fecal end products of cholesterol-4-C14 metabolism was studied in mice. Tissue cholesterol was elevated by feeding a fat-free diet containing cholesterol or cholesterol-4-C14. The mice were then divided into three groups: cholic acid treated, control and hyodeoxycholic acid treated. Fecal collections were made at intervals for 20 days, and steroids extracted and fractionated. The quantity of the sterol fractions and the C14 activity of the sterol and bile acid fractions were determined. Regression of hepatic cholesterol was followed at the same time intervals. Cholic acid inhibited liver cholesterol mobilization, while hyodeoxycholic acid effected a rapid regression of liver cholesterol to subnormal levels. Cholic acid depressed total steroid excretion, the depression occurring in the bile acid fraction; while excretion of fecal sterols remained relatively unaltered. Hyodeoxycholic acid greatly increased total steroid excretion. The increase was in the sterol fraction (95%), while bile acid excretion was depressed. These data indicate that bile acids are important factors in determining the rate and route of cholesterol metabolism.
Effect of thioridazine and chlorpromazine on rat liver hemodynamics
Authors: Plaa Gabriel L. , McGough Edwin C. , Blacker Gerry J. , Fujimoto James M.
Published: December 2017

Evidence is presented which indicates that two phenothiazine derivatives—thiroidazine and chlorpromazine— increase hepatic vascular resistance in isolated perfused rat livers. These substances produce the following: a) a decrease in perfusate flow through the organ, b) an increase in portal pressure and c) a decrease in organ weight. These effects were demonstrated with doses as low as 4 mg but were quantitatively more pronounced and of longer duration with higher doses. Tachyphylaxis did not occur. The effects could be blocked with sodium nitrite. Both phenothiazines were found to produce liver ischemia in anesthetized, laparotomized rats. Thioridazine was found to raise portal pressure in anesthetized, laparotomized cats in spite of a marked decrease in mean arterial pressure.
Distribution of sulfate in blood and between cerebrospinal fluid and plasma in vivo
Authors: Richmond Jonas E. , Hastings A. Baird
Published: December 2017

The distribution of carrier-free radiosulfate in body fluids was studied after intravenous and intrathecal administration of Na2S35O4 to dogs and rabbits. Plasma radiosulfate exchanged with red blood cell sulfate in 30–60 minutes to give ratios of distribution of approximately 0.40 in the circulating blood of rabbits and dogs. Exchange of plasma radiosulfate with cerebrospinal fluid sulfate was complete in 2–3 hours. Intrathecally administered radiosulfate exchanged with plasma and body sulfate in 5–8 hours. The ratio of the concentration of radiosulfate in cerebrospinal fluid to its concentration in plasma was found to reach a steady-state value of approximately 0.12–0.18 in anesthetized dogs. The rate constants of the penetration of radiosulfate from plasma water into red blood cell and cerebrospinal fluid water was found to be K = 0.03 and K = 0.01/ min., respectively, after intravenous injections of Na2S35O4 into dogs. The route of administration of the tracer did not alter the final distribution ratios appreciably.
Oxidative phosphorylation in liver mitochondria from cold-exposed rats
Authors: Lianides Sylvia Panagos , Beyer Robert E.
Published: December 2017

The efficiency of oxidative phosphorylation in mitochondrial preparations from rats exposed to 25°C and to 0°–2°C for 1 day, 2 weeks, 1 month and 3–6 months was compared by direct in vitro estimation of the P/O ratio and by measurement of respiratory control. In addition, other criteria, such as aging and Ca++ sensitivity, were used to investigate the lability of the phosphorylative systems under conditions which tend to alter the mitochondria structure. The results confirm earlier reports that in mitochondria from rats chronically exposed to cold oxidative phosphorylation is depressed, and show further that the latter are more susceptible than that of the controls to factors which uncouple this process. Measurements of optical densities also indicate that the structure of mitochondria from cold-acclimated rats is the more susceptible to aging. Such changes did not appear in rats exposed to the cold for only 1 day.