bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of NO in the O2 and CO2 responsiveness of cerebral and ocular circulation in humans
Authors: Schmetterer Leopold , Findl Oliver , Strenn Karin , Graselli Ursula , Kastner Johannes , Eichler Hans-Georg , Wolzt Michael
Published: December 2017

It is well known that changes in [Formula: see text] or[Formula: see text] strongly influence cerebral and ocular blood flow. However, the mediators of these changes have not yet been completely identified. There is evidence from animal studies that NO may play a role in hypercapnia-induced vasodilation and that NO synthase inhibition modulates the response to hyperoxia in the choroid. Hence we have studied the effect of NO synthase inhibition by N G-monomethyl-l-arginine (l-NMMA, 3 mg/kg over 5 min as a bolus followed by a continuous infusion of 30 μg ⋅ kg−1 ⋅ min−1) on the changes of cerebral and ocular hemodynamic parameters elicited by hypercapnia and hyperoxia in healthy young subjects. Mean flow velocities in the middle cerebral artery and the ophthalmic artery were measured with Doppler ultrasound, and ocular fundus pulsation amplitude, which estimates pulsatile choroidal blood flow, was measured with laser interferometry. Administration ofl-NMMA reduced ocular fundus pulsations (−19%, P < 0.005) but only slightly reduced mean flow velocities in the larger arteries. Hypercapnia ([Formula: see text] = 48 mmHg) significantly increased mean flow velocities in the middle cerebral artery (+26%, P < 0.01) and fundus pulsation amplitude (+16%, P < 0.005) but did not change mean flow velocity in the ophthalmic artery. The response to hypercapnia in the middle cerebral artery ( P < 0.05) and in the choroid ( P < 0.05) was significantly blunted by l-NMMA. On the contrary,l-NMMA did not affect hyperoxia-induced ([Formula: see text] = 530 mmHg) hemodynamic changes. The hemodynamic effects ofl-NMMA (at baseline and during hypercapnia) were reversed by coadministration ofl-arginine. The present study supports the concept that NO has a role in hypercapnia-induced vasodilation in humans.
Surfactant regulates pulmonary fluid balance in reptiles
Authors: Orgeig Sandra , Smits Allan W. , Daniels Christopher B. , Herman Jay K.
Published: December 2017

Reptilian lungs are potentially susceptible to fluid disturbances because they have very high pulmonary fluid filtration rates. In mammals, pulmonary surfactant protects the lung from developing alveolar edema. Reptiles also have an order of magnitude more surfactant per square centimeter of respiratory surface area compared with mammals. We investigated the role of reptilian surfactant 1) in the entry of vascularly derived fluid into the alveolar space of the isolated perfused lizard ( Pogona vitticeps) lung and 2) in the removal of accumulated fluid from the alveolar space of the isolated perfused turtle ( Trachemys scripta) lung by both the pulmonary venous and lymphatic circulations. The flux of fluorescent (fluorescein isothiocyanate) inulin from the vasculature into the alveolar compartment increased 60% after the removal of surfactant, but capillary fluid filtration over a 10-min period was not affected. Surfactant removal decreased alveolar inulin clearance by both the pulmonary venous circulation and the pulmonary lymphatic system ∼1.5- and 3-fold, respectively. In reptiles, fluid flux from capillary to air space must occur indirectly via the interstitium. In the absence of surfactant, this may result in interstitial drying, which affects both pulmonary venous and pulmonary lymphatic clearance of alveolar fluid.
Cardiac β-adrenergic receptor function in fetal sheep exposed to long-term high-altitude hypoxemia
Authors: Browne Vaughn A. , Stiffel Virginia M. , Pearce William J. , Longo Lawrence D. , Gilbert Raymond D.
Published: December 2017

In this study, we hypothesized that a reduction in β-adrenergic receptor number or a decrease in functional coupling of the receptor to the adenylate cyclase system may be responsible for the blunted inotropic response to isoproterenol observed in fetal sheep exposed to high altitude (3,820 m) from 30 to 138–142 days gestation. We measured the contractile response to increasing doses of isoproterenol and forskolin in papillary muscles from both ventricles, estimated β-adrenergic receptor density (Bmax) and ligand affinity ( Kd) using [125I]iodocyanopindolol, and measured adenosine 3′,5′-cyclic monophosphate (cAMP) levels before and after maximally stimulating doses of isoproterenol and forskolin. Left ventricular wet weight was unchanged, but right ventricular weight was 20% lower than controls. At the highest concentration of isoproterenol (10 μM), maximum active tension was 32 and 20% lower than controls in hypoxemic left and right ventricles, respectively. The contractile response to forskolin was severely attenuated in both hypoxemic ventricles. Bmaxwas unchanged in the left ventricle, but increased by 55% in the hypoxemic right ventricle. Kdwas not different from controls in either ventricle. Basal cAMP levels were not different from controls, but isoproterenol-stimulated and forskolin-stimulated cAMP levels were 1.4- to 2-fold higher than controls in both hypoxemic ventricles. The results suggest mechanisms downstream from cAMP in the β-adrenergic receptor pathway are responsible for the attenuated contractile responses to isoproterenol.
Role of carbohydrate type on diet selection in neuropeptide Y-stimulated rats
Authors: Glass Michael J. , Cleary James P. , Billington Charles J. , Levine Allen S.
Published: December 2017

We tested whether carbohydrate source (corn starch, sucrose, Polycose) influences the choice between a high-fat and high-carbohydrate diet in spontaneously feeding rats and in rats stimulated to eat by neuropeptide Y (NPY) administration or food deprivation. Rats were tested under three diet options: 1) a high-fat diet versus a high-corn starch diet; 2) a high-fat diet versus a high-sucrose diet; and 3) a high-fat diet versus a high-Polycose diet. During daily and stimulated feeding rats ate more of the high-carbohydrate diet than the fat diet when the source of carbohydrate was sucrose or Polycose; however, when corn starch was provided as the carbohydrate source rats ate more of the high-fat diet. Food-deprived rats increased intake of both the high-fat and the high-carbohydrate diets, with the proportion of energy ingested from each of the diets resembling that noted during 3 days of spontaneous feeding. NPY-injected rats ate more of both the high-fat and high-carbohydrate diets during diet options 1 and 3, but not during option 2 when the high-sucrose and high-fat diets were offered concurrently. In that case, rats did not significantly increase their intake of the high-fat diet. Although carbohydrate source and NPY administration each influenced diet selection, altering the source of carbohydrate had a more marked effect.
Pathways of Fos expression in locus ceruleus, dorsal vagal complex, and PVN in response to intestinal lipid
Authors: Mönnikes Hubert , Lauer Gerd , Bauer Christoph , Tebbe Johannes , Zittel Tillmann T. , Arnold Rudolf
Published: December 2017

Exogenous cholecystokinin (CCK) injected peripherally mimics effects of lipid entering the intestine on food intake and gastric motility via vagal afferents and induces c- fos expression in the locus ceruleus complex (LCC), nucleus of the solitary tract (NTS), area postrema (AP), and paraventricular nucleus (PVN). However, the role of peripheral endogenous CCK in induction of c- fos expression in the brain at ingestion of nutrients is controversial. In awake rats, intraduodenal lipid infusion markedly increased Fos protein-like immunoreactivity (FLI) in these brain nuclei. Perivagal capsaicin pretreatment reduced the increase of FLI in the LCC, NTS, and PVN by 66–86% and in the AP by 46%. The CCK-A receptor antagonist MK-329 (0.1 mg/kg ip) diminished the FLI increase in LC, NTS, AP, and PVN by 39–100%; the CCK-B receptor antagonist L-365,260 reduced the increased FLI in the AP by 54%. After capsaicin pretreatment, both CCK antagonists had additional inhibitory effects only on FLI in the AP. These findings suggest that entry of lipid into the intestine activates c- fos in the LCC, NTS, and PVN predominantly via CCK-A receptors on vagal afferents and in the AP via vagal and nonvagal pathways, as well as CCK-B and CCK-A receptors.
Intravenous iron supplementation effect on tissue iron and hemoproteins in chronically phlebotomized lambs
Authors: Guiang Sixto F. , Georgieff Michael K. , Lambert David J. , Schmidt Robert L. , Widness John A.
Published: December 2017

Chronic phlebotomy is an important mechanism of iron loss in premature infants. We studied inter- and intraorgan iron allocation in 10 twin lamb pairs undergoing an acute 40–50% reduction in red cell volume followed by smaller intermittent phlebotomies over an 11-day period. One twin received no supplemental iron sucrose, while the other received an average daily intravenous dose of iron sucrose of either 1 ( n = 3), 2 ( n = 3), 5 ( n = 3), or 15 ( n = 1) mg ⋅ kg−1⋅ day−1. The total iron content of the red blood cells, liver, skeletal muscle, heart, and brain was directly related to iron dose up to 2 mg ⋅ kg−1⋅ day−1. Tissue iron concentrations remained stable until liver iron was <200 g/g dry wt, after which iron was preferentially directed to red blood cells over skeletal muscle, heart, and brain. Hemoprotein concentrations decreased proportionately to tissue iron, except myocardial cytochrome c, which remained preserved. Any available iron in phlebotomized, rapidly growing lambs is preferentially directed to red blood cells, and lambs require iron supplementation to maintain tissue iron and hemoprotein concentrations. A decrease in nonheme tissue iron results in the high prioritization of iron among iron-containing proteins.
Quantitative analysis of the age-related fragmentation of hamster 24-h activity rhythms
Authors: Penev Plamen D. , Zee Phyllis C. , Turek Fred W.
Published: December 2017

The continuous monitoring of spontaneous locomotor activity has emerged as one of the most widely used metrics in rodent circadian research. This behavioral measure is also extremely useful for the description of the effects of aging on circadian rhythms. The present study describes the successful use of a log-survivorship approach to identify discrete bouts of hamster wheel-running activity and provides a detailed description of the age-related fragmentation in the 24-h profile of this behavioral variable. In addition, stepwise discriminant analysis identified the most important quantitative measures for distinguishing between the individual patterns of wheel-running activity of young (3 mo) and old (17–18 mo) golden hamsters. The results suggest that this method of bout analysis can be a valuable tool for the study of genetic, developmental, neurochemical, physiological, and environmental factors involved in the temporal control of rodent locomotor behavior.
Underestimation of plasma volume changes in humans by hematocrit/hemoglobin method
Authors: Johansen Lars Bo , Videbæk Regitze , Hammerum Mette , Norsk Peter
Published: December 2017

During water immersion in humans, the use of changes in hematocrit (Hct) and hemoglobin concentration (Hb) underestimates the relative changes in plasma volume (PV) as measured directly with Evans blue (EB). It is not known whether the same is the case during posture changes. Therefore, changes in PV were determined with an EB dilution technique in 10 males before, during, and after an acute posture change from seated to 6° head-down tilt (HDT). The EB method was improved to take into account changes in transcapillary escape rate of albumin-bound EB. Furthermore, blood was sampled from a central venous catheter. Hct and Hb were simultaneously measured. During HDT, PV determined with EB increased by 9.3 ± 2.0% but increased only 4.5 ± 0.9% when calculated with the Hct/Hb method ( P < 0.05 vs. EB measurements). Thus use of the Hct/Hb method in humans leads to underestimation of the change in PV by as much as 50% during an acute change in posture. Therefore, a direct tracer-dilution method must be used for accurate estimations of changes in PV during changes in posture or other antiorthostatic maneuvers.
Cardiovascular actions of ET-B activation in vivo and modulation by receptor antagonism
Authors: Rasmussen Todd E. , Jougasaki Michihisa , Supaporn Thanom , Hallett John W. , Brooks David P. , Burnett John C.
Published: December 2017

The endothelin (ET)-B receptor subtype is expressed on vascular endothelial and smooth muscle cells and participates in vasodilatation and vasoconstriction. Controversy exists regarding the role of the ET-B receptor as a mediator of systemic, pulmonary, and renal vasoconstriction in states of marked ET-1 activation. Moreover, the potential activation of endogenous ET-1 with secondary stimulation of the ET-A receptor in response to sarafotoxin S6c (S6c) remains unclear. This study was designed to assess the cardiovascular actions of ET-B activation with S6c in the presence and absence of selective ET-A antagonism with FR-139317 and dual ET-A/ET-B antagonism with SB-209670 in the anesthetized dog. Compared with time control ( n = 5), S6c increased from baseline systemic vascular resistance (SVR) [28 ± 7 vs. 14 ± 3 resistance units (RU), P < 0.05] and pulmonary vascular resistance (PVR) (3.2 ± 0.7 vs. 0.9 ± 0.3 RU, P < 0.05) and decreased cardiac output (CO) (−1.7 ± 0.3 vs. −0.5 ± 0.1 l/min, P < 0.05), with no differences in renal vascular resistance in association with increases in plasma ET-1. S6c also decreased mixed venous oxygen saturation ([Formula: see text]) (56 ± 6 vs. 76 ± 5%, P < 0.05). Selective ET-A receptor antagonism did not affect the actions of S6c, with the exception that ET-A receptor antagonism blocked the increase in SVR to high-dose S6c. Dual ET-A/ET-B receptor antagonism attenuated the increase from baseline in SVR (7 ± 1 vs. 28 ± 7 RU, P < 0.05) and PVR (0.7 ± 0.2 vs. 3.2 ± 0.7 RU, P < 0.05) and decrease from baseline in CO (−0.9 ± 0.1 vs. −1.7 ± 0.3 l/min, P < 0.05) and[Formula: see text] (−7 ± 3 vs. −20 ± 3%, P < 0.05) observed with S6c alone. In summary, this study demonstrates an important role of ET-B receptor activation in vivo, which results in increases in plasma ET-1 and systemic and pulmonary vasoconstriction and reductions in CO and [Formula: see text]. This study also supports a modest role for the ET-A receptor in mediating the systemic vasoconstrictor response to high-dose S6c.
Estrogen influences osmotic secretion of AVP and body water balance in postmenopausal women
Authors: Stachenfeld Nina S. , Dipietro Loretta , Palter Steven F. , Nadel Ethan R.
Published: December 2017

To determine if estrogen upregulates osmotic secretion of arginine vasopressin (AVP) and alters body water balance, we infused hypertonic (3% NaCl) saline in 6 women (68 ± 3 yr) after 14 days of 17β-estradiol (transdermal patch, ∼0.1 mg/day, E2) and placebo (control) administration. Hypertonic saline was infused at 0.1 ml ⋅ kg−1⋅ min−1for 120 min, and after a 30-min equilibration period, the subjects drank water ad libitum for 180 min. E2increased basal plasma estradiol concentration from ≤12 to 80 ± 12 pg/ml and plasma AVP concentration (P[AVP]) from 2.1 ± 0.7 to 3.1 ± 0.8 pg/ml ( P< 0.05), but not plasma osmolality (Posm, 288 ± 1 and 287 ± 1, for control and E2, respectively). Hypertonic saline infusion increased Posmby 18 ± 1 and 17 ± 1 mosmol/kgH2O and P[AVP]by 5.2 ± 0.5 and 4.9 ± 0.4 pg/ml for control and E2treatments, respectively. The P[AVP]-Posmrelationship shifted upward after E2, with no change in sensitivity (slope, 0.36 ± 0.02 and 0.33 ± 0.03 pg ⋅ ml−1⋅ mosmol−1for control and E2, respectively). Water intake was similar between control and E2(24 vs. 22 ml/kg), but by 180 min of drinking, urine output and free water clearance ([Formula: see text]) were reduced by 5.6 ± 2.3 ml/kg and 2.6 ± 2.0 ml/min, respectively ( P < 0.05) after E2. Plasma aldosterone concentration was unaffected by E2, but fractional sodium excretion was reduced from 2.7 ± 0.5 to 1.7 ± 0.4% ( P < 0.05) at 180 min of drinking. Our data suggest that E2augments osmotic AVP secretion, thereby implicating elevated AVP as a contributor to water retention in high E2states; however, an increase in renal sodium reabsorption was a major component of the enhanced fluid retention.
Sepsis-induced increase in muscle proteolysis is blocked by specific proteasome inhibitors
Authors: Hobler Scott C. , Tiao Greg , Fischer Josef E. , Monaco John , Hasselgren Per-Olof
Published: December 2017

Recent studies suggest that sepsis stimulates ubiquitin-dependent protein breakdown in skeletal muscle. The 20S proteasome is the catalytic core of the ubiquitin-dependent proteolytic pathway. We tested the effects in vitro of the proteasome inhibitors N-acetyl-l-leucinyl-l-leucinal-l-norleucinal (LLnL) and lactacystin on protein breakdown in incubated muscles from septic rats. LLnL resulted in a dose- and time-dependent inhibition of protein breakdown in muscles from septic rats. Lactacystin blocked both total and myofibrillar muscle protein breakdown. In addition to inhibiting protein breakdown, LLnL reduced muscle protein synthesis and increased ubiquitin mRNA levels, probably reflecting inhibited proteasome-associated ribonuclease activity. Inhibited muscle protein breakdown caused by LLnL or lactacystin supports the concept that the ubiquitin-proteasome pathway plays a central role in sepsis-induced muscle proteolysis. The results suggest that muscle catabolism during sepsis may be inhibited by targeting specific molecular mechanisms of muscle proteolysis.
Hyperphagia in cold-exposed rats is accompanied by decreased plasma leptin but unchanged hypothalamic NPY
Authors: Bing Chen , Frankish Helen M. , Pickavance Lucy , Wang Qiong , Hopkins David F. C. , Stock Michael J. , Williams Gareth
Published: December 2017

Chronic cold exposure stimulates sympathetically driven thermogenesis in brown adipose tissue (BAT), resulting in fat mobilization, weight loss, and compensatory hyperphagia. Hypothalamic neuropeptide Y (NPY) neurons are implicated in stimulating food intake in starvation, but may also suppress sympathetic outflow to BAT. This study investigated whether the NPY neurons drive hyperphagia in rats that have lost weight through cold exposure. Rats exposed to 4°C for 21 days weighed 14% less than controls maintained at 22°C ( P < 0.001). Food intake increased after 3 days and remained 10% higher thereafter ( P < 0.001). Increased BAT activity was confirmed by 64, 96, and 335% increases in uncoupling protein-1 mRNA at 2, 8, and 21 days. Plasma leptin decreased during prolonged cold exposure. Cold-exposed rats showed no significant changes in NPY concentrations in any hypothalamic regions or in hypothalamic NPY mRNA at any time. We conclude that the NPY neurons are not activated during cold exposure. This is in contrast with starvation-induced hyperphagia, but is biologically appropriate since enhanced NPY release would inhibit thermogenesis causing potentially lethal hypothermia. Other neuronal pathways must therefore mediate hyperphagia in chronic cold exposure.
Nitrergic and cholinergic innervation of the rat lower urinary tract after pelvic ganglionectomy
Authors: Persson Katarina , Alm Per , Uvelius Bengt , Andersson Karl-Erik
Published: December 2017

The possible coexistence of nitric oxide (NO) and acetylcholine in the rat major pelvic ganglion (MPG) was examined by double immunohistochemistry using antisera raised against NO synthase (NOS) and choline acetyltransferase (ChAT). The smooth muscle responses of the isolated bladder and urethra were recorded after bilateral cryoganglionectomy of the MPG, focusing on the possible development of denervation supersensitivity. In the MPG, NOS immunoreactivity (ir) was seen in a large number of cell bodies, but it was not as abundant as ChAT-ir cell bodies. Double immunolabeling showed that all NOS-ir cell bodies also displayed ChAT-ir. In ganglionectomized bladders, the electrical field stimulation (EFS)-evoked contractile response was markedly reduced. When compared with control bladders, detrusor strips from ganglionectomized rats were more sensitive to carbachol as revealed by a lower negative logarithm of the drug concentration eliciting 50% relaxation (6.5 ± 0.04 vs. 5.9 ± 0.07). In the urethra, the NO-mediated relaxant response to EFS was practically abolished by ganglionectomy, whereas no difference was found in sensitivity to 3-morpholinosydnonimine hydrochloride (SIN-1). SIN-1 produced an equal increase in tissue levels of guanosine 3′,5′-cyclic monophosphate in urethral preparations from control and ganglionectomized rats. The results suggest that the NOS-ir nerves that mediate inhibition of rat urethral smooth muscle tone originate from the MPG and contain ChAT. No denervation supersensitivity to nitrergic stimulation was observed in the urethra after ganglionectomy.
Effects of rearing temperature on body weight and abdominal fat in male and female rats
Authors: Young James B. , Shimano Yasunobu
Published: December 2017

Thermoregulatory mechanisms are influenced by the temperature of the postnatal environment. Animals reared in cool environments are more tolerant of cold as adults, whereas those reared in warm conditions are more tolerant of heat. Because diet-induced and thermoregulatory thermogenesis share common features, studies examined the impact of rearing temperature on weight gain and fat accumulation. Rats reared at 18°C gained more weight and accumulated more fat in abdominal depots than animals reared at 30°C when both were housed at a common temperature, responses that were exacerbated by ad libitum access to sucrose. Male rats reared at 30°C were less affected by sucrose than 18°C-reared males, whereas female rats reared at 18 or 30°C were similarly susceptible. During exposure to 18°C, fat accumulation in abdominal depots increased in males but decreased in females. These data suggest that early temperature exposure influences weight gain and fat accumulation in later life, a difference that is most apparent when animals are housed at a common temperature.
Markers of protein oxidation by hydroxyl radical and reactive nitrogen species in tissues of aging rats
Authors: Leeuwenburgh Christiaan , Hansen Polly , Shaish Aviv , Holloszy John O. , Heinecke Jay W.
Published: December 2017

Many lines of evidence implicate oxidative damage in aging. Possible pathways include reactions that modify aromatic amino acid residues on proteins. o-Tyrosine is a stable marker for oxidation of protein-bound phenylalanine by hydroxyl radical, whereas 3-nitrotyrosine is a marker for oxidation of protein-bound tyrosine by reactive nitrogen species. To test the hypothesis that proteins damaged by hydroxyl radical and reactive nitrogen accumulate with aging, we used isotope dilution gas chromatography-mass spectrometry to measure levels of o-tyrosine and 3-nitrotyrosine in heart, skeletal muscle, and liver from young adult (9 mo) and old (24 mo) female Long-Evans/Wistar hybrid rats. We also measured these markers in young adult and old rats that received antioxidant supplements (α-tocopherol, β-carotene, butylated hydroxytoluene, and ascorbic acid) from the age of 5 mo. We found that aging did not significantly increase levels of protein-bound o-tyrosine or 3-nitrotyrosine in any of the tissues. Antioxidant supplementation had no effect on the levels of protein-bound o-tyrosine and 3-nitrotyrosine in either young or old animals. These observations indicate that the o-tyrosine and 3-nitrotyrosine do not increase significantly in heart, skeletal muscle, and liver in old rats, suggesting that proteins damaged by hydroxyl radical and reactive nitrogen species do not accumulate in these tissues with advancing age.
Signaling mechanisms of elevated neutrophil O 2 − generation after burn injury
Authors: Sabeh Farideh , Hockberger Philip , Sayeed Mohammed M.
Published: December 2017

A full skin thickness burn injury was produced in anesthetized rats by exposing 25% of total body surface area to 98°C water for 10 s. Sham (exposed to 37°C water) and burn rats were killed 1, 3, 7, or 10 days later. The role of Ca2+signaling and Ca2+-related protein kinase C (PKC) activation in neutrophil[Formula: see text] generation was ascertained by evaluating the effect of treatment of the rats with the Ca2+entry blocker, diltiazem. There was an overt enhancement of[Formula: see text] generation by polymorphonuclear leukocytes from burn rats on days 1, 3, and 7 postburn, with the peak release occurring on day 3 postburn.[Formula: see text] generation comparable to the sham was noted on day 10 after the burn.[Formula: see text] releases on days 1, 3, and 7 postburn were accompanied by marked elevation of [Formula: see text] and PKC responses. Like the [Formula: see text] release, intracellular Ca2+concentration ([Ca2+]i) response on day 10 after burn was suppressed to levels found in the sham group. The treatment of burn rats with diltiazem prevented the upregulation of both [Ca2+]iand PKC responses as well as [Formula: see text]generation in neutrophils in rats on days 1, 3, and 7 after the burn. Because previous studies have shown that increases in [Ca2+]iprecede [Formula: see text] generation and degranulation, our results suggest that neutrophil[Formula: see text] release enhancement in the early stages after burn injury (e.g., days 1- 7postburn) results from an overactivation of the[Formula: see text] and PKC signaling pathways. The heightened [Formula: see text] generation during the early burn injury phase might play a role in tissue damage in one or more of host organs.
Cerebellar vascular and synaptic responses in normal mice and in transgenics with Purkinje cell dysfunction
Authors: Yang Guang , Feddersen Rod M. , Zhang Fangyi , Clark H. Brent , Beitz Alvin J. , Iadecola Costantino
Published: December 2017

We used transgenic mice with Purkinje cell dysfunction (PO3 line) to study the role of these neurons in the increase in cerebellar blood flow (BFcrb) produced by stimulation of the cerebellar parallel fibers (PF). Mice (age 8–10 wk) were anesthetized (halothane) and artificially ventilated. Arterial pressure and end-tidal CO2 were monitored continuously. Arterial blood gases were measured. The PF were stimulated electrically (100 μA, 30 Hz; 40 s), and the increases in BFcrb were monitored by a laser-Doppler flow probe. First, we characterized the increases in BFcrb and the field potentials produced by PF stimulation in normal mice. PF stimulation evoked the typical field potentials and increased BFcrb by 60 ± 4% (100 μA, 30 Hz; n = 10). The increases in BFcrb were attenuated by the broad-spectrum glutamate receptor antagonist kynurenate (−84 ± 3%; P < 0.05 analysis of variance; n = 5), by thedl-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (−62 ± 6%; P < 0.05; n = 5), and by the nitric oxide synthase inhibitor N ω-nitro-l-arginine (−46 ± 7%; P < 0.05; n = 5). In PO3 transgenic mice, the increases in BFcrb produced by PF stimulation were reduced ( P < 0.001) at every stimulus intensity and frequency tested (residual increase at 100 μA, 30 Hz: 19 ± 2%; n = 6). The field potentials evoked by PF stimulation also were abnormal in that they lacked the late negative wave ( n = 6), a finding consistent with lack of depolarization of Purkinje cells. The residual flow response in the transgenics was abolished by N ω-nitro-l-arginine ( n = 5; P > 0.05). Ultrastructural studies showed that the density of PF-Purkinje cell synapses is reduced in PO3 mice, whereas the morphology of molecular layer interneurons (stellate cells) is normal. The findings suggest that Purkinje cells are responsible for a sizable component of the flow response whereas molecular layer interneurons mediate the remainder of the response. The study provides evidence that mouse mutants with spontaneous or genetically engineered cerebellar abnormalities could be useful to study the cellular and molecular correlates of functional hyperemia in the central nervous system.
Benzamil blockade of brain Na+channels averts Na+-induced hypertension in rats
Authors: Nishimura Masato , Ohtsuka Ken , Nanbu Akira , Takahashi Hakuo , Yoshimura Manabu
Published: December 2017

To determine the possible involvement of brain amiloride-sensitive Na+channels in Na+-induced hypertension, we investigated the effects of benzamil hydrochloride, a specific blocker of these Na+channels, on the acute pressor mechanisms of intracerebroventricular infusion of hypertonic NaCl and the continuous pressor mechanisms of Na+-induced chronic hypertension, such as deoxycorticosterone acetate-salt hypertensive or stroke-prone spontaneous hypertensive rats, and of non-Na+-induced hypertension, such as renovascular hypertensive rats. Intracerebroventricular preinjection with benzamil (1 or 10 nmol/kg) abolished the increase in mean arterial pressure, heart rate, abdominal sympathetic discharge, and plasma vasopressin concentration induced by an acute increase in cerebrospinal Na+concentrations at intracerebroventricular infusion of 1.5 M hypertonic NaCl. Continuous intracerebroventricular infusion of benzamil (1 or 10 nmol ⋅ kg−1⋅ day−1) for 7 days attenuated Na+-induced chronic hypertension in both deoxycorticosterone acetate-salt and stroke-prone spontaneous hypertensive rats, accompanied by reduction of urinary excretion of vasopressin and norepinephrine but not in renovascular hypertensive rats. Intravenous infusion of benzamil (10 nmol ⋅ kg−1⋅ day−1) for 7 days affected neither arterial pressure nor urinary excretion of vasopressin and norepinephrine in either model of hypertension. Benzamil-blockable brain amiloride-sensitive Na+channels are expected to function as one of the Na+receptors in the brain and to be involved in the pressor mechanism of Na+-induced hypertension.
Role of AT1receptors in the renal papillary effects of acute and chronic nitric oxide inhibition
Authors: Ortíz M. Clara , Fortepiani Lourdes A. , Ruiz-Marcos Francisco M. , Atucha Noemí M. , García-Estañ Joaquín
Published: December 2017

Nitric oxide (NO) is a vasodilator substance controlling renal papillary blood flow (PBF) in the rat. In this study we have evaluated the role of AT1angiotensin II receptors as modulators of the whole kidney and papillary vasoconstrictor effects induced by the acute or chronic inhibition of NO synthesis. Experiments have been performed in anesthetized, euvolemic Munich-Wistar rats prepared for the study of renal blood flow (RBF) and PBF. In normal rats, acute administration of the NO synthesis inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) increased mean arterial pressure (MAP) and decreased RBF and PBF. Either acute or chronic treatment with the AT1receptor blocker losartan did not modify the decreases in RBF or PBF secondary to l-NAME. In animals made hypertensive by chronic inhibition of NO, basal MAP was higher, whereas RBF and PBF were lower than in the controls. In these animals, acute or chronic administration of losartan decreased MAP and increased both RBF and PBF significantly. These results indicate that, under normal conditions, the decreases in RBF or PBF induced by the acute inhibition of NO synthesis are not modulated by AT1-receptor stimulation. However, the arterial hypertension, renal vasoconstriction, and reduced PBF present in chronic NO-deficient hypertensive rats is partially due to the effects of angiotensin II, via stimulation of AT1-receptors.
Distinct arginase isoforms expressed in primary and transformed macrophages: regulation by oxygen tension
Authors: Louis Claudine A. , Reichner Jonathan S. , Henry William L. , Mastrofrancesco Balduino , Gotoh Tomomi , Mori Masataka , Albina Jorge E.
Published: December 2017

Experiments were performed to identify arginase isoforms expressed in primary and transformed rodent macrophages and to determine the molecular mechanisms for the previously observed increase in arginase activity in macrophages cultured in hypoxia or anoxia. Results demonstrate the following: 1) mRNA and protein for hepatic-type AI arginase are expressed in primary cultures of rat and mouse peritoneal macrophages and are enhanced seven- and ninefold, respectively, by lipopolysaccharide (LPS). 2) mRNA for extrahepatic-type AII arginase is constitutively expressed in mouse, but not rat, peritoneal macrophages and is detected in RAW264.7 cells after LPS treatment; neither J774A.1 nor P388D1cells contain arginase mRNA. 3) AI arginase mRNA, arginase activity in cell lysates, andl-arginine flux through arginase in intact cells are all increased in rat wound-derived and mouse peritoneal macrophages by hypoxic or anoxic culture; AII arginase mRNA is, in contrast, suppressed >50% by O2deprivation. 4) Expression of thel-arginine transporter mCAT-2 is increased greater than twofold by reduced O2culture. These results demonstrate substantial variability in arginase isoform expression among primary and transformed rodent macrophages. They also identify AI and AII arginase and the mCAT-2 l-arginine transporter as O2-regulated genes.
Role of angiotensin in renal sympathetic activation in nephrotic syndrome
Authors: Sanchez-Palacios Manuel , Jones Susan Y. , Dibona Gerald F.
Published: December 2017

The effect of type 1 angiotensin II receptor antagonist treatment (losartan) on cardiac baroreflex regulation of renal sympathetic nerve activity (RSNA) and renal sodium handling in rats with nephrotic syndrome was examined. After intravenous losartan administration, with arterial pressure normalized by intravenous methoxamine, basal RSNA was decreased 14 ± 3% in arterial baroreceptor-intact rats and by 21 ± 5% in arterial baroreceptor-denervated rats. Intracerebroventricular losartan, which did not affect arterial pressure, decreased basal RSNA activity by 15 ± 1%. Both intravenous and intracerebroventricular losartan augmented the renal sympathoinhibitory response to acute volume loading, and this was associated with an enhanced natriuretic response to the acute volume load. In nephrotic syndrome, acute losartan administration improved cardiac baroreflex regulation of RSNA, which was associated with improved ability to excrete acute sodium loads.
Hemodynamic effects of acute stressors in the conscious rabbit
Authors: Schadt James C. , Hasser Eileen M.
Published: December 2017

Chronically instrumented, conscious rabbits were used to test the hypothesis that sensory stimulation with an air jet or oscillation produces differential hemodynamic changes that may be appropriate for an active or a passive behavioral response, respectively. Both stressors increased arterial pressure, central venous pressure, and hindquarters blood flow and produced visceral vasoconstriction. Neither stimulus altered hindquarters conductance. Although air jet increased heart rate and cardiac output, oscillation did not. The two stressors affected arterial baroreflex control of heart rate differently. Oscillation reset arterial pressure to a higher level with no change in heart rate maximum or minimum, whereas air jet reset both heart rate and arterial pressure to higher levels. Neither stressor affected baroreflex sensitivity. We conclude that the conscious rabbit shows at least two distinct cardiovascular responses when exposed to acute stressors. Air jet produces a cardiovascular response including tachycardia, which resembles the defense reaction and appears appropriate for active defense or flight. The response to oscillation, on the other hand, appears better suited for a passive response such as “freezing” behavior. During exposure to either stressor, the baroreflex is altered to allow simultaneous increases in heart rate and arterial blood pressure, but the sensitivity is maintained, allowing normal moment to moment control of heart rate.
Does muscle creatine phosphokinase have access to the total pool of phosphocreatine plus creatine?
Authors: Hochachka Peter W. , Mossey Mark K. P.
Published: December 2017

Two fundamental assumptions underlie currently accepted dogma on creatine phosphokinase (CPK) function in phosphagen-containing cells: 1) CPK always operates near equilibrium and 2) CPK has access to, and reacts with, the entire pool of phosphocreatine (PCr) and creatine (Cr). We tested the latter assumption in fish fast-twitch or white muscle (WM) by introducing [14C]Cr into the WM pool in vivo. To avoid complications arising from working with muscles formed from a mixture of fast and slow fibers, it was advantageous to work with fish WM because it is uniformly fast twitch and is anatomically separated from other fiber types. According to current theory, at steady state after [14C]Cr administration, the specific activities of PCr and Cr should be the same under essentially all conditions. In contrast, we found that, in various metabolic states between rest and recovery from exercise, the specific activity of PCr greatly exceeds that of Cr. The data imply that a significant fraction of Cr is not free to rapidly exchange with exogenously added [14C]Cr. Releasing of this unlabeled or “cold” Cr on acid extraction accounts for lowered specific activities. This unexpected and provocative result is not consistent with traditional models of phosphagen function.
Interindividual variation in total and carrier-mediated lactate influx into red blood cells
Authors: Väihkönen Leena K. , Pösö A. Reeta
Published: December 2017

To study in standardbred horses interindividual variation in the influx of lactate into red blood cells, venous blood samples were collected from 89 horses from 2 wk to 9 yr of age. For 62 horses, the rate of influx was normally distributed with a mean rate of 4.09 nmol ⋅ mg protein−1⋅ min−1at a lactate concentration of 10 mM, and the respective value for the other 27 horses was 0.58 nmol ⋅ mg protein−1⋅ min−1. At 30 mM of lactate, the rates were 8.71 and 1.97 nmol ⋅ mg protein−1⋅ min−1, respectively. This bimodal distribution was independent of age. In horses with high transport activity, the monocarboxylate transporter (MCT) appears to be the major carrier, whereas, in those with low transport activity, no activity of the MCT could be detected. The band 3 protein may account for 18–39% of transport activity. With all age groups combined, the transport activity tended to be higher in mares than in stallions. Lactate transport into red blood cells seems thus to be an inherent property in which participation of various transporters varies interindividually.
Chloroquine inhibits proinflammatory cytokine release into human whole blood
Authors: Karres Ina , Kremer Jean-Pierre , Dietl Ingrid , Steckholzer Ursula , Jochum Marianne , Ertel Wolfgang
Published: December 2017

Excessive synthesis and release of proinflammatory cytokines during endotoxemia causes severe pathophysiological derangements and organ failure. Because the lysosomotropic agent chloroquine has been effective in the treatment of diseases associated with increased secretion of proinflammatory cytokines such as malaria or rheumatoid arthritis, this study evaluates the potential effect of chloroquine on endotoxin-induced cytokinemia using human whole blood from healthy volunteers. Chloroquine revealed a dose-dependent inhibitory effect on endotoxin-induced secretion of tumor necrosis factor-α, interleukin-1β, and interleukin-6 that was associated with reduced cytokine mRNA expression. Moreover, ammonia and methylamine, which react as weak bases like chloroquine, reduced synthesis and secretion of proinflammatory cytokines. These data indicate a potent anti-inflammatory effect of chloroquine on endotoxin-induced synthesis of proinflammatory cytokines that may be due to its weak base effect. Thus chloroquine may be of therapeutic benefit not only during chronic inflammation but also in diseases that are related to bacteria-induced inflammation.
Effects of l-NAME on cerebral metabolic, vasopressin, oxytocin, and blood pressure responses in hemorrhaged rats
Authors: Kadekaro Massako , Terrell Mary Lee , Liu Hanwu , Gestl Shelley , Bui Vuong , Summy-Long Joan Y.
Published: December 2017

N G-nitro-l-arginine methyl ester (l-NAME; 250 μg/5 μl), an inhibitor of NO synthase, or the vehicle artificial cerebrospinal fluid (aCSF; 5 μl) was administered intracerebroventricularly to conscious rats hemorrhaged (0.7 ml/min) to a 20% volume depletion. Hypotension was maximal 5 min after hemorrhage ended, with compensatory recovery to basal levels 20 min later, regardless of drug treatment.l-NAME, however, elevated ( P < 0.05) blood pressure (vs. aCSF controls) 40–45 min after intracerebroventricular administration. In normovolemic rats, l-NAME produced a significant pressor response and increased plasma levels of vasopressin (VP) and oxytocin (OT). After hemorrhage, both hormone levels increased, but only OT was further enhanced byl-NAME. Thus centrally produced NO tonically inhibits OT and VP secretion under basal normovolemic conditions and selectively inhibits OT release during hypovolemia. Hemorrhage increased the rates of glucose utilization in the neural lobe, indicative of enhanced efferent neural functional activity.l-NAME further enhanced the metabolic activity in the entire hypothalamoneurohypophysial system of hemorrhaged animals. Several other brain structures involved in the regulation of blood pressure and the stress response were also metabolically affected by the hemorrhage andl-NAME.
Role of the liver in long-term control of drinking behavior, Na+ balance, and arterial pressure in Dahl rats
Authors: Morita Hironobu , Tsunooka Kiyoshi , Hagiike Masanobu , Yamaguchi Osamu , Lee Ken
Published: December 2017

The role of postabsorptive mechanisms in long-term control of drinking behavior, Na+ balance, and arterial pressure was examined in Dahl salt-sensitive (DS) and salt-resistant (DR) rats. NaCl (0.15 M) was infused (0.5 ml/h) into either the inferior vena cava (IVC) or the portal vein (PV) for 7 days, and then 1.5 M NaCl was infused for 10 days. During 1.5 M infusion, the IVC group retained more Na+ than the PV group. Furthermore, in DS rats, mean arterial pressure was higher in the IVC group than in the PV group. Regardless of the strain and infusion route, 1.5 M infusion had no effect on volume of daily saline consumption. However, when the data for light and dark periods were analyzed separately, dark period saline consumption in the PV group was decreased by 1.5 M infusion but was not changed in the IVC group. These results indicate that, in Dahl rats, the postabsorptive mechanism plays a significant role in controlling long-term saline drinking behavior and Na+ balance and has a significant role in controlling arterial pressure in DS, but not DR, rats.
Role of K+ channels in adrenal catecholamine secretion in anesthetized dogs
Authors: Nagayama Takahiro , Masada Kimiya , Yoshida Makoto , Suzuki-Kusaba Mizue , Hisa Hiroaki , Kimura Tomohiko , Satoh Susumu
Published: December 2017

We examined the role of K+ channels in the secretion of adrenal catecholamine (CA) in response to splanchnic nerve stimulation (SNS), acetylcholine (ACh), 1,1-dimethyl-4-phenyl-piperazinium (DMPP), and muscarine in anesthetized dogs. K+ channel blockers and the cholinergic agonists were infused and injected, respectively, into the adrenal gland. The voltage-dependent K+ channel (KA type) blocker mast cell degranulating (MCD) peptide infusion (10–100 ng/min) enhanced increases in CA output induced by SNS (1–3 Hz), but it did not affect increases in CA output induced by ACh (0.75–3 μg), DMPP (0.1–0.4 μg), or muscarine (0.5–2 μg). The small-conductance Ca2+-activated K+(SKCa) channel blocker scyllatoxin infusion (10–100 ng/min) enhanced the ACh-, DMPP-, and muscarine-induced increases in CA output, but it did not affect the SNS-induced increases in CA output. These results suggest that KA channels may play an inhibitory role in the regulation of adrenal CA secretion in response to SNS and that SKCa channels may play the same role in the secretion in response to exogenously applied cholinergic agonists.
Experimental separation of time of day and homeostatic influences on sleep
Authors: Åkerstedt Torbjörn , Hume Ken , Minors David , Waterhouse Jim
Published: December 2017

The purpose of the present study was to evaluate the simultaneous effects on sleep of prior time awake (PRW) and time of day (TOD). Eight male subjects spent 13 days in an isolated sleep lab and had three 8-h baseline sleeps and then 18 4-h sleeps, distributed to provide three sleeps starting at 2400, 0400, 0800, 1200, 1600, and 2000. The three sleeps were preceded by 4, 8, and 12 h of PRW, respectively. ANOVA showed that TST and subjective sleepiness increased with PRW and with closeness to the trough of the circadian rhythm of rectal temperature, whereas sleep latency showed the opposite pattern, and rapid eye movement sleep (REM) latency strongly decreased with PRW and with closeness to the trough. Slow-wave sleep (SWS) increased with PRW, whereas SWS latency and final time awake decreased. REM sleep increased with closeness to the circadian trough, and time awake decreased. Multiple-regression analysis showed that REM latency was closely related to increased SWS in the first sleep cycle, reduced SWS latency, and increased PRW [a short PRW before sleep at noon yielded an extremely short (14 min) REM latency]. Sleep latency and final time awake showed almost exactly the same relationship to TOD and PRW. It is concluded that both homeostatic and circadian influences simultaneously affect sleep, that REM latency is very sensitive to the need for SWS, and that the circadian acrophase strongly interferes with sleep. It should be emphasized that the conclusions should not be extrapolated to longer (>12 h) wake spans.
Direct fetal glucocorticoid treatment alters postnatal adaptation in premature newborn baboons
Authors: Ervin M. Gore , Seidner Steven R. , Leland M. Michelle , Ikegami Machiko , Jobe Alan H.
Published: December 2017

Abnormalities of premature newborn adaptation after preterm birth result in significant perinatal mortality and morbidity. We assessed the effects of short-term (24 h) fetal betamethasone exposure on preterm newborn baboon pulmonary and cardiovascular regulation and renal sodium handling during the first 24 h after birth. Male fetal baboons ( Papio) (124-day gestation, term 185 days) received ultrasound-guided intramuscular injections of saline ( n = 5) or betamethasone (0.5 mg/kg; n = 5). Fetuses were cesarean delivered 24 h later, treated with 100 mg/kg surfactant, and ventilated by adjusting peak inspiratory pressures to maintain[Formula: see text] values of 35–50 mmHg for 24 h. Betamethasone- vs. saline-treated mean ± SE newborn body weights (0.45 ± 0.02 vs. 0.41 ± 0.01 kg) were similar. Although prenatal betamethasone did not affect postnatal lung function ([Formula: see text], arterial/alveolar O2gradient, or dynamic compliance), plasma hormone (cortisol or thyroxine), or catecholamine levels, mean arterial pressure (25 ± 1 vs. 32 ± 1 mmHg), plasma sodium concentration (132 ± 2 vs. 138 ± 1 meq/l), glomerular filtration rate (0.07 ± 0.02 vs. 0.16 ± 0.02 ml ⋅ min−1⋅ kg−1), and renal total sodium reabsorption (1.5 ± 0.5 vs. 16.0 ± 3.0 μeq ⋅ min−1⋅ kg−1) values were significantly lower in saline-treated than in betamethasone-treated newborns at 24 h. We conclude that despite the fact that there are no pulmonary and endocrine effects, antenatal glucocorticoid exposure alters premature newborn baboon vascular and renal glomerular function and improves sodium reabsorption after preterm delivery.