bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular regulation during hypoxia in embryos of the domestic chickenGallus gallus
Authors: Crossley Dane A. , Burggren Warren W. , Altimiras Jordi
Published: March 2015

Renewed interest in the use of the embryonic chicken as a model of perinatal cardiovascular regulation has inspired new questions about the control mechanisms that respond to acute perturbations, such as hypoxia. The objectives of this study were to determine the cardiovascular responses, the regulatory mechanisms involved in those cardiovascular responses, and whether those mechanisms involved the central nervous system (CNS) of embryonic chickens. Heart rate (fH) and blood pressure were measured in chicken embryos of different incubation ages during exposure to different levels of hypoxia (15, 10, and 5% O2). At all levels of hypoxia and at all developmental ages, a depression of fHand arterial pressure was observed, with the exception of day 20 embryos in 15 and 10% O2. The intensity of the embryonic fHand blood pressure responses were directly related to the level of hypoxia used. Muscarinic and α-adrenergic receptor stimulation limited the hypoxic hypotension on days 15– 19 and 15– 21, respectively, as indicated after blockade with atropine and phentolamine. During the final 3 days of incubation, the intensity of the hypoxic hypotension was magnified due to α-vasodilation caused by β-adrenergic and muscarinic receptor stimulation. In 19- to 21-day-old embryos, the fHresponse to hypoxia was limited by α-adrenergic receptor stimulation as indicated by the accentuated bradycardia after blockade with phentolamine. Furthermore, on day 21, atropine limited the hypoxic bradycardia, indicating that muscarinic receptors also play a role in the fHresponse at this age. In addition, the muscarinic actions on the heart and the adrenergic effects on the vasculature appeared to occur through a hypoxic-induced direct release from chromaffin tissue and autonomic nerve terminals. Thus, in embryonic chickens, the only cardiovascular response to hypoxia that involves the CNS was the cholinergic regulation of arterial pressure after day 15 of incubation. Therefore, although embryonic chickens and fetal sheep, the standard models of perinatal cardiovascular physiology, respond to hypoxia with a similar redistribution of cardiac output, the underlying mechanisms differ between these species.
Countercurrent exchange in the renal medulla
Authors: Pallone Thomas L. , Turner Malcolm R. , Edwards Aurélie , Jamison Rex L.
Published: March 2015

The microcirculation of the renal medulla traps NaCl and urea deposited to the interstitium by the loops of Henle and collecting ducts. Theories have predicted that countercurrent exchanger efficiency is favored by high permeability to solute. In contrast to the conceptualization of vasa recta as simple “U-tube” diffusive exchangers, many findings have revealed surprising complexity. Tubular-vascular relationships in the outer and inner medulla differ markedly. The wall structure and transport properties of descending vasa recta (DVR) and ascending vasa recta (AVR) are very different. The recent discoveries of aquaporin-1 (AQP1) water channels and the facilitated urea carrier UTB in DVR endothelia show that transcellular as well as paracellular pathways are involved in equilibration of DVR plasma with the interstitium. Efflux of water across AQP1 excludes NaCl and urea, leading to the conclusion that both water abstraction and diffusion contribute to transmural equilibration. Recent theory predicts that loss of water from DVR to the interstitium favors optimization of urinary concentration by shunting water to AVR, secondarily lowering blood flow to the inner medulla. Finally, DVR are vasoactive, arteriolar microvessels that are anatomically positioned to regulate total and regional blood flow to the outer and inner medulla. In this review, we provide historical perspective, describe the current state of knowledge, and suggest areas that are in need of further exploration.
Histamine inhibits atrial myocytic ANP release via H2receptor-cAMP-protein kinase signaling
Authors: Li Dan , Wen Jin Fu , Jin Jing Yu , Jin Hua , Ann Hai Sun , Kim Sung Zoo , Kim Suhn Hee , Lee Ho Sub , Cho Kyung Woo
Published: March 2015

Changes in cyclic nucleotide production and atrial dynamics have been known to modulate atrial natriuretic peptide (ANP) release. Although cardiac atrium expresses histamine receptors and contains histamine, the role of histamine in the regulation of ANP release has to be defined. The purpose of the present study was to define the effect of histamine on the regulation of ANP release in perfused beating rabbit atria. Histamine decreased ANP release concomitantly with increases in cAMP efflux and atrial dynamics in a concentration-dependent manner. Histamine-induced decrease in ANP release was a function of an increase in cAMP production. Blockade of histamine H2receptor with cimetidine but not of H1receptor with triprolidine abolished the responses of histamine. Cell-permeable cAMP analog, 8-Br-cAMP, mimicked the effects of histamine, and the responses were dose-dependent and blocked by a protein kinase A (PKA)-selective inhibitor, KT5720. Nifedipine failed to modulate histamine-induced decrease in ANP release. Protein kinase nonselective inhibitor staurosporine blocked histamine-induced changes in a concentration-dependent manner. KT5720 and RP-adenosine 3′,5′-cyclic monophosphorothioate, another PKA-selective inhibitor, attenuated histamine-induced changes. These results suggest that histamine decreases atrial ANP release by H2receptor-cAMP signaling via PKA-dependent and -independent pathways.
Changes in brain glycogen after sleep deprivation vary with genotype
Authors: Franken Paul , Gip Phung , Hagiwara Grace , Ruby Norman F. , Heller H. Craig
Published: March 2015

Sleep has been functionally implicated in brain energy homeostasis in that it could serve to replenish brain energy stores that become depleted while awake. Sleep deprivation (SD) should therefore lower brain glycogen content. We tested this hypothesis by sleep depriving mice of three inbred strains, i.e., AKR/J (AK), DBA/2J (D2), and C57BL/6J (B6), that differ greatly in their sleep regulation. After a 6-h SD, these mice and their controls were killed by microwave irradiation, and glycogen and glucose were quantified in the cerebral cortex, brain stem, and cerebellum. After SD, both measures significantly increased by ∼40% in the cortex of B6 mice, while glycogen significantly decreased by 20–38% in brain stem and cerebellum of AK and D2 mice. In contrast, after SD, glucose content increased in all three structures in AK mice and did not change in D2 mice. The increase in glycogen after SD in B6 mice persisted under conditions of food deprivation that, by itself, lowered cortical glycogen. Furthermore, the strains that differ most in their compensatory response to sleep loss, i.e., AK and D2, did not differ in their glycogen response. Thus glycogen content per se is an unlikely end point of sleep's functional role in brain energy homeostasis.
Sympathetic-renal interaction in chronic arterial pressure control
Authors: Grisk Olaf , Rose Hans-Joachim , Lorenz Gerd , Rettig Rainer
Published: March 2015

The effects of neonatal sympathectomy of donors or recipients on posttransplantation arterial pressure were investigated in spontaneously hypertensive rats (SHR) by renal transplantation experiments. Conscious mean arterial pressure (MAP) and renal vascular resistance were 136 ± 1 mmHg and 15.5 ± 1.2 mmHg · ml−1 · min · g in sympathectomized SHR ( n = 8) vs. 158 ± 4 mmHg ( P < 0.001) and 20.8 ± 1.1 mmHg · ml−1 · min · g ( P < 0.05) in controls ( n = 10). Seven weeks after transplantation of a kidney from neonatally sympathectomized SHR donors, MAP in SHR recipients ( n = 10) was 20 mmHg lower than in controls transplanted with a kidney from hydralazine-treated SHR ( n = 10) ( P < 0.05) associated with reduced sodium sensitivity of MAP. Neonatal sympathectomy also lowered MAP in F1-hybrids (F1H; SHR × Wistar-Kyoto rats). Within 6 wk after transplantation, renal grafts from untreated SHR increased MAP by 20 mmHg in sympathectomized F1H ( n = 10) and by 35 mmHg in sham-treated F1H ( n = 8) ( P < 0.05). Neonatal sympathectomy induces chronic changes in SHR kidney function leading to a MAP reduction even when extrarenal sympathetic tone is restored. Generalized reduction in sympathetic tone resets the kidney-fluid system to reduced MAP and blunts the extent of arterial pressure rise induced by an SHR kidney graft.
Attenuated defense response and low basal blood pressure in orexin knockout mice
Authors: Kayaba Yuji , Nakamura Akira , Kasuya Yoshitoshi , Ohuchi Takashi , Yanagisawa Masashi , Komuro Issei , Fukuda Yasuichiro , Kuwaki Tomoyuki
Published: March 2015

The perifornical area of the hypothalamus has been known as the center for the defense response, or “fight or flight” response, which is characterized by a concomitant rise in arterial blood pressure (AP), heart rate (HR), and respiratory frequency (Rf). We examined whether orexin, a recently identified hypothalamic neuropeptide, contributes to the defense response and basal cardiovascular regulation using orexin knockout mice. Microinjection of a GABA-A receptor antagonist, bicuculline methiodide (0.1-1 mM in 20 nl), to the perifornical area in urethane-anesthetized wild-type mice elicited dose-dependent increases in AP, HR, and Rf. Although similar changes were observed in orexin knockout mice, intensities were smaller and duration was shorter than those in wild-type mice. Moreover, in an awake and freely moving condition, telemeter-indwelling orexin knockout mice showed diminished cardiovascular and behavioral responses to emotional stress in the resident-intruder test. We also found that basal AP in orexin knockout mice was significantly lower in both anesthetized (117 ± 8 mmHg in wild type and 92 ± 3 in knockout) and conscious (125 ± 6 mmHg in wild type and 109 ± 2 in knockout) conditions. α-Adrenergic blockade with prazosin or ganglion blockade with hexamethonium canceled the difference in basal AP. HR and cardiac contractile parameters by echocardiography did not differ between the two strains of mice. These results indicate lower sympathetic vasoconstrictor tone in knockout mice. The present study suggests that orexin-containing neurons in the perifornical area play a role as one of the efferent pathways of defense response and also operate as a regulator of AP at basal condition by activating sympathetic outflow.
Facilitatory role of NO in neural norepinephrine release in the rat kidney
Authors: Tanioka Hideki , Nakamura Koichi , Fujimura Shinsei , Yoshida Makoto , Suzuki-Kusaba Mizue , Hisa Hiroaki , Satoh Susumu
Published: March 2015

We examined modulation by nitric oxide (NO) of sympathetic neurotransmitter release and vasoconstriction in the isolated pump-perfused rat kidney. Electrical renal nerve stimulation (RNS; 1 and 2 Hz) increased renal perfusion pressure and renal norepinephrine (NE) efflux. Nonselective NO synthase (NOS) inhibitors [ Nω-nitro-l-arginine methyl ester (l-NAME) or Nω-nitro-l-arginine], but not a selective neuronal NO synthase inhibitor (7-nitroindazole sodium salt), suppressed the NE efflux response and enhanced the perfusion pressure response. Pretreatment with l-arginine prevented the effects of l-NAME on the RNS-induced responses. 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), which eliminates NO by oxidizing it to NO2, suppressed the NE efflux response, whereas the perfusion pressure response was less susceptible to carboxy-PTIO. 8-Bromoguanosine cGMP suppressed and a guanylate cyclase inhibitor [4 H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one] enhanced the RNS-induced perfusion pressure response, but neither of these drugs affected the NE efflux response. These results suggest that endogenous NO facilitates the NE release through cGMP-independent mechanisms, NO metabolites formed after NO2rather than NO itself counteract the vasoconstriction, and neuronal NOS does not contribute to these modulatory mechanisms in the sympathetic nervous system of the rat kidney.
Positive correlation of skeletal muscle UCP3 mRNA levels with overweight in male, but not in female, rats
Authors: Rodríguez Ana M. , Roca Pilar , Bonet M. Luisa , Picó Catalina , Oliver Paula , Palou Andreu
Published: March 2015

The objective of this study was to investigate the sex-dependent regulation of skeletal muscle uncoupling protein (UCP)3 mRNA expression in response to overweight and its relationship with serum levels of free fatty acids, leptin, and insulin. Two obesity models were used: rats made obese by feeding them with a cafeteria diet for 14 wk, and postcafeteria overweight rats fed a chow diet for 10 wk after consuming the cafeteria diet for 14 wk. The effects of 24-h fasting were studied in postcafeteria rats and their age-matched controls. The cafeteria rats ate a high-fat diet and attained an excess body weight that was higher in females (+59%) than in males (+39%). A trend to higher induction of abdominal muscle UCP3 mRNA in male rats than in females after cafeteria diet was apparent (+116% increase vs. +26% increase). Postcafeteria male but not female rats still showed the tendency to have increased UCP3 mRNA levels relative to their age-matched controls. A linear regression analysis showed a significant positive correlation of the UCP3 mRNA levels with overweight and with serum levels of leptin and insulin in males, but not in females, and no correlation with serum free fatty acid levels. A subsequent correlation analysis and a multiple linear regression analysis showed that overweight was the only parameter actually related to UCP3 mRNA levels in males. Fasting-induced upregulation of muscle UCP3 mRNA levels was higher in males (5- to 7-fold) than in females (3- to 4-fold). Our results point to the existence of sex-associated differences in the control of muscle UCP3 expression in response to overweight and fasting, with an impaired induction in female rats under both conditions. The correlation of abdominal muscle UCP3 mRNA expression with overweight in males could be related to their relative resistance to gain weight after chronic overeating of a cafeteria diet, by the purported role of UCP3 in the regulation of lipid utilization.
Microvessel formation from mouse embryonic aortic explants is oxygen and VEGF dependent
Authors: Akimoto Tetsu , Liapis Helen , Hammerman Marc R.
Published: March 2015

To delineate the roles of O2and vascular endothelial growth factor (VEGF) in the process of angiogenesis from the embryonic aorta, we cultured mouse embryonic aorta explants (thoracic level to lateral vessels supplying the mesonephros and metanephros) in a three-dimensional type I collagen gel matrix. During 8 days of culture under 5% O2, but not room air, the addition of VEGF to explants stimulated the formation of CD31-positive, Flk-1-positive, Gs-IB4-positive structures in a concentration-dependent manner. Electron microscopy showed the structures to be capillary-like. VEGF-induced capillary-like structure formation was inhibited by sequestration of VEGF via addition of soluble Flt-1 fusion protein or anti-VEGF antibodies. Expression of Flk-1, but not Flt-1, was increased in embryonic aorta cultured under 5% O2relative to room air. Our data suggest that low O2upregulates Flk-1 expression in embryonic aorta in vitro and renders it more responsive to VEGF.
ANG II is involved in the LPS-induced production of proinflammatory cytokines in dehydrated rats
Authors: Miyoshi Michio , Nagata Katsumi , Imoto Toshiaki , Goto Osamu , Ishida Akiko , Watanabe Tatsuo
Published: March 2015

We have previously reported results that led us to speculate that ANG II is involved in the LPS-induced production of proinflammatory cytokines, especially under dehydrated conditions. To test this possibility, in this study we examined the effects of an angiotensin-converting enzyme (ACE) inhibitor and an antagonist of the type-1 ANG II receptor (AT1receptor) on the LPS-induced production of the proinflammatory cytokines IL-1 and IL-6 in dehydrated rats. A single intravenous injection of LPS induced a marked increase in the expression of IL-1β mRNA in the liver, an effect that was significantly attenuated by pretreatment with the ACE inhibitor. Furthermore, the ACE inhibitor reduced the LPS-induced increase in the hepatic concentration of IL-1β protein. When the AT1-receptor antagonist was given intravenously before the LPS, the increase in the hepatic concentration of IL-1β was significantly reduced. Finally, the ACE inhibitor reduced the LPS-induced increase in the plasma concentration of IL-6. These results represent the first in vivo evidence that ANG II and its AT1receptor play important roles in the production of proinflammatory cytokines that is induced by LPS under dehydrated conditions.
Glutamine and KGF each regulate extracellular thiol/disulfide redox and enhance proliferation in Caco-2 cells
Authors: Jonas Carolyn R. , Gu Li H. , Nkabyo Yvonne S. , Mannery Yanci O. , Avissar Nelly E. , Sax Harry C. , Jones Dean P. , Ziegler Thomas R.
Published: March 2015

Glutamine (Gln) and keratinocyte growth factor (KGF) each stimulate intestinal epithelial cell growth, but regulatory mechanisms are not well understood. We determined whether Gln and KGF alter intra- and extracellular thiol/disulfide redox pools in Caco-2 cells cultured in oxidizing or reducing cell medium and whether such redox variations are a determinant of proliferative responses to these agents. Cells were cultured over a physiological range of oxidizing to reducing extracellular thiol/disulfide redox (Eh) conditions, obtained by varying cysteine (Cys) and cystine (CySS) concentrations in cell medium. Cell proliferation was determined by 5-bromo-2-deoxyuridine (BrdU) incorporation. Gln (10 mmol/l) or KGF (10 μg/l) did not alter BrdU incorporation at reducing Eh (-131 to -150 mV), but significantly increased incorporation at more oxidizing Eh (Gln at 0 to -109 mV; KGF at -46 to -80 mV). Cellular glutathione/glutathione disulfide (GSH/GSSG) Eh was unaffected by Gln, KGF, or variations in extracellular Cys/CySS Eh. Control cells largely maintained extracellular Eh at initial values after 24 h (-36 to -136 mV). However, extracellular Eh shifted toward a narrow physiological range with Gln and KGF treatment (Gln -56 to -88 mV and KGF -76 to -92 mV, respectively; P < 0.05 vs. control). The results indicate that thiol/disulfide redox state in the extracellular milieu is an important determinant of Caco-2 cell proliferation induced by Gln and KGF, that this control is independent of intracellular GSH redox status, and that both Gln and KGF enhance the capability of Caco-2 cells to modulate extremes of extracellular redox.
Effects of cortisol and prolactin on Na+and Cl-transport in cultured branchial epithelia from FW rainbow trout
Authors: Zhou Bingsheng , Kelly Scott P. , Ianowski Juan P. , Wood Chris M.
Published: March 2015

The electrophysiological and ion-transporting properties of cultured gill epithelia from freshwater (FW) rainbow trout were examined in the presence of cortisol and prolactin as media supplements. Epithelia were of the double-seeded insert (DSI) type containing both pavement cells (PVCs) and mitochondria-rich cells (MRCs) and were grown in Leibovitz's L15 media on filters allowing exposure to different apical media conditions. Experiments were carried out in two series after 7-9 days symmetrical (L15 apical-L15 basolateral) culture. In both series, 100% L15 was maintained as the basolateral medium throughout and supplemented with physiologically relevant doses of either prolactin (50 ng/ml), cortisol (500 ng/ml), or cortisol + prolactin (500 + 50 ng/ml, respectively). In series 1, epithelia were exposed to progressively diluted apical media (100, 75, 50, 25, 12.5% L15, and FW) at 24-h intervals. The preparations retained integrity [high transepithelial resistance (TER); low ion efflux rates] during this prolonged dilution protocol. Cortisol, or cortisol + prolactin, resulted in a greater TER and reduced ion efflux rates during dilution, likely an effect on junctional permeability of PVCs, but did not promote active Na+and Cl-uptake from apical FW. In series 2, epithelia were directly exposed to apical FW and ion fluxes measured over the first 6 h. Under these conditions, cortisol or cortisol + prolactin promoted active uptake of both Na+and Cl-simultaneously from apical FW, probably attributable to actions on the MRCs. However, Na+-K+-ATPase activities were not significantly altered by any of the treatments in either series. Overall, prolactin alone did not appear to promote FW adaptation but exhibited synergism with cortisol. These results provide further support for the cultured DSI epithelium as an in vitro model for ion transport in FW fish.
Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification
Authors: Janssen Ben J. A. , Smits Jos F. M.
Published: March 2015

Control of blood pressure and of blood flow is essential for maintenance of homeostasis. The hemodynamic state is adjusted by intrinsic, neural, and hormonal mechanisms to optimize adaptation to internal and environmental challenges. In the last decade, many studies showed that modification of the mouse genome may alter the capacity of cardiovascular control systems to respond to homeostatic challenges or even bring about a permanent pathophysiological state. This review discusses the progress that has been made in understanding of autonomic cardiovascular control mechanisms from studies in genetically modified mice. First, from a physiological perspective, we describe how basic hemodynamic function can be measured in conscious conditions in mice. Second, we focus on the integrative role of autonomic nerves in control of blood pressure in the mouse, and finally, we depict the opportunities and insights provided by genetic modification in this area.
Dual effects of acupuncture on gastric motility in conscious rats
Authors: Tatewaki Makoto , Harris Mary , Uemura Kenichiro , Ueno Tomio , Hoshino Etsuo , Shiotani Akiko , Pappas Theodore N. , Takahashi Toku
Published: March 2015

The effects of manual acupuncture on gastric motility were investigated in 35 conscious rats implanted with a strain gauge transducer. Twenty (57.1%) rats showed no cyclic groupings of strong contractions ( type A), whereas 15 (42.9%) rats showed the phase III-like contractions of the migrating motor complex ( type B) in the fasting gastric motility. Acupuncture at the stomach (ST)-36 (Zusanli), but not on the back [Weishu, bladder (BL)-21], increased the peak amplitude of contractions to 172.4 ± 25.6% of basal in the type A rats ( n = 20, P < 0.05). On the other hand, the motility index for 60 min after the acupuncture was not affected by the acupuncture in this group. On the contrary, acupuncture decreased the peak amplitude and motility index to 72.9 ± 14.0% and 73.6 ± 16.2% in the type B rats ( n = 15, P < 0.05), respectively. The stimulatory and inhibitory effects of acupuncture observed in each type were reproducible on the separate days. In 70% of type A rats, acupuncture induced strong phase III-like contractions lasting for over 3 h that were abolished by atropine, hexamethonium, atropine methyl bromide, and vagotomy. Naloxone significantly shortened the duration of the stimulatory effects from 3.52 ± 0.21 to 1.02 ± 0.15 h ( n = 3, P < 0.05). These results suggest that acupuncture at ST-36 induces dual effects, either stimulatory or inhibitory, on gastric motility. The stimulatory effects are mediated in part via vagal efferent and opioid pathways.
Importance of lipolysis in oral cavity for orosensory detection of fat
Authors: Kawai Takayuki , Fushiki Tohru
Published: March 2015

Lingual lipase is usually secreted from von Ebner's glands, although there is great variation between species. Lingual lipase is thought to be an auxiliary enzyme for fat digestion and absorption in mammals; however, the reason for lipolysis in the oral cavity is not known. We focused on the gustatory sense and investigated the significance of lingual lipase in the perception of a fat taste by using orlistat, a potent lipase inhibitor. Five-minute two-bottle preference tests demonstrated that the addition of orlistat diminished the preference for triacylglycerides but not for free fatty acids. Radioactive triolein applied on rats' circumvallate papilla revealed that lingual lipase was released continuously to generate significant amounts of fatty acids and other lipolytic products within 1–5 s, which was enough time to taste fat. These findings suggest that lingual lipase is released to perceive the taste of triacylglycerides and to find nutritive lipids in food.
Chemokines and chemokine receptors in leukocyte trafficking
Authors: Olson Timothy S. , Ley Klaus
Published: March 2015

Chemokines regulate inflammation, leukocyte trafficking, and immune cell differentiation. The role of chemokines in homing of naive T lymphocytes to secondary lymphatic organs is probably the best understood of these processes, and information on chemokines in inflammation, asthma, and neurological diseases is rapidly increasing. Over the past 15 years, understanding of the size and functional complexity of the chemokine family of peptide chemoattractants has grown substantially. In this review, we first present information regarding the structure, expression, and signaling properties of chemokines and their receptors. The second part is a systems physiology-based overview of the roles that chemokines play in tissue-specific homing of lymphocyte subsets and in trafficking of inflammatory cells. This review draws on recent experimental findings as well as current models proposed by experts in the chemokine field.
Attenuated renovascular constrictor responses to angiotensin II in adenosine 1 receptor knockout mice
Authors: Hansen Pernille B. , Hashimoto Seiji , Briggs Josie , Schnermann Jurgen
Published: March 2015

In the present experiments we examined the renovascular constrictor effects of ANG II in the chronic and complete absence of A1 adenosine receptors (A1AR) using mice with targeted deletion of the A1AR gene. Glomerular filtration rate (GFR) was not different between A1AR +/+ and A1AR -/- mice under control conditions (450.5 ± 60 vs. 475.2 ± 62.5 μl/min) but fell significantly less in A1AR -/- mice during infusion of ANG II at 1.5 ng/min (A1AR +/+: 242 ± 32.5 μl/min, A1AR -/-: 371 ± 42 μl/min; P = 0.03). Bolus injection of 1, 10, and 100 ng of ANG II reduced renal blood flow and increased renal vascular resistance significantly more in A1AR +/+ than in A1AR -/- mice. Perfused afferent arterioles isolated from A1AR +/+ mice constricted in response to bath ANG II with an EC50of 1.5 ± 0.4 × 10-10mol/l, whereas a right shift in the dose-response relationship with an EC50of 7.3 ± 1.2 × 10-10mol/l ( P < 0.05) was obtained in arterioles from A1AR -/- mice ( P < 0.05). The expression of AT1A receptor mRNA was not different in kidney RNA from A1AR +/+ or A1AR -/- mice. We conclude that chronic A1AR deficiency diminishes the effectiveness of ANG II to constrict renal resistance vessels and to reduce GFR.
Venular-arteriolar communication in the regulation of blood flow
Authors: Hester Robert L. , Hammer Leah W.
Published: March 2015

Muscle blood flow is regulated to meet the metabolic needs of the tissue. With the vasculature arranged as a successive branching of arterioles and the larger, >50 μm, arterioles providing the major site of resistance, an increasing metabolic demand requires the vasodilation of the small arterioles first then the vasodilation of the more proximal, larger arterioles. The mechanism(s) for the coordination of this ascending vasodilation are not clear and may involve a conducted vasodilation and/or a flow-dependent response. The close arteriolar-venular pairing provides an additional mechanism by which the arteriolar diameter can be increased due to the diffusion of vasoactive substances from the venous blood. Evidence is presented that the venular endothelium releases a relaxing factor, a metabolite of arachidonic acid, that will vasodilate the adjacent arteriole. The stimulus for this release is not known, but it is hypothesized that hypoxia-induced ATP release from red blood cells may be responsible for the stimulation of arachidonic release from the venular endothelial cells. Thus the venous circulation is in an optimal position to monitor the overall metabolic state of the tissue and thus provide a feedback regulation of arteriolar diameter.
Differential mechanisms for regulation of the stress response across latitudinal gradients
Authors: Breuner C. W. , Orchinik M. , Hahn T. P. , Meddle S. L. , Moore I. T. , Owen-Ashley N. T. , Sperry T. S. , Wingfield J. C.
Published: March 2015

We examined plasticity of the stress response among three populations of the white-crowned sparrow ( Zonotrichia leucophrys). These populations breed at different elevations and latitudes and thus have breeding seasons that differ markedly in length. We hypothesize that in populations where birds raise only one or rarely two broods in a season, the fitness costs of abandoning a nest are substantially larger than in closely related populations that raise up to three broods per season. Thus individuals with short breeding seasons should be less responsive to stressors and therefore less likely to abandon their young. In our study, baseline and handling-induced corticosterone levels were similar among populations, but corticosteroid-binding globulins differed, leading to a direct relationship between stress-induced free corticosteroid levels and length of breeding season. There were also population-specific differences in intracellular low-affinity (glucocorticoid-like) receptors in both liver and brain tissue. Although investigations of population-based differences in glucocorticoid secretion are common, this is the first study to demonstrate population-level differences in binding globulins. These differences could lead to dramatically different physiological and behavioral responses to stress.
A compartmental model of magnesium metabolism in healthy men based on two stable isotope tracers
Authors: Sabatier Magalie , Pont Frédéric , Arnaud Maurice J. , Turnlund Judith R.
Published: March 2015

The aim of this study was to build a compartmental model of magnesium (Mg) kinetics by using data collected from six healthy adult men after oral administration of26Mg and intravenous administration of25Mg. Blood, urine, and feces were collected for 12 days after administration of the isotopes. Isotopic ratios were determined by inductively coupled plasma-mass spectrometry. Data were analyzed for each subject using SAAMII. We began with a compartmental model previously proposed (Avioli LV and Berman M. J Appl Physiol 21: 1688-1694, 1966) and developed an alternative approach to resolve the discrepancy between model-predicted curves and experimental data. This analysis enables the exploration of 25% of total body Mg that exchanges rapidly from plasma compartment with two extraplasma pools. One of the extraplasma compartments contains 80% of the exchangeable Mg with a transport rate of 48 ± 13 mg/h. The second exchanges 179 ± 88 mg of Mg/h. The model permitted estimation of kinetic parameters as well as fractional Mg absorption and fecal endogenous excretion.
An oxidized metabolite of linoleic acid stimulates corticosterone production by rat adrenal cells
Authors: Bruder Eric D. , Ball Dennis L. , Goodfriend Theodore L. , Raff Hershel
Published: March 2015

Oxidized derivatives of linoleic acid have the potential to alter steroidogenesis. One such derivative is 12,13-epoxy-9- keto-10-( trans)-octadecenoic acid (EKODE). To evaluate the effect of EKODE on corticosterone production, dispersed rat zona fasciculata/reticularis (subcapsular) cells were incubated for 2 h with EKODE alone or together with rat ACTH (0, 0.2, or 2.0 ng/ml). In the absence of ACTH, EKODE (26 μM) increased corticosterone production from 5.3 ± 2.3 to 14.7 ± 5.0 ng · 106cells · h−1. The stimulatory effect of ACTH was increased threefold in the presence of EKODE (26.0 μM). Cholesterol transport/ P-450scc activity was assessed by measuring basal and cAMP-stimulated pregnenolone production in the presence of cyanoketone (1.1 μM). EKODE (13.1 and 26.0 μM) significantly increased basal and cAMP-stimulated (0.1 mM) pregnenolone production. In contrast, EKODE decreased the effect of 1.0 mM cAMP. EKODE had no effect on early or late-pathway activity in isolated mitochondria. We conclude that EKODE stimulates corticosterone biosynthesis and amplifies the effect of ACTH. Increased levels of fatty acid metabolites may be involved in the increased glucocorticoid production observed in obese humans.
Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models
Authors: Khalil Raouf A. , Granger Joey P.
Published: March 2015

Normal pregnancy is associated with reductions in total vascular resistance and arterial pressure possibly due to enhanced endothelium-dependent vascular relaxation and decreased vascular reactivity to vasoconstrictor agonists. These beneficial hemodynamic and vascular changes do not occur in women who develop preeclampsia; instead, severe increases in vascular resistance and arterial pressure are observed. Although preeclampsia represents a major cause of maternal and fetal morbidity and mortality, the vascular and cellular mechanisms underlying this disorder have not been clearly identified. Studies in hypertensive pregnant women and experimental animal models suggested that reduction in uteroplacental perfusion pressure and the ensuing placental ischemia/hypoxia during late pregnancy may trigger the release of placental factors that initiate a cascade of cellular and molecular events leading to endothelial and vascular smooth muscle cell dysfunction and thereby increased vascular resistance and arterial pressure. The reduction in uterine perfusion pressure and the ensuing placental ischemia are possibly caused by inadequate cytotrophoblast invasion of the uterine spiral arteries. Placental ischemia may promote the release of a variety of biologically active factors, including cytokines such as tumor necrosis factor-α and reactive oxygen species. Threshold increases in the plasma levels of placental factors may lead to endothelial cell dysfunction, alterations in the release of vasodilator substances such as nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor, and thereby reductions of the NO-cGMP, PGI2-cAMP, and hyperpolarizing factor vascular relaxation pathways. The placental factors may also increase the release of or the vascular reactivity to endothelium-derived contracting factors such as endothelin, thromboxane, and ANG II. These contracting factors could increase intracellular Ca2+concentrations ([Ca2+]i) and stimulate Ca2+-dependent contraction pathways in vascular smooth muscle. The contracting factors could also increase the activity of vascular protein kinases such as protein kinase C, leading to increased myofilament force sensitivity to [Ca2+]iand enhancement of smooth muscle contraction. The decreased endothelium-dependent mechanisms of vascular relaxation and the enhanced mechanisms of vascular smooth muscle contraction represent plausible causes of the increased vascular resistance and arterial pressure associated with preeclampsia.
Is osmolality a long-term regulator of renal sympathetic nerve activity in conscious water-deprived rats?
Authors: Scrogin Karie E. , McKeogh Donogh F. , Brooks Virginia L.
Published: March 2015

Acute increases in osmolality suppress renal sympathetic nerve activity (RSNA). However, it is not known whether prolonged physiological increases in plasma osmolality chronically inhibit RSNA. To address this hypothesis, mean arterial blood pressure (MAP), heart rate (HR), and RSNA were measured during acute normalization of plasma osmolality in conscious rats made hyperosmotic by 48 h of water deprivation. Water deprivation significantly elevated MAP (120 ± 1 vs. 114 ± 3 mmHg, P < 0.05) and plasma osmolality (306 ± 1 vs. 293 ± 1 mosmol/kgH20, P < 0.01). When plasma osmolality was subsequently lowered to normal (−17 ± 1 mosmol/kgH20) with a 2-h (0.12 ml/min) infusion of 5% dextrose in water (5DW), MAP decreased (−11 ± 1 mmHg), and RSNA increased (25 ± 10% baseline). To assess the role of circulating vasopressin in these changes, rats were pretreated with a V1-vasopressin receptor antagonist before infusion of 5DW. The antagonist lowered MAP (−4 ± 1 mmHg) and raised RSNA (31 ± 3% baseline) and HR (25 ± 5 beats/min) in water-deprived rats (all changes P < 0.05). However, V1-vasopressin receptor blockade did not increase RSNA or HR independently of baroreflex responses to decreases in arterial pressure. After V1 blockade, infusion of 5DW lowered blood pressure (−8 ± 1 mmHg) but did not further affect HR or RSNA. An isotonic saline infusion that produced the same volume expansion as 5DW lowered MAP (−5 ± 2 mmHg) and HR (−68 ± 2 beats/min) but had no effect on osmolality or RSNA in water-deprived rats. Finally, 5DW infusion had negligible effects in water-replete animals. In conclusion, these results fail to support the hypothesis that sustained increases in plasma osmolality, either directly or via increased vasopressin, tonically suppress RSNA.
Arachidonic acid inhibits K channels in basolateral membrane of the thick ascending limb
Authors: Gu Rui-Min , Wang Wen-Hui
Published: March 2015

We have used the patch-clamp technique to study the effect of arachidonic acid (AA) on the basolateral K channels in the medullary thick ascending limb (mTAL) of rat kidney. An inwardly rectifying 50-pS K channel was identified in cell-attached and inside-out patches in the basolateral membrane of the mTAL. The channel open probability ( Po) was 0.51 at the spontaneous cell membrane potential and decreased to 0.25 by 30 mV hyperpolarization. The addition of 5 μM AA decreased channel activity, identified as NPo, from 0.58 to 0.08 in cell-attached patches. The effect of AA on the 50-pS K channel was specific because 10 μM cis-11,14,17-eicosatrienoic acid had no significant effect on channel activity. To determine whether the effect of AA was mediated by AA per se or by its metabolites, we examined the effect of AA on channel activity in the presence of indomethacin, an inhibitor of cyclooxygenase, or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), an inhibitor of cytochrome P-450 monooxygenase. Inhibition of cyclooxygenase increased channel activity from 0.54 to 0.9. However, indomethacin did not abolish the inhibitory effect of AA on the 50-pS K channel. In contrast, inhibition of cytochrome P-450 metabolism not only increased channel activity from 0.49 to 0.83 but also completely abolished the effect of AA. Moreover, addition of DDMS can reverse the inhibitory effect of AA on channel activity. The notion that the effect of AA was mediated by cytochrome P-450-dependent metabolites of AA is also supported by the observation that addition of 100 nM of 20-hydroxyeicosatetraenoic acid, a main metabolite of AA in the mTAL, can mimic the effect of AA. We conclude that AA inhibits the 50-pS K channel in the basolateral membrane of the mTAL and that the effect of AA is mainly mediated by cytochrome P-450-dependent metabolites of AA.
Developmental changes in rabbit proximal straight tubule paracellular permeability
Authors: Quigley Raymond , Baum Michel
Published: March 2015

The early proximal tubule preferentially reabsorbs organic solutes and bicarbonate over chloride ions, resulting in a luminal fluid with a higher chloride concentration than that in blood. From this late proximal tubular fluid, one-half of NaCl reabsorption by the adult proximal tubule is active and transcellular and one-half is passive and paracellular. The purpose of the present in vitro microperfusion study was to determine the characteristics of passive chloride transport and permeability properties of the adult and neonatal proximal straight tubules (PST). In tubules perfused with a late proximal tubular fluid, net passive chloride flux was 131.7 ± 37.7 pmol · mm−1· min−1in adult tubules and −17.1 ± 23.3 pmol · mm−1· min−1in neonatal proximal tubules ( P < 0.01). Chloride permeability was 10.94 ± 5.21 × 10−5cm/s in adult proximal tubules and −1.26 ± 1.84 × 10−5cm/s in neonatal proximal tubules ( P< 0.05). Thus neonatal PST have a chloride permeability not different from zero and have no net passive chloride transport. Bicarbonate permeability is also less in neonates than adults in this segment (−0.07 ± 0.03 × 10−5vs. 0.93 ± 0.27 × 10−5cm/s, P < 0.01). Neonatal PST have higher sodium-to chloride and bicarbonate-to-chloride permeability ratios than adult PST. However, mannitol and sucrose permeabilities were not different in adult proximal tubules and neonatal PST. Transepithelial resistance was measured using current injection and cable analysis. The resistance was 6.7 ± 0.7 Ω · cm2in adult tubules and 11.3 ± 1.4 Ω · cm2in neonatal PST ( P < 0.01). In conclusion, there are significant maturational changes in the characteristics of the PST paracellular pathway affecting transport in this nephron segment.
Circulating endothelial cells: tea leaves for renal disease
Authors: Segal Mark S. , Bihorac Azra , Koç Mehmet
Published: March 2015

Fully differentiated endothelial cells and their precursors circulate in the bloodstream. Since their initial description more than 30 years ago, circulating endothelial cells have been quantified in a number of different clinical conditions that affect the endothelium. Only recently, however, have investigators begun to examine the protein expression and functionality of these cells. Because a number of diseases prevalent in the field of nephrology affect endothelial cells, the study of circulating endothelial cells may allow the direct examination of the state of the endothelium in these conditions. This review will discuss the endothelium and renal disease, the methods to quantify these circulating endothelial cells, their origins, and their therapeutic potential.
Protective effect of glycine on renal injury induced by ischemia-reperfusion in vivo
Authors: Yin Ming , Zhong Zhi , Connor Henry D. , Bunzendahl Hartwig , Finn William F. , Rusyn Ivan , Li Xiangli , Raleigh James A. , Mason Ronald P. , Thurman Ronald G.
Published: March 2015

Although glycine prevents renal tubular cell injury in vitro, its effect in vivo is not clear. The purpose of this study was to investigate whether a bolus injection of glycine given before reperfusion plus continuous dietary supplementation afterward would reduce renal injury caused by ischemia-reperfusion. Female Sprague-Dawley rats received a semisynthetic powdered diet containing 5% glycine and 15% casein (glycine group) or 20% casein (control group). Two days later, renal ischemia was produced by cross-clamping the left renal vessels for 15 min, followed by reperfusion. The right kidney was removed before reperfusion. The postischemic glomerular filtration rate (GFR) showed that renal function was less impaired and recovered more quickly in rats receiving glycine. For example, at day 7, GFR in controls (0.31 ± 0.03 ml · min−1 · 100 g−1) was about one-half that of glycine-treated rats (0.61 ± 0.06 ml · min−1 · 100 g−1, P < 0.05). Furthermore, tubular injury and cast formation observed in controls was minimized by glycine (pathology score, 3.2 ± 0.4 vs. 1.0 ± 0.4, P < 0.05). Urinary lactate dehydrogenase (LDH) concentration was elevated by ischemia-reperfusion in the control group (260 ± 22 U/l), but values were significantly lower by about fourfold (60 ± 30 U/l) in glycine-fed rats. Similarly, free radical production in urine was significantly lower in glycine-treated animals. Importantly, on postischemic day 1, binding of pimonidazole, an in vivo hypoxia marker, was increased in the outer medulla in controls; however, this phenomenon was prevented by glycine. Two weeks later, mild leukocyte infiltration and interstitial fibrosis were still observed in controls, but not in kidneys from glycine-treated rats. In conclusion, these results indicate that administration of glycine indeed reduces mild ischemia-reperfusion injury in the kidney in vivo, in part by decreasing initial damage and preventing chronic hypoxia.
Stenosis-dependent role of nitric oxide and prostaglandins in chronic renal ischemia
Authors: Tokuyama Hirobumi , Hayashi Koichi , Matsuda Hiroto , Kubota Eiji , Honda Masanori , Okubo Ken , Ozawa Yuri , Saruta Takao
Published: March 2015

The role of nitric oxide (NO) and prostaglandins (PG) in modifying renal hemodynamics was examined in clipped and nonclipped kidneys of unilateral renal artery stenosis. Chronic unilateral renal ischemia was established by 4-wk-clipping the left renal artery of canine kidneys, and renal interstitial nitrate+nitrite and PGE2contents were evaluated by the microdialysis technique. Unilateral renal artery stenosis caused 45 ± 1 and 73 ± 1% decrements in renal plasma flow (RPF) in moderately and severely clipped kidneys and 21 ± 3% decrements in nonclipped kidneys with severe stenosis. Renal nitrate+nitrite decreased in moderately (−31 ± 1%) and severely clipped kidneys (−63 ± 4%). Nω-nitro-l-arginine methyl ester reduced RPF (−56 ± 3%) and glomerular filtration rate (GFR; −54 ± 3%) in moderately clipped kidneys, whereas this inhibitory effect was abolished in severely clipped kidneys. In contrast, renal PGE2contents increased modestly in moderate clipping and were markedly elevated in severely clipped kidneys (from 111 ± 7 to 377 ± 22 pg/ml); sulpyrine impaired renal hemodynamics only in severely clipped kidneys. In contralateral nonclipped kidneys, although renal PGE2was not increased, sulpyrine reduced RPF (−32 ± 1%) and GFR (−33 ± 3%) in severe stenosis. Collectively, NO plays a substantial role in maintaining renal hemodynamics both under basal condition and in moderate renal artery stenosis, whereas the contributory role shifts from NO to PG as renal artery stenosis progresses. Furthermore, because intrarenal angiotensin II is reported to increase in nonclipped kidneys, unilateral severe ischemia may render the nonclipped kidney susceptible to PG inhibition.
Sodium transporter abundance profiling in kidney: effect of spironolactone
Authors: Nielsen Jakob , Kwon Tae-Hwan , Masilamani Shyama , Beutler Kathleen , Hager Henrik , Nielsen Søren , Knepper Mark A.
Published: March 2015

Renal tubule profiling studies were carried out to investigate the long-term effects of administration of spironolactone, a mineralocorticoid receptor antagonist, on abundances of the major Na transporter and Na channel proteins along the rat renal tubule. Oral administration of spironolactone for 7 days to NaCl-restricted rats did not significantly alter abundances of Na transporters expressed proximal to the macula densa, while substantially decreasing the abundances of the thiazide-sensitive Na-Cl cotransporter (NCC), the α-subunit of the amiloride-sensitive epithelial Na channel (ENaC), and the 70-kDa form of the γ-subunit of ENaC. A dependency of NCC expression on aldosterone was confirmed by showing increased NCC expression in response to aldosterone infusion in adrenalectomized rats. Immunoperoxidase labeling of ENaC in renal cortex confirmed that dietary NaCl restriction causes a redistribution of ENaC to the apical domain of connecting tubule cells and showed that high-dose spironolactone administration does not block this apical redistribution. In contrast, spironolactone completely blocked the increase in α-ENaC abundance in response to dietary NaCl restriction. We conclude that the protein abundances of NCC, α-ENaC, and the 70-kDa form of γ-ENaC are regulated via the classical mineralocorticoid receptor, but the subcellular redistribution of ENaC in response to dietary NaCl restriction is not prevented by blockade of the mineralocorticoid receptor.