bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidermal growth factor and fluid and electrolyte balance in the rat
Authors: Grant S. L. , Gow C. B. , Phillips P. A.
Published: December 2017

Epidermal growth factor (EGF) has been shown to induce a renal diuresis and natriuresis in sheep and stimulate prostaglandin synthesis from inner rat medullary collecting duct cells in culture. The aims of our study were 1) to investigate whether the renal effects of intravenous infusion of EGF were species specific and 2) to determine the mechanism of these effects by studying the interaction between EGF and indomethacin (a prostaglandin synthase inhibitor) in the conscious rat. Sprague-Dawley rats received intravenous infusions of either 0.9% saline or 0.2 or 2.0 micrograms EGF.kg-1.h-1 over a 6-day period after an initial baseline period. Infusion of 2.0 micrograms EGF.kg-1.h-1 caused an increase in urine volume (baseline: 5.5 +/- 0.2 ml to day 5: 9.0 +/- 0.4 ml, P < 0.01) and corresponding polydipsia, but not natriuresis. Administration of indomethacin with 2.0 micrograms EGF.kg-1.h-1 attenuated (P < 0.05) the diuretic (day 5 EGF + vehicle: 12.2 +/- 1.1 ml vs. EGF + indomethacin: 8.7 +/- 0.9 ml) and polydipsic effects of EGF. These studies demonstrate that intravenous infusion of EGF causes a diuretic effect in rats without natriuresis and that prostaglandins play a role in the diuretic effect of EGF in the rat.
Water deprivation and rat adrenal mRNAs for tyrosine hydroxylase and the norepinephrine transporter
Authors: Brooks V. L. , Huhtala T. A. , Silliman T. L. , Engeland W. C.
Published: December 2017

Experiments were performed in rats to test the hypothesis that adrenal mRNA levels of tyrosine hydroxylase (TH) and the norepinephrine transporter (NET) would be modified by water deprivation via activation of the sympathetic nervous system. TH and NET mRNA levels were measured using the ribonuclease protection assay. Adrenal TH mRNA was higher (P < 0.001) in water-deprived (921 +/- 39 fg/microgram total RNA) compared with the water-replete rats (657 +/- 45 fg/microgram total RNA). In contrast, water deprivation decreased (P < 0.01) adrenal NET mRNA levels (275 +/- 66 vs. 433 +/- 63 fg/microgram total RNA). The dehydration-induced increase in TH mRNA was prevented by prior splanchnicectomy, but the decrease in NET mRNA was produced even in the absence of adrenal nerves. Water deprivation also increased (P < 0.05) plasma adrenocorticotropic hormone (84 +/- 16 vs. 42 +/- 14 pg/ml) and corticosterone (358 +/- 87 vs. 44 +/- 15 ng/ml) levels. Interestingly, the corticosterone response was reduced (P < 0.05) by unilateral adrenal denervation. These results suggest that water deprivation increases both adrenal medullary and adrenocortical activity at least in part by stimulation of sympathetic nerve activity.
Differential effects of tumor necrosis factor-alpha and -beta on rat ventromedial hypothalamic neurons in vitro
Authors: Katafuchi T. , Motomura K. , Baba S. , Ota K. , Hori T.
Published: December 2017

The effects of tumor necrosis factor (TNF)-alpha and -beta on the spontaneous firing rate of ventromedial hypothalamic (VMH) neurons were examined in rat brain slice preparations. Of 89 neurons, 36 (40%) showed a decrease in the firing rate to -78.2 +/- 4.0% (n = 36, mean +/- SE) of the preapplication level after a bath application of 20 ng/ml (approximately 1.2 nM) of TNF-alpha. This response to TNF-alpha still persisted in a low-Ca2+, high-Mg2+ medium. Six (7%) of the 89 neurons were excited and 47 (53%) were unaffected by TNF-alpha. The inhibitory responses induced by TNF-alpha were abolished in a solution that contained sodium salicylate (1.9 x 10(-8)M). In contrast, TNF-beta at a dose of 20 ng/ml (approximately 1.1 nM) increased the firing rate to +39.2 +/- 6.5% (n = 11) of the preapplication level in 11 (24.5%) of 45 VMH neurons. Two of the 45 neurons (4.5%) were inhibited and 32 (71%) were unaffected by TNF-beta. The threshold concentration of TNF-alpha to alter the VMH neuron activity was lower than that of TNF-beta. Heat-inactivated TNFs were without effect. These findings suggest that TNF-alpha and -beta act as neuromodulators in the VMH, at least partly through prostaglandin synthesis, and differentially modulate the VMH neuron activity.
Chronic corticosterone treatment increases myocardial infarct size in rats with ischemia-reperfusion injury
Authors: Scheuer D. A. , Mifflin S. W.
Published: December 2017

Experiments were conducted to determine the effect of chronic elevations in corticosterone on myocardial infarct size. Male Sprague-Dawley rats were treated for 7-22 days with corticosterone. Plasma corticosterone concentrations averaged 0.8 +/- 0.3 in control and 14.9 +/- 1.2 micrograms/dl in corticosterone-treated conscious rats. Experiments were performed in anesthetized rats. After a 30-min control period, myocardial ischemia (30 min)-reperfusion (3 h) was performed in control and corticosterone-treated rats. Mean arterial pressure (+/-SE) in control rats during control, ischemia, and reperfusion periods averaged 111 +/- 4, 100 +/- 5, and 94 +/- 4 mmHg (n = 6), respectively. Chronic treatment with corticosterone increased mean arterial pressure in all three periods 128 +/- 6, 117 +/- 7, and 109 +/- 7 mmHg; n = 8; P < 0.05). Infarct size (as % area at risk) was significantly larger in rats with chronic elevations in corticosterone compared with control rats (77 +/- 2 vs. 51 +/- 5%, P < 0.05). Acute (2 h) blockade of the glucocorticoid type II receptors with mifepristone antagonized the increases in arterial pressure and infarct size produced by chronic administration of corticosterone. Neither mifepristone nor acutely administered corticosterone affected arterial pressure or infarct size in rats without chronic corticosterone treatment. The effect of chronic elevations in plasma corticosterone concentration to increase infarct size could contribute to the increased risk of cardiovascular disease in clinical conditions associated with elevated glucocorticoid levels.
Physiological responses to cold stress during prolonged intermittent low- and high-intensity walking
Authors: Weller A. S. , Millard C. E. , Stroud M. A. , Greenhaff P. L. , Macdonald I. A.
Published: December 2017

In a previous study [Am. J. Physiol. 272 (Regulatory Integrative Comp. Physiol. 41): R226-R233, 1997], the physiological responses to 240 min of intermittent low-intensity walking exercise in a cold (+5 degrees C), wet, and windy environment (Cold) may have been influenced by a 120-min preceding phase of intermittent higher-intensity exercise. Furthermore, the physiological responses observed during this latter phase may have been different if it had been more prolonged. To address these questions, active men attempted a 360-min intermittent (15 min of rest, 45 min of exercise) exercise protocol in Cold and a thermoneutral environment (+15 degrees C, Neutral) at a low (0% grade, 5 km/h; Low; n = 14) and a higher (10% grade, 6 km/h; High; n = 10) intensity. During Low, rectal temperature was lower in Cold than in Neutral, whereas O2 consumption, carbohydrate oxidation, plasma norepinephrine and epinephrine, and blood lactate were higher. During High, Cold had a similar but less marked influence on the thermoregulatory responses to exercise than during Low. In conclusion, the physiological responses to Low are similarly influenced by Cold whether or not they are preceded by High. Furthermore, during intermittent exercise up to an intensity of approximately 60% of peak O2 consumption, a cold, wet, and windy environment will influence the physiological responses to exercise and potentially impair performance.
Endotoxin impedes vasoconstriction in the spleen: role of endogenous interleukin-1 and sympathetic innervation
Authors: Rogausch H. , del Rey A. , Kabiersch A. , Reschke W. , Ortel J. , Besedovsky H.
Published: December 2017

Processes relevant for an appropriate immune response such as immune cell traffic and recirculation require a tight control of blood supply to lymphoid organs. Interactions between endogenous cytokines and sympathetic nerve fibers in lymphoid organs can contribute to this control. The results reported in this paper show that 1) administration of low doses of lipopolysaccharide (LPS), an endotoxin derived from gram-negative bacteria, causes an increase in splenic blood flow (SBF); 2) this increase is mediated by the production of endogenous interleukin-1 (IL-1); 3) the effect of LPS on SBF requires an intact splenic sympathetic innervation; 4) the LPS-induced increase in SBF is exerted at the postganglionic level; 5) the endotoxin inhibits the vasoconstriction induced by the in vivo stimulation of the splenic nerve but does not affect the vasoconstriction induced by norepinephrine (NE); and 6) although IL-1 and LPS stimulate general sympathetic activity as reflected by increased peripheral vascular resistance, they do not increase NE concentration in splenic dialysates. Together these in vivo results indicate that endogenous IL-1 affects blood supply to the spleen by inhibiting the sympathetic vasoconstrictor tonus at a postganglionic, prejunctional level. This effect is expected to be relevant for immune cell recirculation, homing, and traffic as well as antigen trapping in the spleen, an organ specialized in the control of these processes during immune responses.
A novel submandibular gland peptide protects against endotoxic and anaphylactic shock
Authors: Mathison R. D. , Befus A. D. , Davison J. S.
Published: December 2017

Submandibular glands release peptides and proteins that, through exocrine and endocrine actions, facilitate tissue repair in the oral cavity, gastrointestinal tract, and more distal sites such as liver. It has been shown that salivary gland factors also modulate inflammatory responses, because we found that removal of the submandibular glands increases the hypotensive responses to endotoxin. From this observation we proposed that these glands contain a factor that regulates cardiovascular response to shock. With the use of classical peptide isolation procedures, a heptapeptide (TDIFEGG) called submandibular gland peptide T was identified in rat submandibular glands. A synthetic form of this peptide reduced endotoxic shock in sialadenectomized rats by 50% at doses as low as 1 microgram/kg and prevented allergen-induced hypotension by 90% in rats with intact salivary glands at a dose of 100 micrograms/kg. This novel peptide is probably generated from a prohormone, submandibular gland rat 1 protein, a product of the VCSA1 gene. These data indicate that submandibular glands participate in the regulation of systemic homeostasis.
Endogenous plasma atrial natriuretic peptide and the control of salt gland function in the Pekin duck
Authors: Gray D. A. , Downing C. , Sayed N.
Published: December 2017

Polyclonal antibodies raised in a rabbit against avian atrial natriuretic peptide (ANP) were used to investigate the role of endogenous plasma ANP in the control of salt gland function of conscious, saltwater-adapted Pekin ducks. Salt gland secretion was initiated and maintained either by a hypervolemic (290 mosmol/kg NaCl i.v. at 2 ml/min) or hyperosmotic (1,000 mosmol/kg NaCl i.v. at 0.4 ml/min) stimulus. Both experimental conditions caused significant elevations in endogenous plasma ANP concentrations. At steady states of secretion driven by hypervolemia, the administration of ANP antiserum (anti-ANP), which reduced plasma ANP concentrations by 90%, caused an immediate 30% reduction in fluid secretion rate and sodium excretion that lasted for 20-30 min. The activity of salt glands driven by hyperosmolality was not changed by anti-ANP. The results show that the high circulating concentrations of endogenous ANP associated with conditions of sustained volume expansion promote salt gland secretion.
A sublethal dose of LPS to pregnant rats induces TNF-alpha tolerance in their 0-day-old offspring
Authors: Goto M. , Yoshioka T. , Young R. I. , Battelino T. , Anderson C. L. , Zeller W. P.
Published: December 2017

The newborn has high mortality in septic shock. Induction of endotoxin tolerance may prevent endotoxic shock in the newborn. The present study showed that a small dose of Salmonella enteritidis lipopolysaccharide (S. ent. LPS), Rc mutant Escherichia coli lipopolysaccharide (J5 LPS), or tumor necrosis factor-alpha (TNF-alpha) given to pregnant rats on the 19th day of gestation induced endotoxin tolerance in their 0-day-old offspring. S. ent. LPS or J5 LPS injected into pregnant rats increased plasma endotoxin-like activity in dams, although not in their fetuses, and increased plasma TNF-alpha concentration in both dams and their fetuses. The endotoxin-tolerant newborn rats were also resistant to TNF-alpha. In those newborn rats, an LPS injection increased plasma TNF-alpha concentration and liver TNF-alpha mRNA abundance. These experiments showed that the endotoxin tolerance could be due to TNF-alpha tolerance. In conclusion, prenatal treatment of dams with a small dose of S. ent. LPS, J5 LPS, or TNF-alpha was beneficial in preventing endotoxic shock in the newborn.
Electroencephalogram activity in the anoxic turtle brain
Authors: Fernandes J. A. , Lutz P. L. , Tannenbaum A. , Todorov A. T. , Liebovitch L. , Vertes R.
Published: December 2017

The anoxia-tolerant turtle brain slowly undergoes a complex sequence of changes in electroencephalogram (EEG) activity as the brain systematically downregulates its energy demands. Following N2 respiration, the root mean square voltage rapidly fell, reaching approximately 20% of normoxic levels after approximately 100 min of anoxia. During the first 20- to 40-min transition period, the power of the EEG decreased substantially, particularly in the 12- to 24-Hz band, with low-amplitude slow wave activity predominating (3-12 Hz). Bursts of high voltage rhythmic slow (approximately 3-8 Hz) waves were seen during the 20- to 100-min period of anoxia, accompanied by large sharp waves. During the next 400 min of N2 respiration, two distinct patterns of electrical activity characterized the anoxic turtle brain: 1) a sustained but depressed activity level, with an EEG amplitude approximately 20% of the normoxic control and with total EEG power reduced by one order of magnitude at all frequencies, and 2) short (3-15 s) periodic (0.5-2/min) bursts of mixed-frequency activity that interrupted the depressed activity state. We speculate that the EEG patterns seen during sustained anoxia represent the minimal or basic electrical activities that are compatible with the survival of the anoxic turtle brain as an integrated unit, which allow the brain to return to normal functioning when air respiration resumed.
K(+)-Cl- cotransport and volume regulation in the light and the dense fraction of high-K+ dog red blood cells
Authors: Fujise H. , Abe K. , Kamimura M. , Ochiai H.
Published: December 2017

We examined a chloride (Cl-)-dependent K+ transport (K(+)-Cl- cotransport) and regulatory volume decrease in dog red blood cells with high K+, low Na+, and high glutathione (GSH) content (HK/HG) due to the presence of an Na(+)-K+ pump. The HK/HG cells were separated according to their density, and the age-marker enzyme activities, such as glucose-6-phosphate dehydrogenase and cholinesterase, were determined. Unexpectedly, we found that young cells were heavier (more dense) and smaller in size compared with the old cells, which were lighter (less dense) and larger. The K(+)-Cl- cotransport was nearly 10-fold higher in the most dense cells, representing a 12% fraction of the total population compared with the lightest cohort. Although K(+)-Cl- cotransport in both the dense and the light cells was activated by N-ethylmaleimide, swelling and depletion of cellular divalent cations and the activation of the transport in the dense cells was greater. Both the dense and light cells regulated their volume when they were isosmotically swollen. Therefore, the lower activity of K(+)-Cl- cotransport might not explain the relative large volume in old HK/HG cells. The concentration of GSH and glutamate was higher in the light cells. Thus the higher the GSH and glutamate concentration, the greater the cell volume and the lower the K(+)-Cl- cotransport.
Preference conditioning alters taste responses in the nucleus of the solitary tract of the rat
Authors: Giza Barbara K. , Ackroff Karen , McCaughey Stuart A. , Sclafani Anthony , Scott Thomas R.
Published: December 2017

Aversive conditioning has an impact on the neural signal for the gustatory conditioned stimulus (CS). Here, we determined whether the code is also affected by preference conditioning. We paired the taste of MgCl2(CS+) with intragastric nutrients in some rats (MG), and citric acid (CS+) with nutrients in others (CI). A control group (Control) experienced both tastants without nutrients. Preferences (>90%) developed for each CS+. We recorded responses to 16 taste stimuli in the nucleus of the solitary tract. Responsiveness of acid-oriented neurons to MgCl2in MG rats was lower than in Controls, and its profile was more distinct from those of acidic and bitter stimuli. Total activity to citric acid was unchanged in CI rats. However, its temporal profile showed a decreased phasic component, making citric acid temporally distinct from nonsugars. Therefore, the responses to both CS+ were modified, each in its own manner, to be more distinct from those of aversive stimuli. The effects of preference conditioning, however, were weaker than those of aversive conditioning.
Subdiaphragmatic vagotomy blocks the sleepand fever-promoting effects of interleukin-1β
Authors: Hansen Michael K. , Krueger James M.
Published: December 2017

The mechanism by which peripheral cytokines signal the central nervous system to elicit central manifestations of the acute phase response remains unknown. Recent evidence suggests that cytokines may signal the brain via the vagus nerve. To test this possibility, we examined sleep-wake activity and brain temperature (Tbr) after the intraperitoneal administration of saline or three doses (0.1, 0.5, and 2.5 μg/kg) of interleukin-1β (IL-1β) in subdiaphragmatically vagotomized (Vx) and sham-operated (Sham) rats. The lowest dose of IL-1β (0.1 μg/kg) increased non-rapid eye movement sleep (NREMS) and slightly elevated Tbr in Sham rats; both responses were blocked in Vx animals. The middle dose tested (0.5 μg/kg) increased NREMS and Tbr in Sham animals; however, in Vx rats, the increase in NREMS was attenuated and the increase in Tbr was blocked. The highest dose of IL-1β used (2.5 μg/kg) induced increases in NREMS, decreases in rapid eye movement sleep, and a hypothermic response followed by a biphasic fever; these responses were similar in both Sham and Vx rats. These data provide strong evidence that the subdiaphragmatic vagus plays an important role in communicating both sleep and fever signals to the brain. However, there is clearly an alternative pathway by which IL-1 can signal the brain; whether it occurs through activation of other vagal afferents or through direct or indirect actions on the brain remains unknown.
Effect of oral versus gastric delivery on gastric emptying of corn oil emulsions
Authors: Kaplan Joel M. , Siemers William , Grill Harvey J.
Published: December 2017

Several studies have shown that fluids delivered to the stomach tend to empty more rapidly than when ingested by mouth. To better characterize the “delivery route effect” for corn oil, rats received intragastric or intraoral infusions matched for concentration and for the rate and duration of stimulus delivery. We showed, first, that more than twice as much oil emptied by the end of 12-min intragastric versus intraoral infusions but that the emptying curves remained roughly parallel for 1 h after infusion offset. Remaining experiments therefore focused on stimulus parameters of relevance to emptying control during stomach fill. Emptying during intragastric infusions approximately doubled with doublings of oil concentration (25–50%), infusion duration (6–12 and 12–24 min), and infusion rate (0.5–1.0 ml/min). Emptying during intraoral infusions, by contrast, was entirely unaffected by these manipulations. Unlike oil emptying, glucose emptying did not vary as a function of delivery route. The nutrient specificity of the delivery route effect cannot be explained in terms of energy density, as the effect was obtained for oil but not for glucose when their energy densities were equated (50% glucose, 25% corn oil). In discussion, we suggest that the oral influence on corn oil emptying during stomach fill is a gating factor that enables the expression of inhibition derived from postgastric nutrient stimulation.
Cardiovascular responses to vaginocervical stimulation in the spinal cord-transected rat
Authors: Sansone Giorgio R. , Bianca Ralph , Cueva-Rolón Rafael , Gómez Lisbeth E. , Komisaruk Barry R.
Published: December 2017

The present study ascertained whether increases in heart rate (HR) and systolic blood pressure (SBP) produced by vaginocervical stimulation (VS; 500 g force) persist in the unanesthetized rat after chronic spinal cord transection at selected levels. Three groups were used: spinal cord transection at T7 ( n = 10) or L5 ( n = 10) or a sham-operated control group (Sh, n = 10). In the Sh group, VS increased significantly both HR, by 95 ± 14.3 beats/min (bpm) (22 ± 3.7% above baseline), and BP, by 37 ± 5.7 mmHg (37 ± 7.7% above baseline), confirming earlier findings. In the T7 group, VS significantly decreased HR by 107 ± 21.4 bpm (27 ± 4.1% below baseline) and increased BP by 41.3 ± 12.9 mmHg (32 ± 8.3% above baseline). In response to VS, HR increased in every rat in the Sh group and decreased in every rat in the T7 group. In the L5 group, VS failed to significantly affect HR or BP. In the present study, specific levels of spinal cord transection produced differential HR and BP responses to VS in the rat. A model is presented addressing the component responses of autonomic dysreflexia that can occur, contingent on the level of spinal cord injury, in women during parturition or sexual intercourse.
cAMP and protein kinase A modulate cholinergic rapid eye movement sleep generation
Authors: Capece M. L. , Lydic R.
Published: December 2017

Cholinergic neurotransmission in the medial pontine reticular formation (mPRF) modulates rapid eye movement (REM) sleep generation. Microinjection of cholinergic agonists and acetylcholinesterase inhibitors into the mPRF induces a REM sleep-like state, and microdialysis data reveal increased mPRF levels of acetylcholine during REM sleep. Muscarinic cholinergic receptors (mAChRs) participate in REM sleep generation, and data suggest that mAChRs of a non-M1subtype modulate REM sleep generation. The signal transduction pathway activated by m2and m4mAChRs involves a pertussis toxin-sensitive G protein, adenylate cyclase (AC), adenosine 3′,5′-cyclic monophosphate (cAMP), and protein kinase A (PKA). Therefore, the present study tested the hypothesis that cAMP and PKA within the mPRF modulate the carbachol-induced REM sleep-like state. To test this hypothesis, the mPRF was microinjected with compounds known to facilitate the effects of cAMP (dibutyryl cAMP and 8-bromo-cAMP), stimulate PKA (Sp-cAMP[S]), and inhibit PKA (Rp-cAMP[S]). The results showed that compounds that fostered the intracellular effects of cAMP significantly decreased cholinergic REM sleep, while having no effect on spontaneously occurring REM sleep. These data are consistent with the recent finding that within the mPRF, AC and a pertussis toxin-sensitive G protein modulate cholinergic REM sleep generation. These new data suggest a modulatory role for pontine cAMP and PKA in cholinergic REM sleep regulation.
Decreases in arterial pressure activate oxytocin neurons in conscious rats
Authors: Schiltz Jennifer C. , Hoffman Gloria E. , Stricker Edward M. , Sved Alan F.
Published: December 2017

Hemorrhage and nonhypotensive hypovolemia are known to increase plasma levels of oxytocin (OT) and vasopressin (VP) in rats. The present experiments demonstrated that secretion of OT and VP also are stimulated by acute drug-induced hypotension. Injection of hydralazine abruptly decreased arterial blood pressure in conscious rats and induced Fos expression, a marker of neuronal activation, within OT and VP neurons in the hypothalamus. Hydralazine also elicited substantial increases in plasma levels of both OT and VP. Injection of chlorisondamine similarly elicited acute hypotension and increased plasma levels of OT and VP. Furthermore, when the hypotensive effect of chlorisondamine was blunted by coinfusion of phenylephrine, the induced increases in OT and VP were markedly attenuated. Across all treatments, arterial blood pressure was inversely related to plasma levels of OT and VP. Plasma osmolality was not increased by hydralazine, nor was there evidence of gastric malaise, two known stimuli for OT secretion in rats. These results suggest that arterial hypotension increases neurohypophysial release of OT and VP in conscious rats.
Changes in rat sleep after single and repeated injections of the long-acting somatostatin analog octreotide
Authors: Beranek L. , Obál F. , Taishi P. , Bodosi B. , Laczi F. , Krueger J. M.
Published: December 2017

Somnogenic activity is attributed to both growth hormone (GH) and GH-releasing hormone (GHRH). The aim of our experiments was to study sleep after suppression of the somatotropic axis by means of administration of a long-lasting somatostatin analog, octreotide. Rats received subcutaneous injections of physiological saline (baseline), octreotide (1, 10, and 200 μg/kg), or a control solution just before light onset, and sleep-wake activity and cortical brain temperature were recorded for 23 h. Each dose of octreotide slightly promoted rapid eye movement sleep (REMS) during the 12-h light period. Non-REM sleep (NREMS) was strongly suppressed for 1 h in response to 10 and 200 μg/kg octreotide. This was followed by slight increases in NREMS time and significant enhancements in electroencephalogram slow-wave activity during NREMS after 200 μg/kg octreotide. The octreotide-induced inhibition of the somatotropic axis, as determined by plasma GH levels, vanished by the time sleep increased. Another group of rats received 10 μg/kg octreotide twice a day for 5 days. This treatment elicited persistent decreases in both NREMS time and NREMS intensity. The results support the previously reported REMS-promoting activity of somatostatin in rats. The decreases in sleep after repeated injections of octreotide are attributed to a withdrawal of the normal sleep-promoting activity of GH. The role of GHRH-GH in octreotide-induced acute suppression of NREMS is currently not clear. Other mechanisms, such as mimicking central transmitter functions of somatostatin by octreotide, should also be considered.
Lateral hypothalamic injection of GABAAantagonist induces gastric vagus-mediated hypocalcemia in the rat
Authors: Shiramine Katsuhiko , Aou Shuji , Hori Tetsuro
Published: December 2017

The involvement of lateral hypothalamic area (LHA) neurons in the regulation of blood calcium homeostasis was investigated in unanesthetized rats. The microinjection of the γ-aminobutyric acid A receptor antagonist bicuculline methiodide (BM, 4–40 ng ⋅ 0.5 μl−1⋅ 5 min−1) into the LHA decreased the blood concentration of ionized calcium. Total serum calcium also decreased after the BM injection. This hypocalcemic effect was eliminated by a bilateral vagotomy of the gastric branches. An intravenous injection of atropine methyl bromide (a muscarinic antagonist), nadolol (a β-adrenergic blocker), or ranitidine (a histamine H2blocker) suppressed the BM-induced hypocalcemia, whereas phenoxybenzamine (an α-adrenergic blocker) proved to be ineffective. Although the intra-LHA injection of BM increased the serum gastrin, which is known to have a hypocalcemic effect, neither secretin nor somatostatin (gastrin-release inhibitors) blocked the hypocalcemic response. These results suggest that the hypocalcemia observed after the excitation of LHA neurons was mediated by muscarinic, β-adrenergic, and histamine H2receptors through the gastric vagus.
Angiotensin AT1receptor blockade fails to attenuate pressure-overload cardiac hypertrophy in fetal sheep
Authors: Segar Jeffrey L. , Scholz Thomas D. , Bedell Kurt A. , Smith Oliva M. , Huss David J. , Guillery Edward N.
Published: December 2017

We examined the hypothesis that endogenous angiotensin II and angiotensin type 1 (AT1) receptors participate in the development of fetal right ventricular hypertrophy by studying the effects of AT1receptor blockade on cardiac growth in fetal sheep subjected to constrictive banding of the pulmonary artery (PA). Seven pairs of twin fetuses were studied beginning at 126 ± 1 days gestation (term = 145 days). One twin was given losartan (10 mg ⋅ kg−1⋅ day−1iv) for 7 consecutive days after PA banding, and the other twin served as a saline-treated, PA-banded control. Four additional pairs of twins served as sham-operated controls. Fetal heart rate (HR) and mean arterial blood pressure (MABP) were similar in the two groups of PA-banded animals before treatment and remained unchanged in the PA-banded control group. Losartan resulted in a significant decrease ( P < 0.05) in MABP between days 0 and 7, whereas HR was not affected. Total body weight of the losartan-treated animals was significantly less ( P < 0.05) than twin PA-banded controls and nonbanded fetuses. Right ventricle weight-to-body weight ratios were similar in saline (2.29 ± 0.34 g/kg) and losartan-treated (2.11 ± 0.15 g/kg) PA-banded animals and significantly greater than that in nonbanded fetuses (1.52 ± 0.07 g/kg). Similar differences were seen in the right ventricle weight-to-left ventricle weight ratios. Right and left ventricle AT1receptor mRNA and protein expression were also similar among the three groups, as were AT2receptor mRNA levels. These data suggest that endogenous angiotensin II does not contribute to the development of pressure overload-induced right ventricular hypertrophy during fetal life and that expression of angiotensin receptors is not altered by increased afterload in the ovine fetus.
Melatonin attenuates photic disruption of circadian rhythms in Siberian hamsters
Authors: Ruby Norman F. , Kang Tom , Heller H. Craig
Published: December 2017

Body temperature (Tb) was recorded via a biotelemetry system from 28 adult male Siberian hamsters maintained in a light-dark (LD) cycle of 16 h light/day for several months. After Tb was recorded for 3 wk, the LD cycle was phase delayed by extending the light phase by 5 h for 1 day; animals remained on a 16:8 LD cycle for the remainder of the experiment. Hamsters were injected daily with melatonin or vehicle solution for several weeks, beginning either 2 mo after ( experiment 1) or on the day of ( experiment 2) the phase shift; injections occurred within 30 min of dark onset. In experiment 1, 75% of animals free ran with circadian periods >24 h, beginning on the day of the phase shift, and never reentrained to the LD cycle; no hamsters unambiguously entrained to daily injections. In contrast, 78% of animals in experiment 2 entrained to melatonin injections, and 71% of those animals subsequently reentrained to the photocycle when the injection regimen ended. No vehicle-treated animals entrained to the injection schedule. Melatonin had no effect on daily mean Tb and Tb rhythm amplitude in either experiment; however, melatonin doubled the duration of a hyperthermic response that occurred after each injection. Thus melatonin can prevent loss of entrainment induced by a phase shift of the LD cycle but cannot restore entrainment to free-running animals. Failure to reentrain in the presence of two appropriately coordinated entraining agents also suggests that a phase shift of the photocycle can diminish the sensitivity of the circadian system to both photic and nonphotic input.
Relations between functional, inflammatory, and degenerative parameters during adjuvant arthritis in rats
Authors: Philippe Lionel , Gegout-Pottie Pascale , Guingamp Corinne , Bordji Karim , Terlain Bernard , Netter Patrick , Gillet Pierre
Published: December 2017

We assessed the time-course of adjuvant arthritis (AA) in Lewis rats, using biotelemetry to monitor the rat’s spontaneous locomotor activity and body temperature, and studied the evolution of the arthritic index, circulating concentrations of inflammation-promoting cytokines, cartilage proteoglycan synthesis, and the effect of indomethacin as a cyclooxygenase inhibitor to evaluate prostaglandin (PG) contribution in AA. The injection of complete Freund’s adjuvant on day 0( D0) induced a marked, transient loss of locomotor activity ( D1– D4; initial phase) and then a second phase of hypomobility peaking on D15 and thereafter irreversible ( D16– D20; arthritic phase). Fever peaked first on D1 and again between D13 and D17. The primary hyperthermia was associated with increases in plasma interleukin-6 and tumor necrosis factor-α concentrations and seemed to be partly PG dependent. Proteoglycan synthesis inhibition in the patellar cartilage increased gradually, spreading from the injected paw to the contralateral paw. It was corrected on D20 by preventive and curative indomethacin treatments. Indomethacin also greatly relieved hypomobility during the systemic phase of AA ( D10– D15). The combination of information about cartilage metabolism, body temperature, locomotor activity, and cytokine in this study permits analysis of analgesic, antipyretic, anti-inflammatory, and chondroprotective properties of drugs in the various phases of AA. Thus, using a new methodology, we have discriminated the different phases of the disease and confirmed the symptomatic and systemic inhibitory effect of indomethacin on fever, activity, and cartilage metabolism.
The I1-imidazoline-binding site is a functional receptor mediating vasodepression via the ventral medulla
Authors: Ernsberger Paul , Haxhiu Musa A.
Published: December 2017

I1-imidazoline-binding sites fulfill all essential criteria for identification as receptors, including specificity of binding, association with physiological functions, appropriate anatomic and cellular and subcellular localization, and specific cell signaling pathways. Moreover, binding affinities correlate with functional drug responses. The evidence linking I1 receptors to vasodepression includes expression in RVLM and consistent correlations between vasodepressor potency in humans and animals and I1 binding affinity. Some I1 agonists are antagonists at α2-adrenergic receptors (α2AR), and these elicit vasodepression in RVLM. Potent α2-agonists with phenylethylamine or guanidine structures are inactive in RVLM, yet highly effective in nucleus of the solitary tract, a region with well-defined α2-mediated vasodepressor responses. Selective I1 agonists are used clinically to lower blood pressure with minimal α2-mediated sedation. Moreover, when microinjected into the RVLM only antagonists active at I1 receptors can block the vasodepressor action of either local or systemic imidazolines. RVLM α2-blockade has no effect. Some reports appear to conflict with the I1 receptor hypothesis; but these reports often make incorrect assumptions regarding drug specificity, overlook systemic effects of α2-antagonists, or inappropriately analyze data. Blockade of γ-aminobutyric acid (GABA) receptors blocks the vasodepressor action of imidazolines, implying a multisynaptic pathway. Thus imidazolines act via I1receptors in RVLM to lower blood pressure, although α2AR are also important, especially in NTS.
Ascorbic acid disposition kinetics in the plasma and tissues of calves
Authors: Toutain P. L. , Béchu D. , Hidiroglou M.
Published: December 2017

Kinetic plasma disposition parameters and tissue distribution of ascorbic acid (AA) and dihydroascorbic acid (DHA) were determined in newborn calves. After a radiolabeled AA intravenous administration, the plasma clearance (Cl) was low (40.8 ± 9.5 ml ⋅ kg−1⋅ h−1), the steady-state volume of distribution (Vss) was very high (8.9 ± 2.2 l/kg), and the AA mean residence time (MRT) was long (230 ± 85 h). After administration of a 3-g dose of AA, the Cl was high (450 ± 146 ml ⋅ kg−1⋅ h−1), the Vsswas low (0.658 ± 0.236 l/kg), and the MRT was short (1.49 ± 0.41 h), indicating a strong nonlinearity of AA disposition in calves and the impossibility of preventing scurvy with the use of a loading AA dose. Nonlinearity was explained by the saturation of both kidney reabsorption and tissue uptake. The estimated AA body pool size was 23.1 ± 6.8 mg/kg. On the basis of a compartmental analysis and actual tissue concentration measurements, it is suggested that the lung (19% of the pool) constitutes a low-capacity but rapidly mobilized pool able to cover an acute need for AA, whereas muscle and liver (40 and 33% of the pool, respectively) are high-capacity AA pools, but slowly mobilized and involved in covering the calf’s long-term AA requirements. The average daily AA entry rate over the first 7 days of life was 3.43 ± 1.16 mg/kg, and it is suggested that the calf is able to synthesize AA at an early stage.
Effects of severe hemorrhage on plasma ANP and glomerular ANP receptors
Authors: Frajewicki Victor , Kahana Luna , Yechieli Haya , Brod Vera , Kohan Ricardo , Bitterman Haim
Published: December 2017

Atrial natriuretic peptide (ANP) plays an important role in blood volume and electrolyte homeostasis in normovolemia and in hypervolemic states. The currently available information on the effects of hypovolemia on plasma ANP is contradictory. Moreover, possible regulation of ANP receptors during severe hemorrhagic hypovolemia has not been investigated. This study evaluated the effects of severe hemorrhage on plasma ANP and on the regulation of glomerular ANP receptor subtypes in anesthetized rats. Constant rate bleeding of 50% of total blood volume within 2 h induced a reproducible shock state characterized by marked decreases in blood pressure, heart rate, and hematocrit and an increase in plasma renin activity and aldosterone. Hemorrhaged rats exhibited a gradual significant increase in plasma ANP from 39.3 ± 2.9 to 114.7 ± 20.0 pmol/l 1 h after the bleeding ( P< 0.001 from the initial value and P< 0.02 from the final value of sham-shock rats). Hemorrhage induced a significant decrease in total glomerular ANP binding sites (172 ± 25 vs. 363 ± 39 fmol/mg protein in hemorrhaged and sham-shock rats, respectively, P < 0.05). This decrease was mainly due to a significant decrease in ANPCreceptors (132 ± 22 vs. 312 ± 40 fmol/mg protein in hemorrhaged and sham-shock rats, respectively, P < 0.05). Hemorrhage did not change glomerular ANPAreceptor density. No significant differences in the affinity of the glomerular receptor subtypes for ANP were detected. Our data indicate that plasma ANP increases after prolonged severe hemorrhage. It is suggested that downregulation of renal ANPCreceptors leads to reduced clearance of ANP and contributes to elevation of its plasma level after severe hemorrhage.
Metabolic costs of mounting an antigen-stimulated immune response in adult and aged C57BL/6J mice
Authors: Demas Gregory E. , Chefer Vladimir , Talan Mark I. , Nelson Randy J.
Published: December 2017

Animals must balance their energy budget despite seasonal changes in both energy availability and physiological expenditures. Immunity, in addition to growth, thermoregulation, and cellular maintenance, requires substantial energy to maintain function, although few studies have directly tested the energetic cost of immunity. The present study assessed the metabolic costs of an antibody response. Adult and aged male C5BL/6J mice were implanted with either empty Silastic capsules or capsules filled with melatonin and injected with either saline or keyhole limpet hemocyanin (KLH). O2consumption was monitored periodically throughout antibody production using indirect calorimetry. KLH-injected mice mounted significant immunoglobulin G (IgG) responses and consumed more O2compared with animals injected with saline. Melatonin treatment increased O2consumption in mice injected with saline but suppressed the increased metabolic rate associated with an immune response in KLH-injected animals. Melatonin had no effect on immune response to KLH. Adult and aged mice did not differ in antibody response or metabolic activity. Aged mice appear unable to maintain sufficient heat production despite comparable O2production to adult mice. These results suggest that mounting an immune response requires significant energy and therefore requires using resources that could otherwise be allocated to other physiological processes. Energetic trade-offs are likely when energy demands are high (e.g., during winter, pregnancy, or lactation). Melatonin appears to play an adaptive role in coordinating reproductive, immunologic, and energetic processes.
Influence of GABA in the nucleus of the solitary tract on blood pressure in baroreceptor-denervated rats
Authors: Ito Satoru , Sved Alan F.
Published: December 2017

We have previously reported that inhibition of the nucleus of the solitary tract (NTS) in chronically sinoaortic baroreceptor-denervated (SAD) rats has no effect on blood pressure in contrast to the marked increase in blood pressure it elicits in baroreceptor-intact rats. This could result either from a lack of tonic excitatory input to this region or from overriding inhibition of NTS neurons involved in the control of blood pressure. The present study aimed to distinguish between these two possibilities by examining the changes in blood pressure elicited by injection of bicuculline (Bic), a γ-aminobutyric acid (GABA) antagonist, into the NTS of SAD and control rats. In chloralose-anesthetized baroreceptor-intact rats or acutely SAD rats, injection of 10 pmol Bic into the NTS elicited minimal changes in blood pressure. In contrast, in chronic SAD rats injection of Bic into the NTS elicited a large decrease in blood pressure. The maximal decrease in blood pressure elicited by Bic in chronic SAD rats was equivalent to the maximal decrease in blood pressure that could be evoked by direct excitation of the NTS withl-glutamate. These results suggest that the lack of a tonic role of the NTS in the regulation of blood pressure in chronic SAD rats is a result of maximal GABA-mediated inhibition of relevant NTS neurons.
Effect of interactions between nitric oxide and angiotensin II on pressure diuresis and natriuresis
Authors: Madrid María Isabel , García-Salom Miguel , Tornel Jerónimo , De Gasparo Marc , Fenoy Francisco J.
Published: December 2017

The present study examined the effect of an angiotensin II AT1or AT2receptor antagonist on the impairment of the pressure diuresis and natriuresis response produced by nitric oxide (NO) synthesis blockade. Nω-nitro-l-arginine methyl ester (l-NAME, 37 nmol ⋅ kg−1⋅ min−1) lowered renal blood flow and reduced the slopes of the pressure diuresis and natriuresis responses by 44 and 40%, respectively. Blockade of AT1receptors with valsartan increased slightly sodium and water excretion at low renal perfusion pressure (RPP). Blockade of AT2receptors with PD-123319 had no effect on renal function. The administration of valsartan or PD-123319 to rats given l-NAME had no effect on the renal vasocontriction induced by NO synthesis blockade. In addition, in rats givenl-NAME, valsartan elevated baseline excretory values at all RPP studied, but it had no effect on the sensitivity of the pressure diuresis and natriuresis response. However, the administration of PD-123319 tol-NAME-pretreated rats shifted the slopes of the pressure diuresis and natriuresis responses toward control values, indicating that the impairment produced by NO synthesis blockade on pressure diuresis is dependent on the activation of AT2angiotensin receptors.
Amygdala but not hippocampal lesions impair olfactory memory for mate in prairie voles (Microtus ochrogaster)
Authors: Demas Gregory E. , Williams Joseph M. , Nelson Randy J.
Published: December 2017

Exposure to an unfamiliar male conspecific results in pregnancy interruption (i.e., the Bruce effect) in rodents. Unlike most laboratory rodents, female prairie voles ( Microtus ochrogaster) are induced into estrus by chemosensory stimuli contained in the urine of male conspecifics while grooming the anogenital (A-G) region of unfamiliar males. Female prairie voles maintain a brief “memory” for the stud male for 8–10 days after mating. Subsequent exposure to the same mate within this 8- to 10-day window does not elicit A-G investigation by the female and pregnancy block does not result. However, exposure to the original male after 10 days evokes A-G investigation and pregnancy block. To determine the neuroanatomic area(s) involved in olfactory memory for mate, female voles received bilateral electrolytic lesions of either the amygdala or hippocampus. Females were subsequently exposed to males for 48 h, separated for 3 days, then reintroduced to their original mate for 24 h. Although pregnancy rate did not differ among the experimental groups, a greater proportion of amygdala-lesioned females displayed pregnancy block when reexposed to their previous mates compared with hippocampal- or sham-lesioned voles. Amygdala-lesioned voles also displayed a greater number of A-G investigations compared with the other groups. Performance on olfactory tests was not impaired. Taken together, these results suggest that the amygdala plays an important role in olfactory memory for mate in prairie voles.
Interleukin-1β switches electrophysiological states of synovial fibroblasts
Authors: Kolomytkin Oleg V. , Marino Andrew A. , Sadasivan Kalia K. , Wolf Robert E. , Albright James A.
Published: December 2017

The role of electrophysiological events in signal transduction of interleukin-1β (IL-1β) was investigated in rabbit synovial fibroblasts using the perforated-patch method. Aggregated synovial fibroblasts occurred in two different electrophysiological states having membrane potentials ( Vm) of −63 ± 4 ( n = 71) and −27 ± 10 mV ( n = 55) (high and low Vm, respectively). IL-1β affected the cells with high Vm; it switched the state of the cell from high to low Vm. This effect was strongly dependent on the external potential applied to the cell membrane. Low Vm(−30 mV) alone without IL-1β did not switch the state of the cells. Thus a synergistic effect involving the cytokine and cell Vmin switching the electrophysiological state of the cell was shown, indicating that electrophysiological changes are involved in signal transduction. Gap junctions between aggregated cells were necessary for the cells to have a high Vmand to respond to IL-1β. Gap junction resistance between adjacent cells was estimated as 300 ± 100 MΩ. Our findings suggest that the electrophysiological behavior of synovial fibroblasts is tightly connected to a signaling or intracellular mediator system that is triggered by IL-1β.
Erectile response to hypothalamic stimulation in rats: role of peripheral nerves
Authors: Giuliano François , Bernabé Jacques , Brown Kathleen , Droupy Stéphane , Benoit Gérard , Rampin Olivier
Published: December 2017

The role of peripheral parasympathetic and sympathetic pathways was explored in erectile responses elicited by hypothalamic medial preoptic area (MPOA) stimulation in adult male anesthetized rats. Under control conditions, MPOA stimulation reliably elicited erectile responses evidenced by an increase of the intracavernous pressure-to-blood pressure ratio. The erectile response was abolished by 1) acute bilateral section of cavernous or pelvic nerves or cauda equina and 2) chronic lesions of pelvic nerves or cauda equina. Acute section of the hypogastric nerve did not significantly decrease the erectile response. The erectile response was significantly depressed after acute or chronic sections of the paravertebral sympathetic chain at the L4-L5 level or chemical sympathectomy with 6-hydroxydopamine. The decrease due to acute sympathetic chain lesion was reversed by bilateral ligation of the external iliac arteries. Accordingly MPOA stimulation elicits erectile responses via 1) activation of the parasympathetic outflow conveyed by the pelvic and cavernous nerves and 2) activation of neural fibers conveyed by the sympathetic pathways. We propose that sympathetic fibers running in the paravertebral sympathetic chain are responsible for vasoconstriction of nonpenile areas to divert blood to the penis, allowing the dramatic increase of penile arterial inflow required for erection.