bluuebunny/crossref_metadata_2025 huggingface dataset:
Macula densa stimulation of renin is reversed by selective inhibition of neuronal nitric oxide synthase
Authors: Beierwaltes W. H.
Published: December 2017

The neuronal isoform of nitric oxide synthase (nNOS) exists in the renal cortex predominantly in the macula densa, suggesting that nitric oxide (NO) derived from the macula densa plays a role in feedback regulation of renin in response to altered sodium metabolism. To determine if nNOS is a critical component in renin stimulation induced by dietary sodium restriction, rats received either normal sodium or a sodium-restricted diet (0.03%) for 7 days and subsequently were or were not treated with the selective inhibitor of nNOS 7-nitroindazole (7-NI) either acutely (50 mg/kg body wt ip) on the final day or chronically (20 mg/kg body wt ip 2 x/day) over the final 5 days. On the last day, rats were anesthetized with Inactin and fitted with arterial and renal venous catheters to collect blood and monitor blood pressure (BP) and a flow probe to measure renal blood flow (RBF). BP (105 vs. 108 mmHg) was similar in normal and low-sodium dietary groups, respectively, whereas RBF tended to be higher in the sodium-restricted group (6.5 +/- 0.3 vs. 7.6 +/- 0.4 ml.min-1.g kidney wt-1). Both renal venous renin (RR) and renin secretion rate (RSR) were elevated approximately fourfold by sodium restriction [RR = 5.8 +/- 0.8 vs. 20.5 +/- 2.7 ng angiotensin (ANG) I.ml-1.h-1; P < 0.001; RSR = 3.0 +/- 0.9 vs. 13.1 +/- 4.1 ng ANG I.h-1.min-1; P < 0.025]. Acute 7-NI did not change BP, RR, or RSR, but reduced RBF in sodium-restricted rats by 8% (P < 0.05). Chronic 7-NI had no effect on renin in rats on a normal diet, but reduced RR by one-half in the sodium-restricted group (to 9.9 +/- 1.6 ng ANG I-ml-1.h-1; P < 0.001) and reduced RSR to normal (diet) levels (to 3.9 +/- 1.4 ng ANG I.h-1.min-1; P < 0.05). Although selective NOS inhibition by 7-NI did not affect BP, RBF, or renin in control rats on a normal diet, chronic 7-NI reversed the stimulation of renin induced by dietary sodium restriction. These data suggest that nNOS-derived NO plays an important role in the macula densa during feedback stimulation of renin induced by dietary sodium restriction.
Substance P decreases fluid absorption in the renal proximal tubule
Authors: Fildes R. D. , Atkins J. L.
Published: December 2017

Substance P is a neuropeptide found principally in the central nervous system and peripheral afferent nerve fibers. It is widely distributed in the body, and its local release is thought to have important effects in the normal physiology and pathophysiology of several organ systems. Substance P releases histamine from mast cells and nitric oxide from endothelial cells. Systemic infusion of substance P causes a brisk natriuresis. Previously, proximal tubule transport in the kidney was measured in vivo during the infusion of substance P. Transport was inhibited. This could have been a direct action of substance P or secondary to the release of histamine or nitric oxide. Therefore, we have now studied the effect of substance P on isolated proximal tubules perfused in vitro. We found that 10(-10) M substance P caused a 50% reduction in the rate of fluid absorption in rabbit proximal straight tubule. This effect was reversible on removal of substance P from the bath. Inhibition of nitric oxide production with NG-monomethyl-L-arginine (10(-4) M) did not influence the action of substance P at 10(-10) M. The sensitivity of the proximal tubule to low concentrations of substance P, together with the recent findings of substance P-containing afferent fibers within the cortex of the kidney, suggest a role for substance P in the control of proximal tubule reabsorption, particularly in pathophysiological conditions associated with increased afferent nerve activity, such as ureteric occlusion.
Central nitric oxide donors attenuate cardiovascular and central norepinephrine responses to stress
Authors: Hashiguchi H. , Ye S. H. , Ross-Cisneros F. , Alexander N.
Published: December 2017

An earlier study showed that norepinephrine (NE) was released in the paraventricular nucleus (PVN) and posterior hypothalamus (PH) along with increases of mean arterial pressure (MAP) and heart rate (HR) during shaker stress (SS). Here we investigated the possibility that nitric oxide (NO) donors, infused into hypothalamus, could modulate responses to SS. In conscious rats, an injector-microdialysis probe, for direct application of donor and collection of extracellular NE, respectively, was inserted into PVN or PH; MAP and HR were recorded continuously from conscious rats. The NO donor, molsidomine (Mol), infused 5 or 30 min before SS, did not alter baseline values of NE, MAP, or HR, but did attenuate changes elicited by 5 min of SS; methylene blue blocked the effects of Mol. The NO donor, sodium nitroprusside, was much less effective than Mol as a modulator of stress-related effects. The results indicate that MAP, HR, and hypothalamic NE responses to environmental stress, but not baseline values, can be modulated by NO donors in the hypothalamus.
Vasopressin modulation of medullary blood flow and pressure-natriuresis-diuresis in the decerebrated rat
Authors: Franchini K. G. , Mattson D. L. , Cowley A. W.
Published: December 2017

Studies in our laboratory and others have demonstrated that arginine vasopressin (AVP) exerts potent vasoconstrictor actions on the vessels supplying the renal medulla. The physiological importance of these vascular effects of AVP has been difficult to assess because of high endogenous levels of AVP in anesthetized, surgically prepared animals. We have developed a decerebrated, hypophysectomized, renal-denervated rat model that enables us to study the effects of low levels of AVP on the pressure-diuresis, relationship under acute conditions. These rats maintain normal mean arterial pressure (MAP) and plasma AVP (2.5 pg/ml). Cortical and medullary blood flow (CBF and MBF, respectively) were measured by laser-Doppler flowmetry and total renal blood flow (RBF) by transit time flowmetry. Renal interstitial fluid pressure (RIFP) and urinary sodium excretion (UNaV) responses were determined during controlled increases of MAP produced by aortic occlusion below the renal arteries. From a baseline of 97 +/- 2 mmHg, 30% increases in MAP resulted in a 63% increase in MBF, 35% increase in RIFP, and sixfold increase in UNaV, whereas CBF and RBF remained unchanged. Infusion of AVP (0.50 ng.kg-1.min-1, which increased plasma AVP from normal control levels of 3 pg/ml to 11 pg/ml) produced no change in baseline MAP, RBF, or CBF but lowered MBF by 24%, RIFP by 26%, and UNaV by 71%. The slope of the relationship of AP and UNaV, MBF, and RIP was reduced to nearly zero by these small increases of plasma AVP. We conclude that an increase of plasma AVP in the range that occurs with water restriction decreases MBF selectively and greatly attenuates the arterial pressure-MBF and pressure-natriuretic relationship.
Reduction of intake in the rat due to gastric filling
Authors: Davis J. D. , Smith G. P. , Sayler J. L.
Published: December 2017

With two exceptions, the literature shows that confining ingested fluid to the stomach of a rat during an intake test had no effect on the volume ingested. In the two exceptions (J. D. Davis and J. L. Sayler, Physiol. Behav. In press. J. A. Deutsch, Handbook of Behavioral Neurobiology. Neurobiology of Food and Fluid Intake, edited by E. M. Stricker. New York: Plenum, 1990, vol. 10), intake with the cuff open was very large, suggesting that, when intake on cuff-open tests exceeds some critical volume, confining all of it to the stomach during the test will reduce intake. To test this, we measured intake of three different solutions known to stimulate large intake with the pylorus open and closed. In cuff-closed tests, intake was less than in cuff-open tests. In cuff-closed tests, rate of licking began to decline within 5-6 min when only about one-quarter of the ultimate contents of the stomach had accumulated, indicating that some signal from the stomach slowed the rate of ingestion before the full capacity of the stomach was reached. This shows that the stomach is sensitive to its contents when it contains only a small proportion of its capacity.
Glutamate release in parabrachial nucleus and baroreflex alterations after vagal afferent activation
Authors: Saleh T. M. , Bauce L. G. , Pittman Q. J.
Published: December 2017

The parabrachial nucleus (PBN) is a regulatory nucleus that relays visceral information from the brain stem to the cortex. Immunohistochemical studies have shown that the levels of various neuropeptides in the PBN were changed after visceral afferent activation. Because the major transmitter relaying visceral information through the PBN is glutamate, the present study asked if glutamate release into the PBN also was changed after vagal afferent activation in anesthetized male rats. The distally crushed vagus was stimulated (50 Hz, 1-2 mA, 1 s on, 2 s off) for 2 h. Dialysates of the PBN were collected every 30 min and assayed for glutamate using high-performance liquid chromatography. Extracellular glutamate concentrations were reduced during the vagal stimulation, increased fourfold compared with prestimulated levels after the stimulation was terminated, and returned to prestimulated levels over the next 2 h poststimulation. These changes were not due to alterations in blood pressure because sodium nitroprusside infusion for the same interval resulted in a similar hypotension, but increased glutamate release. Phenylephrine and sodium nitroprusside were infused intravenously to measure the cardiac baroreflex before, during, and after vagal stimulation. The pressor (but not the depressor) response was elevated during the period of enhanced glutamate release, and the baroreflex curve was shifted to the right (increased threshold) without a change in gain. These changes in the cardiac baroreflex were reduced, but still seen, when the PBNs were dialyzed bilaterally with the glutamate antagonists MK-801 and 6-cyano-7-nitroquinoxaline-2,3-dione. Thus visceral activation alters glutamate release in the PBN and has enduring effects on cardiac baroreflex function.
Electrical fields enhance growth of cancer spheroids by reactive oxygen species and intracellular Ca2+
Authors: Wartenberg M. , Hescheler J. , Sauer H.
Published: December 2017

A single electrical field pulse (500 V/m) with a duration of 60 s increased tumor outgrowth over a postpulse period of 24 h. RNA staining with acridine orange showed a rise in RNA content in pulsed spheroids, indicating stimulation of cell cycle activity. The electropulse induced an intracellular Ca2+ concentration ([Ca2+]i) transient that started approximately 40 s after the onset of the electrical field. Neither the presence of extracellular Ni2+ (0.5 mM) nor the absence of extracellular Ca2+ impeded the [Ca2+]i rise. It was, however, totally blocked by thapsigargin (1 microM), indicating that the initial Ca2+ response is due to Ca2+ release from intracellular stores. The [Ca2+]i transient was paralleled by an increase in reactive oxygen species (ROS), as revealed using 2',7'-dichlorofluorescein diacetate as an indicator. The radical scavengers N-acetyl-L-cysteine (NAC)(20 mM) and dehydroascorbate (5 mM) inhibited both ROS production and the [Ca2+]i transient during electrical field treatment. The mitogenic activation was dependent on the rise in [Ca2+]i because inhibition of Ca2+ release during electrical field treatment by addition of either thapsigargin or NAC to the incubation medium abolished the observed effect. We conclude that a single, direct current electrical field pulse induces production of ROS, which in turn mediate Ca2+ release from intracellular stores and activate cell cycle activity in multicellular spheroids.
Role of endogenous angiotensin II on sympathetic reflexes in conscious rabbits
Authors: Bendle R. D. , Malpas S. C. , Head G. A.
Published: December 2017

In the present study we sought to determine the contribution of endogenous brain stem angiotensin to renal sympathetic reflexes in conscious rabbits. Initial studies determined the subtype of receptor involved in the pressor response to angiotensin II (ANG II) administration into the fourth ventricle (4V). The AT1 antagonist losartan (0.001-10 micrograms 4V) had no effect on blood pressure alone but caused a dose-dependent blockade of the pressor effect of ANG II, with complete blockade produced by 10 micrograms, an effect that lasted for at least 3 h. The AT2 antagonist PD-123319 (0.1-1,000 micrograms) and vehicle had no effect on the ANG II pressor response. The effect of losartan (10 micrograms) on the baroreceptor, chemoreceptor, and trigeminal reflexes was examined in eight rabbits that had been implanted with 4V catheters and an electrode for recording renal sympathetic nerve activity (RSNA) 1 wk earlier. Baroreflex assessments were made during normoxia and two conditions of hypoxia (10% O2 and 10% O2 + 3% CO2) before and after 10 micrograms losartan or vehicle, on separate experimental days. During normoxia and hypoxia+CO2 losartan increased resting RSNA, the range, and upper plateau of the RSNA-MAP baroreflex curves. By contrast the marked increase in RSNA due to activation of trigeminal afferents was not affected by losartan. In conclusion the effect of losartan to increase RSNA activity in conscious rabbits, particularly during hypoxia and baroreceptor unloading, suggests that endogenous ANG II via AT1 receptors normally inhibits renal sympathetic baroreceptor and chemoreceptor reflexes.
Role of endogenous ANG II and AT1 receptors in regulating arterial baroreflex responses in newborn lambs
Authors: Segar J. L. , Minnick A. , Nuyt A. M. , Robillard J. E.
Published: December 2017

The present study was designed to test the hypothesis that endogenous angiotensin II (ANG II) influences baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) early in life and to determine whether these actions are mediated by angiotensin AT1 or AT2 receptors. To test this hypothesis, we studied the effects of systemic and central administration of losartan, a selective AT1 receptor antagonist, and PD-123319, a selective AT2 antagonist, on baroreflex-mediated control of HR and RSNA in conscious newborn lambs. Systemic administration of losartan decreased resting mean arterial blood pressure (MABP) from 70 +/- 3 to 58 +/- 4 mmHg (P < 0.05) without producing reflex increases in HR or RSNA. The baroreflex response curves were shifted to the left as indicated by a decrease in the arterial pressure at the midpoint of the curve for HR (83 +/- 3 to 75 +/- 4 mmHg) and RSNA (74 +/- 2 to 69 +/- 3 mmHg; P < 0.05 for both). Losartan also reset HR and RSNA baroreflex curves when changes in baseline blood pressure were prevented by simultaneous infusion of phenylephrine. In contrast, a sustained decrease in arterial pressure of 10-12 mmHg with nitroprusside failed to shift the baroreflex function curves. PD-123319 had no effect on baseline HR, MABP, RSNA, or baroreflex responses. Lateral ventricle administration of losartan but not PD-123319 also produced a decrease in arterial pressure (81 +/- 4 to 73 +/- 3 mmHg, P < 0.05) and reset the baroreflex for HR and RSNA toward lower pressure. These results demonstrate that, early in life, endogenous ANG II exerts a tonic effect on baroreflex control of HR and RSNA to shift the curves toward higher pressure levels. The alterations in arterial baroreflex function appear independent of direct ANG II effects on arterial pressure and are mediated by AT1 receptors.
Mechanism of the natriuretic action of gamma-melanocyte-stimulating hormone
Authors: Chen X. W. , Ying W. Z. , Valentin J. P. , Ling K. T. , Lin S. Y. , Wiedemann E. , Humphreys M. H.
Published: December 2017

To explore the mechanism underlying the natriuretic effect of gamma-melanocyte-stimulating hormone (gamma-MSH), we infused the peptide intravenously at 200 pmol/min into anesthetized rats. gamma-MSH led to a progressive increase in urinary sodium excretion (UNaV), whereas continuous infusion of the vehicle did not affect UNaV. Plasma immunoreactive gamma-MSH was nine times greater at 120 min after the start of the infusion than in vehicle-infused rats. Plasma atrial natriuretic peptide (ANP) concentration also increased as a consequence of the gamma-MSH infusion, and a strong correlation existed between the concentrations of the two peptides (n = 17, r = 0.81, P < 0.001). Urinary excretion of guanosine 3',5'-cyclic monophosphate and adenosine 3',5'-cyclic monophosphate increased as a result of the infusion. Antiserum to rat ANP blunted the natriuresis only slightly, suggesting that the increase in plasma ANP concentration was not a critical element in gamma-MSH natriuresis. gamma-MSH had no effect on ANP release from isolated rat right atrial strips superfused in vitro. Infusion of gamma-MSH (500 fmol/min) directly into one renal artery led to an ipsilateral natriuresis without change in UNaV from the contralateral kidney. Prior denervation of the infused kidney prevented the natriuresis resulting from intrarenal infusion. Intrarenal infusion of ANP (800 fmol/min) also produced ipsilateral natriuresis, which, however, was not affected by renal denervation. These studies confirm that the natriuretic action of gamma-MSH occurs primarily by an interaction with the renal nerves. Intravenous infusion of the peptide sufficient to produce a supraphysiological plasma gamma-MSH concentration also results in an increase in plasma ANP concentration; however, this increase at best plays only a minor role in the natriuresis following intravenous gamma-MSH infusion.
Preterm newborn lamb renal and cardiovascular responses after fetal or maternal antenatal betamethasone
Authors: Berry L. M. , Polk D. H. , Ikegami M. , Jobe A. H. , Padbury J. F. , Ervin M. G.
Published: December 2017

The optimal dose, route of administration, and treatment-to-delivery interval necessary to induce beneficial extrapulmonary effects of glucocorticoids are not known. Pregnant ewes (127 days gestation) were randomized to receive maternal or fetal intramuscular injections of betamethasone (0.2 or 0.5 mg/kg body wt) or saline 24 h before cesarean delivery of their lambs. Three hours after delivery, low-dose maternal vs. control lamb mean arterial pressure [64 +/- 4 vs. 47 +/- 2 (SE) mmHg], glomerular filtration rate (1.7 +/- 0.2 vs. 0.7 +/- 0.1 ml.min-1.kg-1), and total renal sodium reabsorption (219 +/- 31 vs. 85 +/- 12 mueq.min-1.kg-1) were increased. Comparable increases were observed in the high-dose maternal and fetal groups without effects in the low-dose fetal group. This study provides the first quantitative data demonstrating that even short-term (24-h) antenatal betamethasone exposure alters preterm newborn cardiovascular and renal functions. These responses are route and dose dependent and are comparable to glucocorticoid-induced maturational effects after longer-term antenatal exposure.
Age-related changes in renal hemodynamics in female rats: role of multiple pregnancy and NO
Authors: Reckelhoff J. F.
Published: December 2017

The objective of the present study was to evaluate 1) the effect of multiple pregnancy and aging on renal function and 2) the effect of NO inhibition on renal function in aged virgin and multiply pregnant rats. Renal hemodynamics were measured in the presence or absence of chronic (2 wk) NO synthase inhibition (nitro-L-arginine methyl ester, L-NAME) in young virgins (YV, 3-4 mo), old virgins (OV, 17-18 mo), and old retired breeders (ORB, 17-18 mo) that had sustained eight to nine pregnancies and lactations. Blood pressure was not different between control YV and OV. Glomerular filtration rate (GFR), renal plasma flow (RPF), and renal vascular resistance (RVR) were similar in OV and control YV. In contrast, the renal vasculature of ORB was more vasoconstricted in ORB than in YV or OV:GFR was decreased by 35% and RVR was higher than in YV or OV. With L-NAME there were similar increases in arterial pressure in all rats. In control YV, L-NAME had no effect on GFR, decreased RPF by 20%, and increased RVR by twofold. In OV, L-NAME decreased GFR by 30% and RPF by 60% and increased RVR by 3.3-fold. In ORB, L-NAME had no effect on GFR, decreased RPF by 30%, and increased RVR by 1.8-fold. These data suggest that the renal vasculature of ORB is vasoconstricted and that the mechanism may be due to a decrease in NO production.
Cardiovascular afferent inputs to ventral tegmental area
Authors: Kirouac G. J. , Ciriello J.
Published: December 2017

Extracellular single-unit recording experiments were done in alpha-chloralose-anesthetized, paralyzed, and artificially ventilated rats to investigate the effect of selective activation of arterial baroreceptors and stimulation of cardiovascular depressor sites in the nucleus of the solitary tract (NTS) on the discharge rate of neurons in the ventral tegmental area (VTA). Electrical stimulation of the aortic depressor nerve (ADN), which is known to carry aortic baroreceptor afferent fibers only, excited 12 of 21 (mean onset latency 42.4 +/- 8.8 ms) and inhibited 2 of 21 (mean onset latency 42.5 +/- 6.5 ms) single units in the VTA. The discharge rate of VTA units was also altered during the reflex activation of arterial baroreceptors by the acute rise in arterial pressure (AP) to systemic injections of phenylephrine (10 micrograms/kg i.v.): 12 of 44 units were excited and 15 of 44 were inhibited. Units that responded to either ADN stimulation or the reflex activation of the baroreflex also responded to stimulation of depressor sites in the NTS. An additional 12 units that were found in barodenervated controls to be responsive to NTS stimulation were nonresponsive to selective activation of arterial baroreceptors. These data indicate that cardiovascular afferent inputs modulate the activity of neurons in the VTA and suggest that changes in systemic AP may exert an effect on the activity of neurons involved in mesolimbic and mesocortical function.
Hemodynamic, hormonal, and renal effects of adrenomedullin in conscious sheep
Authors: Charles C. J. , Rademaker M. T. , Richards A. M. , Cooper G. J. , Coy D. H. , Jing N. Y. , Nicholls M. G.
Published: December 2017

Adrenomedullin is a recently discovered peptide that has been shown to reduce arterial pressure and induce natriuresis. However, few studies have examined the biological actions of adrenomedullin in conscious animals in an integrative manner. Accordingly, we have examined the hemodynamic, renal, and endocrine actions of adrenomedullin infused intravenously at 10 and 100 ng.kg-1.min-1 (each 90 min) in a vehicle-controlled study in eight normal conscious sheep. Adrenomedullin reduced right atrial pressure (P < 0.05) and diastolic (15 mmHg, P < 0.01) and mean arterial pressure (10 mmHg, P < 0.05) and increased cardiac output (3 l/min, P < 0.001). Total peripheral resistance was reduced 40% (P < 0.001). Urinary sodium was reduced to 35% of control during the 90-min clearance period immediately postinfusion (P < 0.05). Adrenomedullin increased plasma adenosine 3',5'-cyclic monophosphate levels (P < 0.001). Plasma renin activity was elevated during adrenomedullin (P < 0.001) coincident with the peak hypotensive effect, whereas plasma aldosterone was not affected and plasma norepinephrine levels fell (P < 0.05). In conclusion, adrenomedullin had clear blood pressure-lowering effects with increased cardiac output and stimulation of renin but suppressed sympathetic activation in conscious sheep. The physiological implications of these findings require further study.
Interrelated adrenocortical and neurohypophysial responses associated with fever in endotoxin-treated pigs
Authors: Parrott R. F. , Vellucci S. V. , Goode J. A. , Lloyd D. M. , Forsling M. L.
Published: December 2017

Low intravenous doses of endotoxin [lipopolysaccharide (LPS), 0.7 microgram/kg] induce monophasic fever, increase anterior and posterior pituitary hormone release, and enhance hypothalamic c-Fos expression in pigs, all of which can be prevented by indomethacin (Ind). The present study shows that the synthetic corticosteroid dexamethasone (Dex, 5 mg/kg) has a similar action to Ind and, when given alone, lowers core temperature. In addition, the corticosteroid synthesis inhibitor metyrapone (Met, 3.3 mg/kg, every one-half hour) reduces LPS fever and amplifies the effect of LPS on vasopressin, but not on oxytocin, release. The similar actions of Dex and Ind suggest that phospholipase A2 pathways controlling prostaglandin synthesis mediate the responses of prepubertal pigs to immunological challenge with LPS. The increased vasopressin release induced when animals receiving Met are also given LPS supports findings in other nonrodent species indicating an inverse relationship between cortisol and vasopressin. The attenuation of LPS fever by Met is suggestive of an endogenous antipyretic mechanism associated with enhanced neurohypophysial vasopressin secretion.
Female protein, amyloidosis, and hormonal carcinogenesis in Turkish hamster: differences from Syrian hamster
Authors: Coe J. E. , Cieplak W. , Hadlow W. J. , Ross M. J.
Published: December 2017

The Syrian hamster (Mesocricetus auratus) has been widely used as an experimental animal and is a unique model for three sex hormone-regulated events: 1) estrogen-initiated renal carcinogenesis, 2) sex-limited expression of amyloidosis, a ubiquitous disease, and 3) sex hormone control of a serum amyloid P component (SAP) called female protein (FP). In this study, we evaluated the closely related Turkish hamster (Mesocricetus brandti) for these three events and found some very different responses: 1) estrogen-initiated renal carcinogenesis was not found in Turkish hamster, 2) amyloidosis was not sex limited and actually was a rare disease in the Turkish hamster, and 3) Turkish hamsters did express a sex-limited SAP-FP in serum that was antigenically identical and structurally very similar (97.5%) to Syrian hamster SAP-FP. However, acute phase regulation of SAP-FP synthesis was different, and serum levels of this pentraxin were much lower than those found in the Syrian hamster. On the other hand, in contrast to findings in the Syrian hamster, hepatic tumors were relatively common in normal and especially in estrogen-treated Turkish hamsters. Therefore, although they are closely related, these two Mesocricetus hamster species have markedly dissimilar responses to sex hormones.
Stimulation of intestinal apolipoprotein A-IV by lipid is independent of capsaicin-sensitive afferent signals
Authors: Kalogeris T. J. , Monroe F. , Tso P.
Published: December 2017

We tested the hypothesis that stimulation of synthesis and secretion of intestinal apolipoprotein A-IV (apo A-IV) by intestinally infused lipid is mediated by capsaicin-sensitive afferent signals. Vehicle or capsaicin (125 mg/kg) was systemically administered to rats; then the effects of intestinal infusion of lipid emulsions on lymph lipid and apo A-IV transport were determined in rats equipped with duodenal infusion cannulas and mesenteric lymph fistulas. Capsaicin treatment did not significantly affect lymph outputs of triglyceride, phospholipid, and apo A-IV during duodenal infusion of triglyceride emulsion. In separate studies the effect of capsaicin treatment on ileal lipid-elicited stimulation of intestinal mucosal apo A-IV synthesis was also examined. Ileal lipid infusion increased apo A-IV synthesis in distal ileum, proximal jejunum, and jejunal Thirty-Vella fistulas; this finding was unaffected by capsaicin pretreatment. However, capsaicin treatment significantly attenuated the inhibitory effects of duodenal acid and fat on gastric emptying. These results do not support a role for capsaicin-sensitive, sensory afferent nerves in the stimulation of intestinal apo A-IV by dietary lipid.
Spectrum analysis of cardiovascular time series
Authors: Persson Pontus B.
Published: December 2017

The demand for noninvasive assessment of cardiovascular control parameters has promoted the use of spectrum analysis. These techniques have been applied on a broad basis; however, because of the abstract mathematical approach, spectrum analysis in physiology is still not fully accepted by some circles in the scientific community. Thus it is the goal of the following review to focus on the rationale for applying spectrum analysis in different fields of circulation research, which range from determining arterial baroreceptor reflex sensitivity to the early detection of heart allograft rejection. Within this scope, major findings regarding the physiological and pathophysiological regulation of the cardiovascular system are discussed. In addition, inherent limitations of these methods are made clear. Toward the end of this survey, a perspective is provided for the general readership.
Regulation of type 1 ANG II receptor in vascular tissue: role of α1-adrenoreceptor
Authors: Du Yong , Qiu Jingxin , Nelson Sharon H. , Wang Donna H.
Published: December 2017

Angiotensin II (ANG II) and norepinephrine (NE) are important regulators of vascular function and structure. Recent studies showed that there are multiple interactions between these two potent vasoconstrictor agents. The present experiment was designed to investigate the effect of NE on the expression of the type 1 ANG II receptor (AT1) in the aorta and cultured vascular smooth muscle cells (VSMC) of rats. Rats were subcutaneously infused with either NE (0.5 μg ⋅ kg−1 ⋅ min−1, n = 6) or the α1-adrenoreceptor antagonist prazosin (3.5 μg ⋅ kg−1 ⋅ min−1, n = 6) for 2 wk. Body weight and tail cuff systolic blood pressure were not modified compared with the vehicle control ( P > 0.05). Northern blot analysis showed that AT1 mRNA levels in aorta were decreased by 38% in NE-treated rats and increased 117% in prazosin-treated rats ( P < 0.05) compared with control. To determine whether NE directly regulates expression of vascular AT1 mRNA and AT1 receptor density, Northern blot analysis and radioligand binding experiments were performed in cultured VSMC. Incubation of VSMC with NE (10− 7M) led to 44% decrease in AT1mRNA levels ( P < 0.05) and 39% decrease in AT1 receptor density ( P < 0.05). Prazosin, but not the α2-adrenoreceptor antagonist yohimbine, prevented NE-induced decrease in AT1 mRNA and AT1 receptor density in these cells. Taken together, our results indicate that vascular AT1 gene expression and receptor protein are regulated by ambient NE levels, and NE-induced downregulation of AT1 mRNA and receptor protein is mediated, at least in part, by activating α1-adrenoreceptors.
Modulation of exercise tachycardia by vasopressin in the nucleus tractus solitarii
Authors: Dufloth Daniel L. , Morris Mariana , Michelini Lisete C.
Published: December 2017

Our objective was to study the role of vasopressinergic synapses at the nucleus tractus solitarii (NTS) in the modulation of exercise-induced tachycardia. We evaluated the effect of NTS administration of vasopressin (AVP) or vasopressin antagonist (AVPant) on heart rate (HR) and mean arterial pressure (MAP) responses during dynamic exercise in male rats with chronic arterial and NTS cannulas. Sedentary (S) and trained (T) animals were tested at three or four exercise levels (from 0.4 up to 1.4 km/h) after NTS injection of AVP or AVPant 20–30 min before treadmill exercise. Plasma and regional brain levels of AVP were measured in separate groups of S and T rats at rest and immediately after acute exercise. When administered into the NTS, exogenous AVP (20 pmol) caused a small but significant decrease in baseline HR and potentiated the tachycardiac response to mild to moderate exercise intensities (on average, increases of 35–46 beats/min over control tachycardic response). The potentiation of exercise tachycardia by AVP was long lasting and more pronounced in T than in S rats. Even 2 days after NTS AVP injection, there was evidence for an alteration in the HR response to exercise. Mediation by V1 receptors was supported by the blunted tachycardiac response to exercise after administration of a V1 antagonist d(CH2)5Tyr MeAVP into the NTS in both T and S rats (average reductions of 23–34 and 13–19 beats/min below control tachycardia, respectively). No changes were observed in baseline MAP or the exercise-induced pressor responses. There were specific changes in brain stem AVP levels that were related to the exercise treatment. T rats showed a marked increase in dorsal and ventral brain stem AVP content after acute exercise. There were no changes in hypothalamus, median eminence, posterior pituitary, or plasma AVP. These data indicate that vasopressinergic synapses and V1 receptors in the NTS are involved in the potentiation of tachycardic response to exercise. The vasopressinergic mechanism operates in both S and T rats, but training alters the sensitization of V1receptors by AVP.
Key role for cyclooxygenase-2 in PGE2and PGF2αreceptor regulation and cerebral blood f low of the newborn
Authors: Li Ding-You , Hardy Pierre , Abran Daniel , Martinez-Bermudez Ana-Katherine , Guerguerian Anne-Marie , Bhattacharya Mousumi , Almazan Guillermina , Menezes Ravi , Peri Krishna G. , Varma Daya R. , Chemtob Sylvain
Published: December 2017

Ibuprofen, a cyclooxygenase (COX) inhibitor nonselective for either COX-1 or COX-2 isoform, upregulates cerebrovascular prostaglandin E2(PGE2) and PGF2αreceptors in newborn pigs. COX-2 was shown to be the predominant form of COX and the main catalyst of prostaglandin synthesis in the newborn brain. We proceeded to establish direct evidence that COX-2-generated prostaglandins govern PGE2and PGF2αreceptor density and function in the cerebral vasculature of the newborn. Hence, we determined PGE2and PGF2αreceptor density and functions in brain vasculature by using newborn pigs treated with saline, ibuprofen, COX-1 inhibitor (valerylsalicylate), or COX-2 inhibitors (DUP-697 and NS-398). Newborn brain PGE2and PGF2αconcentrations were significantly reduced by ibuprofen, DUP-697, and NS-398 but not by valerylsalicylate. In newborn pigs treated with DUP-697, NS-398, and ibuprofen, PGE2and PGF2αreceptor densities in brain microvessels were increased to adult levels; there was also a significant increase in inositol 1,4,5-trisphosphate (IP3) production and cerebral vasoconstrictor effects of 17-phenyl trinor PGE2(EP1receptor agonist), M&B-28767 (EP3receptor agonist), PGF2α, and fenprostalene (PGF2αanalog). Treatment with ibuprofen or DUP-697 also increased the upper blood pressure limit of cerebral cortex and periventricular blood flow autoregulation from 85 to ≥125 mmHg (uppermost blood pressure studied). However, valerylsalicylate treatment did not affect cerebrovascular PGE2and PGF2αreceptors, IP3production, or vasoconstrictor effects in newborn animals. These in vivo and in vitro observations indicate that COX-2 is mainly responsible for the regulation of PGE2and PGF2αreceptors and their functions in the newborn cerebral vasculature.
Serotonergic modulation of hippocampal pyramidal cells in euthermic, cold-acclimated, and hibernating hamsters
Authors: Horrigan D. J. , Horwitz B. A. , Horowitz J. M.
Published: December 2017

Serotonergic fibers project to the hippocampus, a brain area previously shown to have distinctive changes in electroencephalograph (EEG) activity during entrance into and arousal from hibernation. The EEG activity is generated by pyramidal cells in both hibernating and nonhibernating species. Using the brain slice preparation, we characterized serotonergic responses of these CA1 pyramidal cells in euthermic, cold-acclimated, and hibernating Syrian hamsters. Stimulation of Shaffer-collateral/commissural fibers evoked fast synaptic excitation of CA1 pyramidal cells, a response monitored by recording population spikes (the synchronous generation of action potentials). Neuromodulation by serotonin (5-HT) decreased population spike amplitude by 54% in cold-acclimated animals, 80% in hibernating hamsters, and 63% in euthermic animals. The depression was significantly greater in slices from hibernators than from cold-acclimated animals. In slices from euthermic animals. changes in extracellular K+ concentration between 2.5 and 5.0 mM did not significantly alter serotonergic responses. The 5-HT1A agonist 8-hydroxy-2(di- n-propylamino)tetralin mimicked serotonergic inhibition in euthermic hamsters. Results show that 5-HT is a robust neuromodulator not only in euthermic animals but also in cold-acclimated and hibernating hamsters.
Repeated sodium depletion affects gustatory neural responses in the nucleus of the solitary tract of rats
Authors: Tamura Ryoi , Norgren Ralph
Published: December 2017

Furosemide sodium depletions were induced repeatedly to determine the effects on gustatory neural responses in the nucleus of the solitary tract (NST) of chronically prepared, but lightly anesthetized, rats. Sodium-replete and sodium-deplete conditions were alternated four times in each rat. When rats were under depleted conditions, the responses to NaCl were significantly greater than in sodium-replete conditions. This effect was attributable primarily to an increase in the magnitude of response of those neurons that responded better to NaCl than to the other standard stimuli (sucrose, citric acid, and quinine hydrochloride). In addition, the largest change in responsiveness of the NaCl-best neurons occurred during the third and fourth sodium depletions. These results are essentially opposite to those reported for NST neurons when sodium appetite is induced by dietary sodium restriction. This suggests that the coding of intensity in the gustatory system is dependent not only on the animal’s deprivation condition, but also the method through which the deprivation is produced.
Spontaneously hypertensive rat: cholera toxin converts suppression to immunity through a Th2 cell-IL-4 pathway
Authors: Pascual David W. , Coste Michel , Boyaka Prosper N. , Kiyono Hiroshi , McGhee Jerry R.
Published: December 2017

The spontaneously hypertensive rat (SHR) exhibits a number of T cell dysfunctions that develop concurrently with elevated blood pressure. Studies have shown a mitogen-induced lymphocyte suppression mediated in part by the production of interferon-γ (IFN-γ), which stimulated NO production by macrophages. To assess whether this immune suppression is reversible, SHR were immunized with diphtheria toxoid (DT) with or without cholera toxin (CT) as adjuvant. SHR immunized with DT only displayed weak serum immunoglobulin G (IgG) anti-DT titers, tenfold less than similarly treated normotensive Wistar-Kyoto rats (WKYR). SHR CD4+T cells failed to proliferate upon in vitro stimulation with DT. In contrast, SHR coimmunized with DT and CT showed serum IgG antibody titers similar to WKYR and Brown Norway rats. Coimmunization with CT rescued SHR CD4+T cells from suppression and supported DT- or B subunit of CT-specific proliferative responses, and these cells produced more interleukin-4 (IL-4) than IFN-γ, and anti-IFN-γ antibody treatment enhanced IL-4 production. Exogenous IL-4 increased the proliferation of antigen-specific CD4+T cells, whereas IFN-γ was inhibitory. This study shows that the adjuvant CT induces T helper 2-type responses, reversing the T cell dysfunction in the SHR.
Microvillous membrane potential (Em) in villi from first trimester human placenta: comparison toEmat term
Authors: Birdsey T. J. , Boyd R. D. H. , Sibley C. P. , Greenwood S. L.
Published: December 2017

The microvillous membrane (MVM) potential ( Em) of first trimester human placental villi was measured and compared with that in villi from term human placentas. The median Emin first trimester villi (−28 mV) was significantly more negative than that at term (−21 mV; P < 0.001). The median Emmeasured in villi from early ( weeks 6–11) first trimester (−32 mV) was significantly more negative than that in late ( weeks 12 and 13) first trimester villi (−24 mV; P < 0.001). Elevating extracellular KCl concentration induced a significant depolarization of Emin both first trimester and term villi ( P < 0.05 and P < 0.001, respectively). The magnitude of this depolarization was greater in first trimester than at term, indicating that the ion conductance of the MVM changes with gestation. Exposure to ouabain induced a significant depolarization of Em(3 mV: P < 0.05) in first trimester villi but had little effect at term. These results suggest that microvillous membrane electrophysiology changes with placental development. An alteration in the relative K+:Cl−conductance of the MVM is likely to be a major contributor to the change in the magnitude of Em.
Lack of cross tolerance between LPS and muramyl dipeptide in induction of circulating TNF-α and IL-6 in guinea pigs
Authors: Roth Joachim , Aslan Tunay , Störr Birgit , Zeisberger Eugen
Published: December 2017

In guinea pigs, lipopolysaccharide (LPS) from gram-negative bacteria and muramyl dipeptide (MDP) from gram-positive bacteria are potent inducers of systemic production of proinflammatory cytokines and fever. However, there is a striking difference between these two bacterial pyrogens in so far as repeated administration of LPS, but not of MDP, in short-term intervals induces tolerance by a progressive downregulation of the systemic cytokine network. In the present study, we investigated MDP-induced fever and the systemic release of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in LPS-tolerant guinea pigs in comparison with naive animals. Endotoxin tolerance was induced by repeated intramuscular injections of 20 μg/kg LPS at intervals of 3 days. In response to the last of five injections with LPS, systemic production of TNF-α and IL-6 as well as the development of a febrile response was abrogated almost completely. Those guinea pigs that had developed an LPS tolerance could, however, produce the same amounts of TNF-α and IL-6 as naive animals in response to a challenge with MDP. Also, MDP-induced fever was identical in LPS-tolerant and naive guinea pigs. These results provide evidence for a lack of cross tolerance between LPS and MDP in induction of circulating cytokines and fever in guinea pigs.
Prenatal dexamethasone exposure alters brain monoamine metabolism and adrenocortical response in rat offspring
Authors: Muneoka Katsumasa , Mikuni Masahiko , Ogawa Tetsuo , Kitera Katsuki , Kamei Kenji , Takigawa Morikuni , Takahashi Kiyohisa
Published: December 2017

In this study, it has been clearly demonstrated that prenatal dexamethasone treatment (Dex; 0.05 mg/kg on gestational days 17, 18, and 19) resulted in the significant reductions of 5-hydroxytryptamine (5-HT) turnover in four brain regions, including the neocortex, hippocampus, hypothalamus, and midbrain + pons-medulla (M+P-M) but not in the striatum in the offspring at 3 and 14 wk of life, as well as dopamine turnover in the hypothalamus. [3H]paroxetine binding densities were increased in the hypothalamus and M+P-M at 14 wk of life, which corresponded to increased 5-HT contents in both regions. On the other hand, significantly lower norepinephrine contents in the neocortex and hippocampus were observed in the Dex group compared with the control group at 14 wk of life. In addition, the exposure to new environmental condition elevated blood corticosterone levels and enhanced behavioral activities to a greater extent in the Dex group than in controls at 7 wk of life, suggesting that elevated glucocorticoid levels during the pregnancy mimicked prenatal mild stress, producing developmental alterations in brain monoamine metabolism, endocrine response, and behavior in adult offspring.
Circumventricular organs and fever
Authors: Takahashi Yoshimi , Smith Pauline , Ferguson Alistair , Pittman Quentin J.
Published: December 2017

We have examined the roles of three circumventricular organs, the area postrema, the subfornical organ, and the organum vasculosum of the lamina terminalis (OVLT), as possible access points for circulating pyrogens to cause fever. In conscious, unrestrained rats prepared with telemetry devices, intracerebroventricular cannulas, and intravenous catheters, body temperature was monitored after intravenously administered lipopolysaccharide and, on a different occasion, after intracerebroventricular prostaglandin E1.Lipopolysaccharide-induced fevers in sham control lesioned rats were indistinguishable from those observed in animals with lesions of the area postrema, the OVLT, or the tissue immediately adjacent to this structure (peri-OVLT). In contrast, rats with lesions of the subfornical organ displayed reduced fevers. In none of the groups of lesioned animals were prostaglandin E1fevers reduced. Thus lesions did not interfere with central thermogenic pathways responsive to prostaglandin. Our results indicate that subfornical organ neurons respond to circulating pyrogens and through their efferent projections activate central pathways involved in fever.
Human circadian pacemaker is sensitive to light throughout subjective day without evidence of transients
Authors: Jewett Megan E. , Rimmer David W. , Duffy Jeanne F. , Klerman Elizabeth B. , Kronauer Richard E. , Czeisler Charles A.
Published: December 2017

Fifty-six resetting trials were conducted across the subjective day in 43 young men using a three-cycle bright-light (∼10,000 lx) stimulus against a background of very dim light (10–15 lx). The phase-response curve (PRC) to these trials was assessed for the presence of a “dead zone” of photic insensitivity and was compared with another three-cycle PRC that had used a background of ∼150 lx. To assess possible transients after the light stimulus, the trials were divided into 43 steady-state trials, which occurred after several baseline days, and 13 consecutive trials, which occurred immediately after a previous resetting trial. We found that 1) bright light induces phase shifts throughout subjective day with no apparent dead zone; 2) there is no evidence of transients in constant routine assessments of the fitted temperature minimum 1–2 days after completion of the resetting stimulus; and 3) the timing of background room light modulates the resetting response to bright light. These data indicate that the human circadian pacemaker is sensitive to light at virtually all circadian phases, implying that the entire 24-h pattern of light exposure contributes to entrainment.
Effects of plasma from hibernating ground squirrels on monocyte-endothelial cell adhesive interactions
Authors: Yasuma Yoshihide , McCarron Richard M. , Spatz Maria , Hallenbeck John M.
Published: December 2017

Adhesion and subsequent penetration of leukocytes into central nervous system ischemic tissue proceeds via a coordinated inflammatory mechanism involving adhesion molecules at the blood-endothelium interface. Mammalian hibernation is a state of natural tolerance to severely reduced blood flow-oxygen delivery (i.e., ischemia). Hibernating thirteen-lined ground squirrels were investigated in an attempt to identify factors responsible for regulating this tolerance. Since leukocytopenia is closely associated with entrance into hibernation, the role of leukocyte adhesion to endothelium in this phenomenon was examined. Intercellular adhesion molecule-1 (ICAM-1) is expressed by endothelium and regulates interactions with circulating leukocytes that may result in margination or extravasation. ICAM-1 expression by rat cerebral microvascular endothelial cells (EC) cultured with plasma from hibernating (HP) or nonhibernating (NHP) thirteen-lined ground squirrels was dose dependently increased by HP and, to a lesser extent, by NHP. Treatment of EC with HP coincidentally induced significantly greater increases in monocyte adhesion to EC (37.2%) than were observed with NHP (23.9%). Study of the effects of HP and NHP on monocyte adhesion to EC may identify mechanisms responsible for ischemic tolerance in hibernators and could lead to the development of novel therapeutic approaches to the treatment of stroke.