bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of intrarenal NO stimulates renin secretion through a macula densa-mediated mechanism
Authors: Schnackenberg C. G. , Tabor B. L. , Strong M. H. , Granger J. P.
Published: December 2017

Because endothelium-derived factors are known to have multiple actions throughout the body, the role of nitric oxide (NO) produced within the kidney in the regulation of renin release is still unclear. Therefore, the objectives of this study were to determine the effect of local NO synthesis inhibition within the kidney on renin secretion rate (RSR) and to determine whether the macula densa mechanism mediates the effect of NO on renin secretion rate in dogs. The NO synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) was administered via the renal artery at 5 microg x kg(-1) x min(-1) to dogs with normal kidney function and to dogs with the macula densa mechanism blocked, established by using the nonfiltering kidney model. In dogs with normal kidney function, renal arterial pressure (RAP) and glomerular filtration rate (GFR) remained constant throughout the experiment (131 +/- 5 mmHg and 22.6 +/- 3.0 ml/min, respectively). However, intrarenal NO synthesis inhibition decreased renal blood flow (RBF) by 16% (240 +/- 22 to 201 +/- 23 ml/min) and increased renal vascular resistance (RVR) by 24% (0.59 +/- 0.08 to 0.73 +/- 0.09 mmHg x ml(-1) x min). In addition, L-NAME decreased the fractional excretion of lithium by 27% (30.0 +/- 3.7 to 21.6 +/- 4.3%) and decreased the fractional excretion of sodium by 35% (0.86 +/- 0.29 to 0.56 +/- 0.21%). Associated with these changes in renal function, renin secretion rate increased by 194 and 235%. In marked contrast, renin secretion rate remained constant in dogs with the macula densa mechanism blocked. Intrarenal NO synthase blockade decreased RSR by 4 and 10% in dogs with the macula densa mechanism blocked. The RAP, RBF, and RVR responses to intrarenal NO synthesis inhibition in dogs with the macula densa mechanism blocked were similar to the renal hemodynamic response in dogs with normal kidney function. In summary, we have demonstrated that intrarenal NO synthesis blockade enhances renin secretion in dogs. The macula densa mechanism appears to play an important role in mediating the effect of intrarenal NO synthesis inhibition on renin release.
Effects of the fructose analog, 2,5-anhydro-D-mannitol, on food intake and estrous cyclicity in Syrian hamsters
Authors: Schneider J. E.
Published: December 2017

Hyperphagia and anovulation are both triggered by prior food deprivation or other treatments that decrease intracellular availability of metabolic fuels in most species studied. Syrian hamsters fail to show compensatory hyperphagia, but do show anestrus in response to these energetic challenges. In the present experiments, we examined food intake, plasma glucose levels, and estrous cyclicity in Syrian hamsters in response to 2,5-anhydro-D-mannitol (2,5-AM), a fructose analog that is thought to trigger eating in rats by depleting intracellular levels of ATP. In experiment 1, female estrous cycling hamsters were treated with 100, 200, 400, or 800 mg/kg 2,5-AM or the vehicle by intraperitoneal injection. Food intake was measured 1, 2, 4, 8, and 24 h after treatment. There were no statistically significant increases in food intake in response to any dose of 2,5-AM. In experiment 2, blood samples were drawn at 0, 1, 3, 5, 7, and 25 h after hamsters were treated with 0 or 400 mg/kg 2,5-AM. 2,5-AM treatment resulted in a mild but significant decrease in plasma glucose levels similar to those seen in 2,5-AM-treated rats, suggesting that 2,5-AM has similar effects on fuel metabolism in rats and hamsters. In experiment 3, hamsters received 2,5-AM, 2,5-AM plus the fatty acid oxidation inhibitor methyl palmoxirate, or vehicle every 6 h over the first 48 h of the estrous cycle and were tested for indexes of estrous cyclicity at the end of the cycle. All hamsters showed normal estrous cycles, regardless of treatment. If 2,5-AM has similar metabolic consequences in rats and hamsters, the present results suggest that decreased intracellular levels of ATP and mild hypoglycemia do not increase food intake or inhibit estrous cyclicity in Syrian hamsters.
Cholesterol feeding does not alter renal hemodynamic response to acetylcholine and angiotensin II in rabbits
Authors: Carroll J. F. , Mizelle H. L. , Cockrell K. , Reckelhoff J. F. , Clower B. R. , Granger J. P.
Published: December 2017

Aortic ring studies have demonstrated a decrease in endothelium-dependent relaxation or an enhanced response to vasoconstrictors in rabbits fed a high-cholesterol diet. Whether such abnormalities exist in the renal circulation is unclear. The purpose of this study was to determine functional renal responses to acetylcholine (ACh) or angiotensin II (ANG II) infusion in anesthetized rabbits after 8-10 wk of either a control diet (ACh, n = 6; ANG II, n = 6) or a 1% cholesterol diet (ACh, n = 7; ANG II, n = 7). Mean arterial pressure (MAP), renal blood flow (RBF), and glomerular filtration rate (GFR) were measured. Renal vascular resistance (RVR) was calculated as MAP/RBF. For ANG II experiments, captopril (15 microg x kg(-1) x min(-1)) was infused to suppress endogenous ANG II production. After two control clearance periods, either ACh (1 microg x kg(-1) x min(-1)) or ANG II (0.5 ng x kg(-1) x min(-1)) was infused into the renal artery; RBF was allowed to stabilize before experimental clearances. RBF increased with ACh (control: 25 +/- 2 to 39 +/- 2 ml/min; cholesterol: 26 +/- 2 to 40 +/- 3 ml/min) and decreased with ANG II infusions (control: 40 +/- 4 to 25 +/- 3 ml/min; cholesterol: 36 +/- 3 to 24 +/- 2 ml/min). Nitrate/nitrite excretion also increased with ACh infusion (control: 2.3 +/- 1.0 to 5.2 +/- 1.8 nmol x kg(-1) x min(-1); cholesterol: 2.3 +/- 0.3 to 6.0 +/- 1.3 nmol x kg(-1) x min(-1)). However, there were no significant differences between control and cholesterol groups in either response. GFR was unaltered during ACh and ANG II infusions. MAP, RVR, and urinary sodium and potassium excretion did not differ between groups in response to either drug. These results suggest that, despite significant hypercholesterolemia and large-vessel atherosclerosis, both nitric oxideinduced vasodilation and endothelium-dependent modulation of ANG II vasoconstriction in the renal circulation are unaffected by cholesterol feeding.
Twenty-four-hour melatonin and core body temperature rhythms: their adaptation in night workers
Authors: Weibel L. , Spiegel K. , Gronfier C. , Follenius M. , Brandenberger G.
Published: December 2017

To determine whether the melatonin (MT) rhythm is adapted to a permanent nocturnal schedule, 11 night workers were studied during their usual 24-h cycle, and 8 day-active subjects during two 24-h cycles, once with night sleep and once after an acute shift of their sleep period to daytime. Rectal temperature (Tre) was continuously recorded. In day-active subjects, the MT rhythm was not affected by the acute shift in the sleep period, whereas the Tre rhythm was split in a biphasic pattern with the circadian descending phase during the night of sleep deprivation and a second descending trend during day sleep. Night workers showed a great variability in their MT profiles, with the onset of the MT release varying between 2145 and 0505. In contrast, the Tre rhythm was homogeneously entrained to their usual sleep-wake cycle, with the onset of the descending trend initiated before sleep onset so that the large decrease was found, in some subjects, to be uncoupled with their MT increase. The night-active schedule did not induce any amplitude modification of the Tre and the rhythms compared with day-active subjects sleeping at night. No relationship between work-dependent factors and the extent of the MT shift could be found. These results show the great variability in the timing of MT secretion among night workers, in contrast to the homogeneity of their Tre rhythm. The exact mechanisms by which night workers adapt their circadian systems have not yet been identified.
Low-frequency ultradian insulin rhythms are coupled to cardiovascular, autonomic, and neuroendocrine rhythms
Authors: Shannahoff-Khalsa D. S. , Kennedy B. , Yates F. E. , Ziegler M. G.
Published: December 2017

Plasma insulin levels were assayed to compare with earlier reported rhythms of the cardiovascular, autonomic, and neuroendocrine systems in 10 resting normal adults over 5-6 h. Our earlier report included time-series analysis for impedance cardiography measures of stroke volume, heart rate, cardiac output, thoracic fluid index, ejection velocity index, and ventricular ejection time; automated cuff measures of systolic, diastolic, and mean arterial pressures; the nasal cycle as a marker of lateralized autonomic tone; and indwelling venous catheters for sampling blood every 7.5 min to assay for adrenocorticotropic hormone, luteinizing hormone, epinephrine, and norepinephrine. Insulin was later assayed from the same plasma samples. Time-series analysis using the fast orthogonal search method of Korenberg detected insulin periodicities at ranges of 220-340, 115-145, 70-100, and 40-65, with significance across subjects at ranges of 115-145, 70-100, and 40-65 min. Significant periods for the other parameters were reported earlier at 220-340, 170-215, 115-145, 70-100, and 40-65 min, with periods at 115-145, 70-100, and 40-65 min dominating across parameters. These results suggest that insulin secretion has a common pacemaker (the hypothalamus) or a mutually entrained pacemaker with the autonomic, cardiovascular, and neuroendocrine systems.
BNP: pathophysiological and potential therapeutic roles in acute congestive heart failure
Authors: Grantham J. A. , Borgeson D. D. , Burnett J. C.
Published: December 2017

Controversy persists regarding the acute responsiveness of atrial (ANP) and brain (BNP) natriuretic peptides in pathophysiological conditions such as acute heart failure (AHF). This study was designed to test the hypothesis that AHF is characterized by selective activation of ANP, but not BNP. We also hypothesized that BNP replacement in AHF would reduce cardiac filling pressures, increase sodium excretion, and inhibit circulating renin. Two groups of anesthetized dogs underwent rapid left ventricular pacing to induce AHF. Group 1 (n = 7) served as control and group 2 (n = 7) received canine BNP (10 ng x kg(-1) x min(-1)). Cardiorenal parameters, circulating natriuretic peptides, 3',5'-cyclic guanosine monophosphate (cGMP), and plasma renin activity (PRA) were determined at baseline and during AHF in both groups. AHF was characterized by reductions in cardiac output (2.3 +/- 0.2 vs. 3.7 +/- 0.3 l/min, P < 0.05), pulmonary capillary wedge pressure (PCWP; 11.7 +/- 0.8 vs. 5.1 +/- 0.3 mmHg, P < 0.05), and selective activation of ANP (250 +/- 51 vs. 39 +/- 13 pg/ml, P < 0.05), with no increase in circulating BNP (49 +/- 15 vs. 60 +/- 16 pg/ml, P = not significant). Compared with control, exogenous supplemental BNP in AHF resulted in marked increases in circulating cGMP (65 +/- 6 vs. 18 +/- 5 pg/ml, P < 0.05), with reductions in PCWP (9.1 +/- 0.9 vs. 12.9 +/- 1.1 mmHg, P < 0.05) and increased urinary sodium excretion (120 +/- 36.8 vs. 24 +/- 6.3 microeq/min, P < 0.05) via reductions in distal tubular sodium reabsorption (94.3 +/- 1.8 vs. 98.0 +/- 0.4%, P < 0.05). Exogenous BNP prevented the increase in PRA that occurred in the control group. We conclude that AHF is characterized by a failure to increase circulating BNP underscoring differential physiological and pathophysiological roles for ANP and BNP in states of immediate cardiac overload. These studies also support a potential role for BNP in the therapeutics of AHF.
Opioid growth factor is present in human and mouse gastrointestinal tract and inhibits DNA synthesis
Authors: Zagon I. S. , Wu Y. , McLaughlin P. J.
Published: December 2017

Native opioid peptides serve as growth factors in a number of normal and neoplastic cells and tissues. This study investigated the influence of opioids on circadian rhythm-dependent DNA synthesis in mouse esophagus during homeostatic renewal. In contrast to a labeling index (LI) of 24.0% at 0630 and 5.5% at 1600, disruption of opioid-receptor interaction by the potent opioid antagonist naltrexone hydrochloride (NTX; 10 mg/kg) in mice resulted in an elevation of 49% in DNA synthesis of esophageal epithelial cells at 1600, but had no effect at 0630. Mice subjected to [Met5]enkephalin (1 mg/kg) had an LI that was decreased 23% from control levels at 0630, but was unaffected at 1600. This decrease in DNA synthesis was blocked by concomitant administration of naloxone (10 mg/kg); naloxone alone had no influence on cell replicative processes. In tissue culture studies, NTX and OGF markedly increased and decreased, respectively, the LI from control values. Both opioid growth factor (OGF) and its receptor, zeta, were detected in all but the cornified layer of mouse esophageal epithelium and in the epithelial cells of the stomach and small and large intestines. In addition, both peptide and receptor were observed in the basal and suprabasal cells of human esophageal epithelium. These results indicate that an endogenous opioid peptide (OGF) and its receptor (zeta) reside in gastrointestinal epithelium and play a role in cellular renewal processes in a tonically inhibitory, direct, and circadian rhythm-dependent fashion.
Cardiovascular effects of homologous bradykinin in rainbow trout
Authors: Olson K. R. , Conklin D. J. , Weaver L. , Duff D. W. , Herman C. A. , Wang X. , Conlon J. M.
Published: December 2017

Bradykinins have only recently been identified in fish, and a detailed analysis of their cardiovascular actions is lacking. The present study examines the cardiovascular effects of trout bradykinin ([Arg0,Trp5,Leu8]bradykinin; tBK) in conscious trout, Oncorhynchus mykiss. tBK (1-10 nmol/kg body wt bolus) produced triphasic pressor-depressor-pressor responses. In phase 1, cardiac output (CO), ventral aortic (P(VA)), dorsal aortic (P(DA)), and central venous pressure increased, whereas systemic (R(S)) and gill resistance (R(G)) were unchanged. In phase 2, R(G) increased, whereas R(S), CO, and heart rate decreased, reducing P(VA) and P(DA). Plasma prostaglandin E2 and the prostacyclin metabolite, 6-ketoprostaglandin F1alpha, were significantly elevated during phase 2, whereas leukotrienes C4 and B4 and thromboxane B2 were unaffected. Phase 3 was produced by an increased CO and R(S) and the return of R(G) to control. Phase 1 pressor response was not blocked by inhibitors of cyclooxygenase, angiotensin-converting enzyme (ACE) or alpha-adrenoceptors (alpha-AD), whereas phase 2 depressor and plasma prostaglandin responses were prevented by cyclooxygenase inhibition. Phase 3 was partially blocked by ACE and alpha-AD inhibitors and is a response to the preceding hypotension. In vitro, tBK only decreased vascular resistance in the perfused splanchnic or skeletal muscle-kidney preparations. These results show that although tBK has multiple effects on the trout cardiovascular system, none of the effects are due to direct tBK stimulation of vascular smooth muscle. Phase 2 vasodilation has features consistent with release of vasodilator prostaglandins while the mechanism of phase 1 constriction is unknown.
Rapid synthesis and secretion of intestinal apolipoprotein A-IV after gastric fat loading in rats
Authors: Rodriguez M. D. , Kalogeris T. J. , Wang X. L. , Wolf R. , Tso P.
Published: December 2017

To further investigate the possible role of apolipoprotein A-IV (apo A-IV) in the short-term control of food intake, we examined the kinetics of intestinal apo A-IV synthesis and release into lymph and plasma after intragastric delivery of physiological amounts of lipid. Within 30 min of intragastric administration of 0.1 g of triglyceride, plasma and lymph levels of apo A-IV were similar to those produced by exogenous apo A-IV that inhibit food intake. Within 15 min, 5% of gastrically delivered radioactive lipid reached the distal small bowel and cecum; by 30 min radioactivity was evenly distributed throughout the small intestine, with 10-15% of the load in the distal gut. By 30 min, synthesis of apo A-IV was significantly stimulated in proximal and distal jejunum and distal ileum and remained elevated up to 4 h after the delivery of lipid. Our results indicate that the delivery of physiological amounts of lipid into the stomach produces a significant and rapid stimulation of apo A-IV secretion into lymph and plasma, together with a rapid delivery of lipid and increases in mucosal synthesis of apo A-IV along the entire length of the small intestine. The results support a possible role for apo A-IV in the short-term control of food intake and suggest a role for the entire gut in the integrative response of apo A-IV to a fat meal.
Vagal afferent and efferent contributions to the inhibition of food intake by cholecystokinin
Authors: Moran T. H. , Baldessarini A. R. , Salorio C. F. , Lowery T. , Schwartz G. J.
Published: December 2017

To assess the role of subdiaphragmatic vagal afferent and efferent fibers in the mediation of the inhibition of food intake by cholecystokinin (CCK), we compared the ability of a dose range (1-16 microg/kg), of CCK to affect 30-min liquid glucose (0.125 g/ml) intake in rats with either total subdiaphragmatic vagotomy, selective subdiaphragmatic vagal deafferentation, selective subdiaphragmatic vagal deefferentation, or sham surgery. Selective vagal deafferentation and deefferentations were produced by combinations of unilateral subdiaphragmatic vagotomy and contralateral afferent or efferent rootlet transection as fibers enter the caudal medulla. CCK produced a dose-related suppression of glucose intake in sham animals, and this action was eliminated in rats with total subdiaphragmatic vagotomy. CCK suppression of intake was attenuated in rats with vagal deafferentation, such that there was a loss of sensitivity to CCK. Vagal deefferentation resulted in lower levels of baseline intake and a truncation of the feeding-inhibitory actions of CCK. These data demonstrate that CCK's suppression of intake depends on actions of both vagal afferent and efferent fibers. We interpret these data as suggesting that 1) the actions of low doses of CCK depend on activation of vagal afferent CCK receptors and 2) the greater efficacy of higher CCK doses is the result of the potentiation of these vagal afferent actions due to local physiological gastrointestinal effects of the peptide that rely on vagal efferent input.
Role of ET(A) and ET(B) receptors in endothelin-1-induced adrenal catecholamine secretion in vivo
Authors: Yamaguchi N.
Published: December 2017

The present study was designed to test whether endothelin (ET) A and/or B receptors in the adrenal medulla are functionally involved in ET-1-induced catecholamine (CA) release in anesthetized dogs. ET-1 was locally infused into the gland via the left adrenolumbar artery. Plasma CA in adrenal venous and aortic blood was determined by a high-performance liquid chromatography method. In the control group, the local infusion of ET-1 (0.5 microg, 0.4 microM) resulted in a significant increase in CA output. In the presence of a low dose of BQ-123 (5 microg, 16.4 microM), the ET-1-induced CA response was significantly attenuated by approximately 80%. With a high dose of BQ-123 (50 microg, 164 microM), the CA response was further blocked by approximately 95%. This inhibition was significantly greater than that obtained with the low dose of BQ-123. By contrast, a low dose of BQ-788 (5 microg, 15.1 microM) did not significantly affect the CA response. With a high dose of BQ-788 (50 microg, 151 microM), the CA response was only partially inhibited by approximately 70%. The results indicate that BQ-123 significantly inhibited ET-1-induced adrenal CA release in a dose-dependent manner. With the low doses, the CA response was markedly inhibited by BQ-123 but remained unchanged in the presence of BQ-788. Moreover, the high dose of BQ-123 virtually abolished the CA response, whereas BQ-788 failed to do so within the dose range tested. The present study suggests that the ET(A) receptor may play a predominant role in mediating the ET-1-induced CA secretion in the canine adrenal gland in vivo, although the possible involvement of the ET(B) receptor could not completely be excluded under the present experimental conditions.
Dietary n-3 fatty acids differentially affect sickness behavior in mice during local and systemic inflammation
Authors: Kozak W. , Soszynski D. , Rudolph K. , Conn C. A. , Kluger M. J.
Published: December 2017

We tested the hypothesis that increased dietary fish oil levels (via modulation of the production of inflammatory mediators) modulate sickness symptoms (i.e., anorexia, cachexia, fever, lethargy) of systemic and local inflammation. Swiss Webster mice were implanted with biotelemeters to measure body temperature and motor activity and were fed a diet high in n-3 fatty acids (17% wt/wt menhaden oil) or a reference diet (17% wt/wt hydrogenated coconut oil or normal rodent chow) for 6 wk. Local inflammation was induced by subcutaneous injection of turpentine (100 microl/mouse). Systemic inflammation was elicited by intraperitoneal injection of lipopolysaccharide (LPS; 2.5 mg/kg). Fever, lethargy, anorexia, and weight decrease during turpentine abscess were all inhibited (P < 0.05) in mice fed the fish oil diet. Indomethacin, similar to the fish oil diet, attenuated the turpentine-induced symptoms in mice fed a normal diet. Dietary n-3 fatty acids prevented fever and attenuated the decrease in body weight caused by LPS but did not affect the LPS-induced lethargy and anorexia. Within 90 min of LPS injection, the bioactivity of plasma tumor necrosis factor-alpha (TNF-alpha) increased to 98.2 +/- 5.1 ng/ml in mice fed fish oil compared with 32.6 +/- 3.6 ng/ml in those fed the reference diet (P < 0.05). Plasma prostaglandin E2 (PGE2) levels after LPS injection of mice fed the control diet increased within 90 min to 16.4 +/- 5.1 pg/ml. Mice fed the fish oil diet did not show any elevation in plasma PGE2 levels at that time (P < 0.05). We speculate that dietary n-3 fatty acids suppressed PGE2-related responses, including a PGE2-dependent negative feedback on TNF-alpha production, which resulted in differential modulation of sickness behavior depending on the locus of inflammation.
Hexose transport across the basolateral membrane of the chicken jejunum
Authors: Garriga C. , Moreto M. , Planas J. M.
Published: December 2017

The characteristics of the basolateral transport of D-glucose (D-Glc) and D-fructose (D-Fru) have been studied in membrane vesicles from the jejunum of 5- to 6-wk-old chickens. Uptake of hexoses was measured using a rapid filtration method. The maximal rate of transport (Vmax) for D-Glc was 2.36 nmol x mg(-1) x s(-1) and for D-Fru was 3.79 nmol x mg(-1) x s(-1). The Michaelis constants were 17.3 mmol/l for D-Glc and 40.4 mmol/l for D-Fru. D-Glc inhibited its own transport (Ki = 17.4 mmol/l) and the transport of D-Fru (Ki = 18.7 mmol/l). D-Fru inhibited its own transport (Ki = 38.1 mmol/l) and the transport of D-Glc (Ki = 40.3 mmol/l). The transport of both hexoses was Na+ independent, theophylline and cytochalasin B sensitive, and showed cis-inhibition by structural analogs. In preloaded vesicles, the uptake of D-Fru was trans-stimulated by D-Glc and 2-deoxy-D-glucose. These properties indicate the presence of a low-affinity high-capacity glucose transporter isoform (GLUT-2)-type carrier in the chicken intestine, responsible for moving both D-Glc and D-Fru across the basolateral membrane.
Intake suppression after hepatic portal glucose infusion: all-or-none effect and its temporal threshold
Authors: Baird J. P. , Grill H. J. , Kaplan J. M.
Published: December 2017

The effects of hepatic portal infusions of isotonic glucose on glucose intake (3.2%) were evaluated with use of the intraoral intake test, which, unlike traditional tests, permits delivery of portal infusions in explicit temporal relationship to intake onset in nondeprived rats. Continuous or discontinuous portal infusions (0.1 ml/min) of isotonic glucose or saline were initiated 0, 30, 60, or 120 min before meal onset. Jugular infusions of isotonic saline or glucose and portal infusions of isotonic saline were without effect. For all effective portal glucose infusions, intake was suppressed by approximately 30% of baseline values. Because the duration (and quantity) of effective portal glucose infusions varied by a factor of 10, we conclude that intraoral intake suppression under these conditions is all or none in nature. Whether an intake suppression was obtained depended more on when the infusion was delivered than on how much was infused. Thus 1.5 ml of isotonic glucose infused between 60 and 45 min before the intake test was effective, whereas 3.0 ml infused for the 30 min before intake was without effect. These results suggest that the liver participates in the control of future intake but not in the termination of an ongoing meal. The temporal requirement for intake suppression should be considered in analyses of the metabolic, hormonal, and/or neural mechanisms that underlie the liver's contribution to intake control.
Central thromboxane receptors: mRNA expression and mediation of pressor responses
Authors: Gao H. , Peng B. , Welch W. J. , Wilcox C. S.
Published: December 2017

These studies tested whether activation of central thromboxane (Tx)A2/prostaglandin (PG) H2 receptors raises blood pressure (BP). Messenger RNA for TxA2/PGH2 receptors was detected in normal Sprague-Dawley rat brain and in rat neuronal and astroglial brain cells in culture. The mean arterial blood pressure (MAP) was recorded in conscious rats during graded administration of the TxA2/PGH2 receptor agonist U-46,619 given intracerebroventricularly or intravenously. Because the pressor responses to intracerebroventricular (but not intravenous) U-46,619 were significantly greater in-high-salt compared with low-salt rats, high-salt rats were used for subsequent studies. The rise in MAP with intracerebroventricular administration of U-46,619 was greater than with intravenous administration and was more sustained. A comparison of plasma radioactivity after intracerebroventricular or intravenous injection of [3H]U-46,619 demonstrated that approximately 35% of the drug reached the systemic circulation by 5-15 min after intracerebroventricular administration. Coadministration of a TxA2/PGH2 antagonist, ifetroban, by intravenous or intracerebroventricular routes blocked the pressor responses induced by U-46,619. The half-maximal inhibition for blockade of responses was substantially lower for intracerebroventricular than for intravenous responses (intracerebroventricular: 0.03 +/- 0.01 vs. intravenous: 3.1 +/- 0.6 micrograms/kg; P < 0.001). The intravenous administration of ifetroban (10 micrograms/kg) caused a greater (P < 0.02) inhibition of pressor responses to U-46,619 (1 microgram/kg) given intravenously (81 +/- 3%) compared with U-46,619 given intracerebroventricularly (40 +/- 13%). In conclusion, TxA2/PGH2 receptor mRNA is expressed in neurons, glial, and brain stem of normal rats. The central administration of a TxA2/PGH2 mimetic raises blood pressure by interaction with specific central and peripheral receptors. This response is augmented in rats fed a high-salt compared with a low-salt diet.
Cholecystokinin activates area postrema neurons in rat brain slices
Authors: Sun K. , Ferguson A. V.
Published: December 2017

Peripheral cholecystokinin (CCK) reduces food intake and triggers the secretion of both oxytocin and corticotropin-releasing hormone. These responses are partially initiated by activation of receptors in the peripheral endings of the vagus nerve. However, in vivo studies showing that after vagotomy systemic CCK induces fos activation of neurons in the area postrema (AP) suggest that circulating CCK may directly influence the activity of neurons in this structure. The present study was therefore designed to investigate the responsiveness of AP neurons to CCK using in vitro extracellular single-unit recording techniques. Bath application of 100 nM CCK for 200 s resulted in excitatory responses in 41% and inhibitory effects in 6% of 143 AP neurons tested. Application of multiple doses of CCK (1-100 nM) to single neurons demonstrated that CCK effects were dose dependent. The firing rate of tested neurons increased by 48 +/- 15% in response to 1 nM, by 89 +/- 22% in response to 10 nM, and by 242 +/- 77% in response to 100 nM CCK. After we blockaded synaptic transmission with a low-Ca2+/high-Mg2+ artificial cerebrospinal fluid, the excitatory effects of CCK remained in all nine neurons tested. The CCK-receptor antagonist L-364,718 had no significant effect on the responses to CCK (P > 0.1, n = 4), whereas, after perfusion of slices with the CCKB-receptor antagonist L-365,260, mean responses to CCK were significantly reduced to 12.6 +/- 4.7% of the control value (P < 0.001, n = 4). These results demonstrate a direct and dose-dependent excitatory action of CCK on AP neurons that is abolished by CCKB-receptor antagonists. These data emphasize the potential role of AP in processing afferent information derived from circulating peptide concentrations that could be involved in the regulation of food intake.
Nitric oxide increases cutaneous and respiratory heat dissipation in conscious rabbits
Authors: Mathai M. L. , Hjelmqvist H. , Keil R. , Gerstberger R.
Published: December 2017

The influence of systemic nitric oxide (NO) donor infusion and NO synthase inhibition on major thermoregulatory mechanisms was investigated under thermoneutral conditions (24 degrees C) in the conscious rabbit. Both low (25 nmol.min-1.kg-1) and high-dose (75 nmol.min-1.kg-1) infusion of the NO donors 3-morpholinosydnonimine-hydrochloride and S-nitroso-N-acetylpenicillamine augmented respiratory heat dissipation due to raised respiratory frequency (RF) and evaporative water loss (REWL). At the higher dose of NO donor, RF and REWL increased (from 107 +/- 16 to 156 +/- 19 breaths/min and from 7.12 +/- 0.97 to 11.29 +/- 1.29 mg.min-1.kg-1; P < 0.05), and, combined with a moderate rise in cutaneous heat dissipation (ear skin temperature increased from 29.03 +/- 1.76 to 33.29 +/- 2.71 degrees C; P < 0.05), deep body temperature was slightly reduced (-0.1 degrees C, P > 0.05) without a change in metabolic heat production. In contrast, blockade of endogenous NO synthesis induced a sustained rise in body temperature (0.2 degrees C, P < 0.05), concomitant with a reduction in both RF and REWL (from 131 +/- 11 to 94 +/- 12 breaths/min and from 10.86 +/- 1.14 to 8.70 +/- 0.88 mg.min-1.kg-1, P < 0.05), whereas metabolic heat production decreased slightly and cutaneous heat dissipation was minimally altered. The data indicate that, under thermoneutral conditions, systemically applied NO primarily influences body temperature in the conscious rabbit by modulating the rate of respiratory heat dissipation, whereas the roles of cutaneous heat dissipation and metabolic heat production are relatively minor.
Modulation of tissue angiotensinogen gene expression in genetically obese hypertensive rats
Authors: Tamura K. , Umemura S. , Yamakawa T. , Nyui N. , Hibi K. , Watanabe Y. , Ishigami T. , Yabana M. , Tanaka S. , Sekihara H. , Murakami K. , Ishii M.
Published: December 2017

Wistar fatty rats (WFR) show obesity and obesity-related features, including hypertension. In this study, we examined the expression of angiotensinogen mRNA in a variety of tissues at different times in WFR and control Wistar lean rats (WLR). WFR were obese and hypertensive at 16 and 24 wk. Plasma renin activity and plasma angiotensinogen concentration showed age-dependent increases in WFR but decreases in WLR. Northern blot analysis showed no significant differences in the levels of hepatic and renal angiotensinogen mRNA between WFR and WLR, and the levels of fat and adrenal angiotensinogen mRNA were lower in WFR than in WLR. On the other hand, the levels of cardiac angiotensinogen mRNA at 16 and 24 wk and those of aortic angiotensinogen mRNA at 16 wk were significantly higher in WFR than in WLR. These results show that the expression of tissue angiotensinogen mRNA is regulated differently in WFR and WLR and indicate that the development of hypertension in WFR is accompanied at least temporally with increases in plasma angiotensinogen concentration as well as in cardiac and aortic angiotensinogen mRNA. Moreover, these results suggest the existence of obesity hypertension-linked and tissue-specific regulation of angiotensinogen gene expression.
Gestational resistance to the pulmonary vasoconstrictor effect of the TxA2 mimetic U-46619: possible mechanism
Authors: Losonczy G. , Brown G. , Mucha I. , Klocke R. , Muller V. , Merkely B. , Tornoci L. , Rosivall L. , Venuto R.
Published: December 2017

Pregnancy is associated with the reduction of vascular sensitivity to vasoconstrictor compounds. We have examined whether pregnancy in rabbits induces hyposensitivity of the pulmonary vascular system to U-46619. Anesthetized, mechanically ventilated nonpregnant (NP; n = 7) and late-pregnant (P; n = 7) rabbits were studied. The intravenous injection of 0.03, 0.1, and 0.3 microgram/kg U-46619 led to a dose-dependent elevation of mean pulmonary arterial pressure (MPAP) in NP rabbits from a baseline value of 15 +/- 1 to 22 +/- 1 mgHg. There was no significant MPAP response to intravenous administration of U-46619 in P rabbits. The pulmonary arterial pressure response of isolated, ventilated, and buffer-perfused lungs of P rabbits was also blunted (P < 0.001 vs. NP). Pulmonary arterial membrane binding of [125I]BOP, another thromboxane (Tx)A2 analog, indicated 48 +/- 16 fmol receptors/mg protein in P rabbits and 193 +/- 48 fmol receptors/mg protein in NP samples (P < 0.025). Receptor affinity [1/dissociation constant (KD)] was also lower in the tissue of P rabbits (P < 0.01 vs. NP). The urinary excretion of the stable TxA2 metabolite 11-dehydro-TxB2 was lower in P than in NP rabbits (P < 0.02), which made homologous desensitization an unlikely explanation for the changes of vascular TxA2 receptors. These results show that, in late gestation, rabbit pulmonary vascular sensitivity to U-46619 is reduced simultaneously with, and as a possible consequence of, downregulation of specific receptors.
Carbonic anhydrase facilitates CO2 and NH3 transport across the sarcolemma of trout white muscle
Authors: Henry R. P. , Wang Y. , Wood C. M.
Published: December 2017

An isolated, perfused tail preparation was used to study the role of carbonic anhydrase (CA) in CO2 and NH3 transport across the sarcolemma of white muscle in the rainbow trout. Tissue was perfused with either control saline or saline containing the CA inhibitors quaternary ammonium sulfanilamide (QAS) or acetazolamide (Az). Inhibition of extracellular CA by QAS reduced CO2 efflux by approximately 30% and caused a significant increase in intracellular PCO2. Inhibition of total muscle CA activity (extracellular and intracellular) by Az also caused a reduction in CO2 efflux, but selective inhibition of intracellular CA only had no effect. Inhibition of both extracellular and intracellular CA activity resulted in increases in total intracellular ammonia concentrations, intracellular NH3 partial pressure (PNH3) and an increased PNH3 gradient across the sarcolemma. This suggests that both extracellular and intracellular CA function in normal NH3 transport out of the muscle. We suggest that CA in the extracellular boundary layer facilitates CO2 transport via the catalyzed hydration of CO2, thus maintaining the PCO2 gradient across the sarcolemma. H ions produced by that reaction serve to protonate excreted NH3, which helps maintain the PNH3 gradient. Thus CO2 and NH3 excretion are linked by the action of CA.
Characterization of an esophagocardiovascular reflex in the rat
Authors: Loomis C. W. , Yao D. , Bieger D.
Published: December 2017

A cardiovascular reflex evoked by esophageal distension (ECR) in urethan-anesthetized male Sprague-Dawley rats was studied to 1) determine whether the relevant sensory input from the esophagus is conveyed by vagal and/or spinal afferents and 2) evaluate the effects and sites of action of antinociceptive agents. Esophageal distension evoked a rise in arterial blood pressure and heart rate that increased linearly with the log of inflation pressure (25-150 mmHg). Distension (100 mmHg for 20 s) of the lower esophagus was a more effective stimulus than distension of the upper esophagus. The ECR was attenuated by unilateral and abolished by bilateral cervical vagotomy and dose dependently inhibited by morphine (1.0-4.0 mg/kg iv) or by intrathecal (T4-T5) administration of dexmedetomidine (DX, 0.05-0.5 microgram), but not by intrathecal (T4-T5) morphine (4-16 micrograms) or intrathecal (L1-L2) or intravenous DX (0.05-0.5 microgram). The ECR was also inhibited by capsaicin and by the topical administration of DX or morphine to the solitary complex. The pressor response persisted after intravenous pancuronium, scopolamine, and methscopolamine. The ECR circuit appears to consist of vagal afferents, efferent sympathetic preganglionic pathways originating in the thoracic spinal cord, and bulbospinal neurons yet to be identified. This reflex fulfills some criteria of a nociceptive event, but this interpretation requires further investigation.
Enzyme adaptation along a heterothermic tissue: the visceral retia mirabilia of the bluefin tuna
Authors: Fudge D. S. , Stevens E. D. , Ballantyne J. S.
Published: December 2017

We measured enzyme activities along a heterothermic tissue, the visceral retia mirabilia of the bluefin tuna, to test current theories of enzyme temperature adaptation. The heterothermic tissue model is ideal for the study of fundamental temperature adaptation because it eliminates confounding effects of whole animal acclimation. Enzymes were measured at six positions along the rete at four temperatures (15, 20, 25, and 30 degrees C). Five enzymes (aspartate aminotransferase, citrate synthase, glucose-6-phosphate dehydrogenase, glutamate dehydrogenase, and pyruvate kinase) exhibited a significant positive compensatory effect, with activity at the cold end of the rete 1.2-3.1 times higher than at the warm end. Two enzymes (alanine aminotransferase and lactate dehydrogenase) exhibited no significant compensation. On the basis of activation energies of enzymes along the rete, differences in activity were due to differences in enzyme concentration and not isozymes or enzyme modification. Analysis of the compensatory responses of the enzymes in light of their thermal sensitivities leads us to conclude that the pentose phosphate shunt is especially enhanced at the cold end of the rete.
Histaminergic contribution to the metabolic effects of neuroglucopenia
Authors: Molina P. E. , Williams P. , Abumrad N. N.
Published: December 2017

We examined the contribution of central histamine receptor (H1 and H2) blockade to the glucoregulatory responses to intracerebroventricular 2-deoxy-D-glucose (2-DG) in conscious dogs. Intracerebroventricular 2-DG (2.5 mg.kg-1.min-1 for 15 min) increased plasma glucose (2-fold), blood lactate (4-fold), and glycerol (2-fold) levels. The rate of hepatic glucose production (Ra), determined isotopically, was increased two-fold. Significant increases over basal were also noted in plasma epinephrine, norepinephrine, insulin, glucagon, and cortisol. Pretreatment with cyproheptadine and cimetidine (100 micrograms each icv 15 min before 2-DG) attenuated the 2-DG-induced hyperglycemia by approximately 50% and delayed and attenuated the increase in glucose Ra (approximately 85% vs. 2-fold in group 1). Pretreatment with H1 and H2 antagonists inhibited the increases in epinephrine, norepinephrine, and glucagon in response to neuroglucopenia but did not affect the cortisol response. These findings suggest that some of the metabolic effects of neuroglucopenia, particularly the hyperglycemic response, the increased hepatic uptake of gluconeogenic precursors, and the enhanced glucose Ra, are partly mediated through central histaminergic receptor activation. This appears to be through effects of histaminergic activation on the autonomic and hormonal responses to central neuroglucopenia.
Ins(1,4,5)P3 receptors in cerebral arteries: changes with development and high-altitude hypoxia
Authors: Zhou L. , Zhao Y. , Nijland R. , Zhang L. , Longo L. D.
Published: December 2017

We and others have shown that adrenergic-mediated contractile responses in cerebral vessels in vitro differ with vessel segment, with developmental age, and with high-altitude, long-term hypoxia. This is associated with significant differences in alpha 1-adrenergic receptor density and norepinephrine (NE)-induced response of the second messenger inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. To test the hypothesis that vessel-specific, developmental, and hypoxic-associated contractility changes are mediated, in part, by changes in Ins(1,4,5)P3-receptor [Ins(1,4,5)P3-R] density or affinity, we performed the following study. In common carotid (Com), circle of Willis, and main branch anterior, middle, and posterior cerebral arteries (MBC) from normoxic fetal (approximately 140 days), newborn (3-5 days), and adult sheep and fetal and adult sheep acclimatized to high altitude, we quantified Ins(1,4,5)P3-R with [3H]Ins(1,4,5)P3. In normoxic Com, Ins(1,4,5)P3-R density values (fmol/mg protein) in fetus, newborn, and adult were 8 +/- 53, 150 +/- 18, and 357 +/- 21, respectively (P < 0.05). In normoxic MBC cerebral arteries, the receptor density values in the three age groups were 115 +/- 15, 105 +/- 9, 99 +/- 5 fmol/mg protein, respectively. For fetal and adult Com, high-altitude, long-term hypoxemia was associated with decreases in Ins(1,4,5)P3-R density of 32 (to 58 +/- 5) and 70% (to 109 +/- 12), respectively, from control values (P < 0.01). In MBC cerebral arteries of fetus and adult, hypoxic-associated decreases in Ins(1,4,5)P3-R density from control were 80 (to 23 +/- 3) and 47% (to 53 +/- 7), respectively (P < 0.01). Ins(1,4,5)P3 binding affinity to the receptor averaged 11.8 +/- 0.5 nM and did not vary significantly as a function of vessel type, developmental age, or hypoxia. In Com, but not in MBC, Ins(1,4,5)P3-R density increased dramatically with developmental age. This suggests that differences in Ins(1,4,5)P3-R density values may account, in part, for differences in contractile responses of the two artery types in the several age groups. In response to long-term, high-altitude hypoxia, Ins(1,4,5)P3-R density values in both fetal and adult Com and MBC decreased significantly, as did their NE-induced contraction. This suggests a cellular basis for changes in cerebrovascular contractility in response to long-term hypoxia and that Ins(1,4,5)P3-R may play a role in acclimatization responses to high altitude.
Increased force development rates of fatigued mouse skeletal muscle are graded to myosin light chain phosphate content
Authors: Vandenboom R. , Xeni J. , Bestic N. M. , Houston M. E.
Published: December 2017

Phosphorylation of myosin regulatory light chain (R-LC) increases the Ca2+ sensitivity of cross-bridge transitions, which determine rate of force development in skinned skeletal muscle fibers. The purpose of this study was to determine whether phosphorylation of R-LC is the molecular basis for the increased force development rates (+dF/dtmax) observed in fatigued mouse extensor digitorum longus muscle (EDL) (stimulated in vitro at 25 degrees C). Parameters of twitch and tetanic force were obtained after the application of different-frequency conditioning stimuli (CS), which were used to vary R-LC phosphorylation and reduce peak tetanic force (Po). Without CS, R-LC phosphorylation (in moles phosphate per mole R-LC) was not elevated above rest (0.11 +/- 0.02 vs. 0.13 +/- 0.02, respectively), and no aspect of the twitch (Pt) Po was altered. Stimulating muscles at 2.5-20 Hz increased R-LC phosphorylation in a frequency-dependent manner, from 0.23 +/- 0.04 to 0.82 +/- 0.03, respectively. Moreover, stimulation at 2.5-20 Hz potentiated Pt (range: 4 +/- 2-28 +/- 2%), increased the +dF/dtmax of potentiated twitches (range: 5 +/- 1-28 +/- 2%), and reduced Po (range: 6 +/- 1-21 +/- 1%). Higher-frequency stimulation (40 or 100 Hz) did not phosphorylate R-LC or potentiate Pt or twitch +dF/dtmax further. Stimulation at 40 and 100 Hz did, however, have different effects on Po compared with 20-Hz data (Po reduced 27 +/- 2 and 11 +/- 2%, respectively). The increased +dF/dtmax of potentiated twitches observed after different CS procedures were graded to R-LC phosphorylation (r = 0.97, P < 0.001). It is concluded that phosphorylation of R-LC increases extent of twitch force development in mouse EDL muscle fatigued by CS.
Bradykinin-mediated activation of renal sensory neurons due to prostaglandin-dependent release of substance P
Authors: Kopp U. C. , Farley D. M. , Smith L. A.
Published: December 2017

In anesthetized rats, renal pelvic administration of bradykinin results in a prostaglandin (PG)-dependent increase in afferent renal nerve activity (ARNA). We now measured renal pelvic release of PGE and substance P during renal pelvic administration of bradykinin. Bradykinin increased ARNA and renal pelvic release of PGE by 497 +/- 252 pg/min and substance P. by 10.7 +/- 7.2 pg/min. Renal pelvic perfusion with indomethacin abolished the bradykinin-mediated increase in ARNA and reduced renal pelvic release of PGE and substance P by 76 +/- 11 and 72 +/- 8%, respectively. To examine whether the increased substance P release contributed to bradykinin-mediated activation of renal sensory receptors, renal pelvis was perfused with the substance P-receptor antagonists CP-96,345, CP-99,994, or RP-67580. The ARNA response to bradykinin was reduced 73 +/- 11, 55 +/- 12, and 64 +/- 10% by CP-96,345, CP-99,994, and RP-67580, respectively. The inactive enantiomers CP-96,344 and RP-68651 had no effect. These data suggest that bradykinin increases renal pelvic release of PGE, which facilitates the release of substance P, which in turn stimulates substance P receptors. Thus the ARNA response to bradykinin is largely mediated by activation of substance P receptors.
Very low frequency oscillations in arterial blood pressure after autonomic blockade in conscious dogs
Authors: Wagner C. D. , Just A. , Nafz B. , Persson P. B.
Published: December 2017

The aim of this study was to investigate spontaneous variability of arterial blood pressure in conscious foxhounds in the absence of direct sympathetic and parasympathetic influences. Autonomic blockade was achieved by administration of the ganglionic blocking agent hexamethonium (n = 7). In contrast to the control group (n = 7), marked oscillations with a cycle length of 100 s (0.01 Hz) were observed. The relationship of the power densities of the oscillation band (0.01 +/- 0.005 Hz) to the total power increased threefold (0.213 +/- 0.007 vs. 0.057 +/- 0.005; P < 0.01). The 0.01-Hz oscillations typically commenced after some delay. To test whether the absence of the mechanoreceptor afferents was responsible for these fluctuations, we investigated an additional group of foxhounds that were subjected to total baroreceptor and cardiopulmonary receptor denervation (n = 7). Neither in this protocol, nor in a group subjected to denervation and ganglionic blockade (n = 6), did we observe sustained oscillations in this frequency range. Since the oscillations were not seen after combined afferent (mechanoreceptor denervation) and efferent (ganglionic) blockade, central oscillators as a source of the oscillations can be ruled out. A simple model of a circulating pressoric factor may explain the fluctuations, provided that there is a time delay between the stimulus and the release or action of the factor. The findings suggest that a circulating factor accounts for the 0.01-Hz oscillations, which is dependent on intact pathways from the cardiac receptors or baroreceptors to the central nervous system. This hypothesis is put forward since cardiopulmonary and baroreceptor denervation blocked the oscillations seen after ganglionic blockade.