bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of spaceflight on hypothalamic peptide systems controlling pituitary growth hormone dynamics
Authors: Sawchenko P. E. , Arias C. , Krasnov I. , Grindeland R. E. , Vale W.
Published: December 2017

Immunohistochemical and in situ hybridization localization of peptides derived from, and mRNAs encoding, prepro-somatostatin (ppSS) and prepro-growth hormone-releasing factor (ppGRF) was carried out on hypothalami from rats flown on biosatellites COSMOS 1887 and 2044 to investigate possible effects of reduced gravity on central hypophysiotropic systems controlling growth hormone (GH) secretion. Results from the COSMOS 1887 mission indicated that both SS and GRF immunostaining in the median eminence were diminished in flight animals relative to controls; no differences between groups in staining for other peptidergic neurosecretory systems were apparent. Animals flown on COSMOS 2044 displayed a more pronounced depletion of GRF than SS immunoreactivity from neurosecretory terminals in the median eminence. In addition, flight animals displayed significant 46–50% reductions in the number and signal intensity of presumed hypophysiotropic cells in the arcuate nucleus expressing ppGRF mRNA; positively hybridized cells in the region surrounding the ventromedial nucleus were less markedly affected. Both indexes of ppSS mRNA levels in the anterior periventricular nucleus were similar in flight and control rats. An additional group of animals that experienced hindlimb suspension, a manipulation that mimics the effects of weightlessness on several parameters, did not differ from controls in any of the above measures. These data suggest that exposure to microgravity results in a preferential reduction in GRF peptide and mRNA levels in hypophysiotropic neurons, which may contribute to impaired GH secretion described previously in animals subjected to spaceflight. Effects of weightlessness are not mimicked by hindlimb suspension in this system.
Circulating parathyroid hormone and calcitonin in rats after spaceflight
Authors: Arnaud S. B. , Fung P. , Popova I. A. , Morey-Holton E. R. , Grindeland R. E.
Published: December 2017

Parathyroid hormone and calcitonin, two major calcium-regulating hormones, were measured in the plasma of five experimental groups of rats to evaluate postflight calcium homeostasis after the 14-day COSMOS 2044 flight. Parathyroid hormone values were slightly higher in the flight animals (F) than in the appropriate cage and diet controls (S) (44 +/- 21 vs. 21 +/- 4 pg/ml, P less than 0.05), but they were the same as in the vivarium controls (V), which had different housing and feeding schedules. Neither V nor S showed the increase in plasma creatinine phosphorus and magnesium found in F, features of early renal insufficiency. F showed the lowest mean plasma calcitonin that was statistically different from V only. This difference in F and V (22 +/- 11 vs. 49 +/- 16 pg/ml, P less than 0.05) was most likely due to failure of circulating calcitonin in F to show the normal age-dependent increase we demonstrated in age-matched controls in a separate experiment. Basal values for parathyroid hormone and calcitonin were unchanged after 2 wk of hindlimb suspension, a flight simulation model, in age-matched and younger rats. From a time course experiment serum calcium was higher and parathyroid hormone lower after 4 wk than in ambulatory controls. Postflight circulating levels of parathyroid hormone appear to reflect disturbances in calcium homeostasis from impaired renal function of undetermined cause, whereas levels of calcitonin reflect depression of a normal growth process.
Endotoxin tolerance is associated with altered GTP-binding protein function
Authors: Coffee K. A. , Halushka P. V. , Ashton S. H. , Tempel G. E. , Wise W. C. , Cook J. A.
Published: December 2017

Previous studies have suggested that guanine nucleotide regulatory (G) proteins modulate endotoxin-stimulated peritoneal macrophage arachidonic acid (AA) metabolism. Endotoxin-stimulated metabolism of AA by peritoneal macrophages is decreased in endotoxin tolerance (Rogers et al. Prostaglandins 31: 639–650, 1986). These observations led to a study of G protein function and AA metabolism by peritoneal macrophages in endotoxin tolerance. Endotoxin tolerance was induced by the administration of sublethal doses of endotoxin. AA metabolism was assessed by measurement of thromboxane B2 (TxB2), a cyclooxygenase metabolite. NaF (5 mM), an activator of G proteins, significantly stimulated TxB2 synthesis in control macrophages from 7.7 +/- 0.2 to 19.1 +/- 0.6 (SE) ng/ml (P less than 0.05) at 2 h and was partially inhibited by pertussis toxin, suggesting a G protein-dependent mechanism. Salmonella enteritidis endotoxin (50 micrograms/ml) stimulated a similar increase in TxB2 levels (23 +/- 0.4 ng/ml, P less than 0.05). In contrast to control macrophages, macrophages from endotoxin-tolerant rats stimulated with either NaF or S. enteritidis endotoxin had TxB2 levels that were only 30 and 2% of the respective stimulated control cells. Basal guanosine-triphosphatase (GTPase) activity (33 +/- 6 pmol.mg-1.min-1) in endotoxin-tolerant macrophage membranes was significantly lower (P less than 0.05) than control basal activity (158 +/- 5 pmol.mg-1.min-1). This suppression of macrophage GTPase activity was apparent 48 h after the first in vivo sublethal endotoxin injection (100 micrograms/kg ip). The reduced GTPase activity paralleled in vitro cellular hyporesponsiveness to endotoxin-stimulated TxB2 production.(ABSTRACT TRUNCATED AT 250 WORDS)
A peptidergic component to vagally induced tracheal vasodilation in the dog
Authors: Ito T. , Takubo T. , Hussain S. , Martin J. G.
Published: December 2017

The purpose of the study was to determine the extent that peptidergic afferent and efferent pathways contribute to vagally induced vasodilation in the trachea of the dog. The change in vascular resistance of the tracheal branch of the cranial thyroid artery and the trachealis responses were determined in 28 anesthetized, paralyzed, and mechanically ventilated dogs. After propranolol (2 mg/kg) and phentolamine (1.5 mg/kg), stimulation of the superior laryngeal nerves (NS; 15 Hz, 7 V, 2 ms, 30 s) caused a decrease in vascular resistance of 11.7 +/- 0.8% and a tracheal contraction of 5.2 +/- 4.7 cmH2O. Atropine (1.5 mg/kg) reduced the fall in vascular resistance to 4.7 +/- 0.8% (P less than 0.01), whereas tracheal contraction was abolished. Thiorphan (1.5 mg), a neutral endopeptidase inhibitor, augmented the decrease in vascular resistance (8.8 +/- 0.6%; P less than 0.01) to NS. After hexamethonium (0.5 mg/kg), NS still caused a small decrease in TVR (2.9 +/- 0.9%; P less than 0.05), which was abolished by capsaicin. In atropinized dogs, capsaicin reduced the fall in vascular resistance after NS; the residual vasodilation was virtually abolished by hexamethonium. Acetylcholine (10(-3) mg/kg) decreased vascular resistance (15.7 +/- 3.0%), and the effect was abolished by atropine. We conclude that there is noncholinergic nonadrenergic vagally induced tracheal vasodilation that is peptidergic. The peptidergic vasodilation appears to be mediated by both afferent and efferent pathways.
Bronchomotor vagal preganglionic cell bodies in the dog: an anatomic and functional study
Authors: Haselton J. R. , Solomon I. C. , Motekaitis A. M. , Kaufman M. P.
Published: December 2017

A previous study in our laboratory demonstrated that the stimulation with microinjection of DL-homocysteic acid of cell bodies in the rostral portion of the external formation of the nucleus ambiguus (Aext) increased total lung resistance in dogs. In the present study anatomic experiments were conducted in dogs to determine if the rostral Aext contains vagal preganglionic cell bodies that give rise to axons in the pulmonary branches of the vagus nerve. The application of horseradish peroxidase (HRP) to either the pulmonary branches or the vagus at a point between the pulmonary branches and the cardiac branches resulted in retrograde labeling of cell bodies in both rostral Aext and the dorsal motor nucleus of the vagus (DMN). On the other hand, application of HRP to the vagus at a point below the pulmonary branches did not result in any retrogradely labeled cell bodies in rostral Aext but did result in labeled cell bodies in DMN. In another series of experiments DL-homocysteic acid (2.5 nmol in 25 nl) was microinjected at sites in rostral Aext and DMN. As we previously reported the injection of DL-homocysteic acid in rostral Aext increased total lung resistance. In contrast, in the same animals, the injection of DL-homocysteic acid in DMN did not change total lung resistance. We conclude that bronchomotor vagal preganglionic cell bodies are located in rostral Aext but not in DMN. The functional significance of vagal preganglionic cell bodies in DMN whose axons contribute to the pulmonary branches of the vagus nerve remains to be determined.
Low-dose dopamine hastens onset of gut ischemia in a porcine model of hemorrhagic shock
Authors: Segal J. M. , Phang P. T. , Walley K. R.
Published: December 2017

Gut metabolism may become anaerobic before the whole body during progressive phlebotomy in dogs. Because dopamine has selective mesenteric vasodilator effects, we asked whether dopamine could delay onset of bowel ischemia during hemorrhagic shock. We studied whole body and gut O2 consumption (VO2) and O2 delivery (QO2) using progressive phlebotomy in anesthetized pigs. Nine pigs received a dopamine infusion of 2 micrograms.kg-1.min-1, whereas a control group of seven pigs received equivalent saline infusion. Onset of ischemia in whole body and gut was determined as critical O2 delivery (QO2c), the intersection point of biphasic regression on plots of VO2-QO2 relationships. Blood flow and O2 extraction were measured as mechanisms of gut ischemia for entire in situ small and large gut using a superior mesenteric venous fistula. Dopamine hastened onset of gut ischemia relative to onset of whole body ischemia (gut critical point in terms of whole body QO2 9.9 +/- 2.1 ml O2.kg-1.min-1, whole body QO2c 7.8 +/- 0.7 ml O2.kg-1.min-1, P less than 0.01). In contrast, onset of gut ischemia in control animals occurred at same time as onset of whole body ischemia (gut critical point in terms of whole body QO2 7.4 +/- 2.3 ml O2.kg-1.min-1, whole body QO2c 7.1 +/- 2.7 ml O2.kg-1.min-1, P = not significant). Hastening of onset of gut ischemia in dopamine-treated animals was associated with decreased ability of gut to extract O2. Low-dose dopamine was not protective against gut ischemia during shock but rather caused earlier onset of gut ischemia during hemorrhagic shock.
Effect of temperature on the biaxial mechanics of excised lung parenchyma of the dog
Authors: Debes J. C. , Fung Y. C.
Published: December 2017

The influence of temperature on the mechanical properties of excised saline-filled lung parenchyma of the dog was studied at low lung volume. The motivation of this study was to determine whether lung tissue material without the influence of surface tension undergoes a phase transition in the 20–40 degrees C range, as does synthetic elastin studied by Urry in 1984–1986. Dynamic biaxial and uniaxial tensile tests were done, and strain vs. Lagrangian stress curves were recorded during slow cooling and heating between 40 and 10 degrees C. To emphasize the effects of elastin, strains (defined as stretch ratio minus one) were kept below 30%. A slight decrease in compliance occurred with cooling over the entire temperature range. This effect may be attributed to collagen. It was accompanied by a gradual increase in length as the tissue cooled, an effect that may be attributed to elastin. This process was partially reversible with reheating. However, this effect is in contrast with the sudden drastic change in mechanical properties of synthetic elastin described by Urry. Hysteresis, creep, and stress relaxation were small at these low strains. Possible causes of these effects are discussed.
NG-monomethyl-L-arginine paradoxically relaxes preconstricted canine intrapulmonary arteries
Authors: Tseng C. M. , Goodman L. W. , Rubin L. J. , Tod M. L.
Published: December 2017

We studied the effects of NG-monomethyl-L-arginine (LMMA), a nitric oxide (NO) synthesis inhibitor, in canine intrapulmonary arteries constricted with phenylephrine. Isolated vessels were suspended in organ chambers containing modified Krebs solution, and isometric tensions were recorded. In contrast to the expected constriction predicted from other studies, LMMA instead caused dose-dependent vasorelaxation in phenylephrine-constricted canine pulmonary arteries. LMMA (1 and 10 microM) reduced the phenylephrine contraction by 5 and 23%, respectively. Similar dose-dependent relaxations were observed with NG-monomethyl-D-arginine (DMMA) but not with L-arginine (L-Arg), N epsilon-methyl-L-lysine, and another NO synthesis inhibitor, N omega-nitro-L-arginine (LNA), suggesting that a methyl group positioned at the guanidino-nitrogen is important in these responses. Vasorelaxation induced by LMMA and DMMA was not affected by pretreatment with the NO precursor L-Arg; however, responses were abolished by dissimilar cyclooxygenase inhibitors indomethacin (10 microM) and meclofenamate (2 microM). Pretreatment of vessels with LNA (100 microM) augmented LMMA-induced relaxations but attenuated DMMA-induced responses. LMMA- and DMMA-induced vasorelaxations were also observed in endothelium-rubbed vessels; DMMA-induced vasorelaxations were similar in vessels with and without endothelium, whereas LMMA-induced relaxations were increased in endothelium-rubbed vessels. These data suggest that LMMA and DMMA induced vasorelaxation by causing synthesis of dilator prostaglandins, which was independent of the presence of endothelial cells and the L-Arg-NO pathway. In addition, both endothelium removal and LNA pretreatment augmented LMMA-induced but not DMMA-induced relaxations, suggesting that inhibition of NO synthesis by LMMA opposes its cyclooxygenase-dependent vasorelaxant effects.
Developmental differences in vascular smooth muscle mechanics in pulmonary and systemic circulations
Authors: Belik J. , Stephens N. L.
Published: December 2017

To evaluate the maturational changes in vascular muscle mechanics we studied and compared the isotonic half-time relaxation (t1/2P,CE) and maximal load-bearing capacity normalized to stress of pulmonary and systemic arterial muscle from perinatal and adult sheep. For the pulmonary and systemic vessels t1/2P,CE was significantly shorter in adult than in perinatal sheep (P < 0.01). In newborns t1/2P,CE of the pulmonary vessels was 185 +/- 31 (SE) s, longer than that of the systemic vessels (64 +/- 10 s; P < 0.01). In adults t1/2P,CE of the pulmonary vessels (101 +/- 14 s) was longer than that of the systemic vessels (37 +/- 5 s; P < 0.01). Maximal load-bearing capacities normalized to stress of pulmonary vessels of fetal and newborn sheep were twofold greater than those of adult sheep and of the systemic vessels of newborns and adults (P < 0.01). In conclusion, significant maturational changes in the isotonic and isometric mechanical properties of vascular pulmonary and systemic smooth muscle were observed in sheep.
Appearance of airway absorption and exudation tracers in guinea pig tracheobronchial lymph nodes
Authors: Erjefalt I. , Luts A. , Persson C. G.
Published: December 2017

This study examines the fate of extravasated plasma in inflammatory stimulus-challenged large tracheobronchial airways of ketamine-xylazine-anesthetized guinea pigs. Entry of plasma tracers into the airway lumen was determined by a validated noninjurious airway lavage technique. Removal by airway lymphatics was assessed by tracheobronchial lymph node levels of plasma tracers. Mucosal challenges with histamine (5 nmol), bradykinin (5 nmol), capsaicin (0.4 nmol), or allergen (ovalbumin, 3 pmol) increased the appearance of a plasma tracer (131I-labeled albumin previously injected intravenously) in the airway lumen within 10 min (10–20 times control; P < 0.001), whereas the contractile agent carbachol (8 nmol) was without exudative effect. The mediators were without effect, and capsaicin and allergen only slightly increased the lymph node level of plasma exudation tracer (1.5 times control; P < 0.05). Hence, removal via the lymphatic route of plasma macromolecules may be negligible in the acute and postacute phases of an airway exudation response. Experiments were also carried out with luminally applied macromolecular tracers. These were absorbed from the mucosal surface into the circulation, but a small portion was also transported to the lymph nodes, demonstrating the interconnections between the mucosa and the sampled nodes. Only capsaicin produced an increased node level of absorption tracer. Immunohistochemistry showed that the tracheobronchial tissue and lymph nodes are endowed with nerve fibers containing substance P, the release of which may have mediated lymph transport, vascular, and exudative effects of capsaicin in the present studies.(ABSTRACT TRUNCATED AT 250 WORDS)
Role of vasoconstriction in gravity-nondependent central-peripheral gradient in pulmonary blood flow
Authors: Hakim T. S. , Lisbona R. , Michel R. P. , Dean G. W.
Published: December 2017

To examine the effect of vasoconstriction on the gravity-nondependent distribution of pulmonary blood flow, albumin macroaggregates labeled with either 99mTc or 111In were injected at end expiration into dogs (anesthetized, supine, and breathing room air spontaneously). The first dose of macroaggregates was injected during baseline conditions and the second during infusion of serotonin or histamine. Five minutes after the second injection, the chest was opened and the lungs were removed, drained of blood, and dried while fully inflated. Single photon emission computed tomography was performed on the dry lungs to map the three-dimensional distribution of activity of the two isotopes. Images of coronal and sagittal slices were displayed. The results showed that changes in vascular muscle tone did not alter pulmonary blood flow distribution. The absolute flow in a central and peripheral region changed in proportion to cardiac output changes, indicating that during vasoconstriction, as during baseline conditions, there was a preferential perfusion to the interior of the lung. Examination of the average flow in the individual coronal slices showed that during serotonin or histamine infusion, the average flow in each slice changed in proportion to change in cardiac output but that the vertical average flow was not affected significantly. These findings are consistent with the notion that resistive properties (length, diameter, branching pattern) of the pulmonary vascular tree are responsible for the central-peripheral gradient.
Chronic hypoxic pulmonary hypertension in the guinea pig: effect of three levels of hypoxia
Authors: Thompson B. T. , Steigman D. M. , Spence C. L. , Janssens S. P. , Hales C. A.
Published: December 2017

Chronic hypoxia [inspiratory PO2 (PIO2) = 76 Torr for 10 days] produces pulmonary hypertension and vascular remodeling in the guinea pig. Increasing the duration of hypoxia from 10 to 21 days does not increase further pulmonary arterial pressure or medial thickening. To see if increasing severity of hypoxia affects the magnitude of pulmonary hypertension and remodeling, we exposed three groups of male Hartley guinea pigs to three levels of normobaric hypoxia for 10 days: PIO2 = 90 (n = 6), 78 (n = 6), and 65 Torr (n = 5). Pulmonary arterial pressure increased from 14 +/- 1 (+/- SE, n = 7) in room air to 23 +/- 3 mmHg when PIO2 = 90 Torr (P < 0.05). Pulmonary arterial pressure was slightly higher when PIO2 = 78 or 65 Torr (25 +/- 1 and 26 +/- 1 mmHg, respectively) but did not reach statistical significance vs. PIO2 = 90 Torr. Total pulmonary vascular resistance increased from 0.049 +/- 0.004 in room air to between 0.084 +/- 0.006 and 0.101 +/- 0.003 mmHg.min.kg.ml-1 (P < 0.05) in the three hypoxic groups; again there was no difference in total pulmonary vascular resistance among hypoxic groups. Medial thickness of alveolar duct and terminal bronchiole arteries increased with hypoxia, but there was no significant difference among the hypoxic groups. The percentage of intra-acinar vessels with thick walls (a measure of muscular extension) increased when PIO2 = 78 Torr and nearly doubled when PIO2 = 65 Torr in comparison to control.(ABSTRACT TRUNCATED AT 250 WORDS)
Increased cholinergic antagonism underlies impaired beta-adrenergic response in ovalbumin-sensitized guinea pigs
Authors: Wills-Karp M. , Gilmour M. I.
Published: December 2017

The goal of this study was to determine if the hyporesponsiveness to beta-adrenoceptor stimulation observed in ovalbumin-sensitized tracheal smooth muscle is due to increased cholinergic muscarinic tone or to a defect in the beta-adrenergic cascade itself. We examined the effects of ovalbumin-sensitization on the responsiveness of guinea pig tracheae to agents that mediate relaxation at various steps in the beta-adrenergic cascade when the tracheal tissue was preconstricted with either carbachol or histamine. Ovalbumin sensitization caused significant reductions in the maximal relaxations both to the beta-adrenergic agonist isoproterenol and to prostaglandin E2 (PGE2) in guinea pig trachealis when the tracheal tissue was preconstricted with the muscarinic agonist carbachol. In contrast, sensitization had no effect on the ability of PGE2 and isoproterenol to relax histamine contractions. Preconstricting the tissues with increasing concentrations of KCl reduced the effectiveness of isoproterenol to relax equally airway tissues from both sensitized and control animals. Forskolin-induced relaxations of trachealis muscle were not altered with sensitization. When tracheal tissues were precontracted with increasing concentrations of carbachol, the effectiveness of isoproterenol and PGE2 to relax airway tissues decreased. Functional antagonism of relaxations by muscarinic agonists was enhanced in the sensitized tissues, since the concentration of carbachol necessary to reduce beta-adrenoceptor-induced relaxations to the same degree as in the control animals was a log dose lower. These results suggest that the impaired beta-adrenoceptor response in sensitized tissues is not due to an intrinsic defect in the beta-adrenergic cascade but to an enhancement of a muscarinic cholinergic pathway.
Retrotrapezoid nucleus glutamate receptors: control of CO2-sensitive phrenic and sympathetic output
Authors: Nattie E. E. , Gdovin M. , Li A.
Published: December 2017

In decerebrate cats, we asked whether endogenous glutamate in the region of the retrotrapezoid nucleus (RTN) was involved in the control of CO2-sensitive phrenic and phrenic-related sympathetic output and, if so, which type of glutamate receptor was predominant. We made unilateral 10-nl injections into the RTN of the nonspecific glutamate receptor antagonist kynurenic acid (100 and 250 mM), the N-methyl-D-aspartic acid (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 1 and 10 mM), the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX; 1 and 10 mM), and the inactive kynurenic acid analogue xanthurenic acid (100 mM). Each antagonist resulted in a significant dose-dependent decrease in the amplitude of the integrated phrenic nerve signal (PNA) over 30 min (CNQX > AP5 > kynurenic acid). The duration of the phrenic cycle was also decreased because of a shortening of expiratory time (CNQX > kynurenic acid > AP5). All three antagonists significantly decreased the initial slope of the PNA response to increased CO2 by 70–80% with no clear distinction in efficacy. The amplitude of the respiratory-related integrated cervical sympathetic nerve signal (SNA) was significantly decreased after kynurenic acid and CNQX but not AP5. In each case, the decrease in respiratory-related SNA accompanied a decrease in PNA and, at high levels of CO2, the decrease in respiratory-related SNA was greater than that of PNA. Endogenous glutaminergic input to neurons in the RTN via both NMDA and non-NMDA receptors is involved in the control of eucapneic PNA and timing, PNA-related SNA, and the response to increased CO2.
Neurocirculatory consequences of negative intrathoracic pressure vs. asphyxia during voluntary apnea
Authors: Morgan B. J. , Denahan T. , Ebert T. J.
Published: December 2017

To investigate the mechanisms responsible for fluctuations in arterial pressure and sympathetic nerve activity that occur during obstructive sleep apnea, we studied neurocirculatory responses to Mueller maneuvers and breath holds in conscious humans. During 20-s Mueller maneuvers at -40 mmHg, mean arterial pressure fell initially (-11 +/- 3 mmHg) and then rose above baseline (+8 +/- 3 mmHg) on release of the inspiratory strain. Sympathetic outflow to skeletal muscle was almost completely suppressed during the initial moments of the maneuver and rose to more than three times the baseline level at the termination of the maneuver. Simple 20-s breath holds were accompanied by time-dependent increases in both arterial pressure (+11 +/- 3 mmHg) and sympathetic nerve activity (> 3 times baseline). The administration of supplemental O2 greatly attenuated the increases in arterial pressure and sympathetic nerve activity during Mueller maneuvers and breath holds. We conclude that carotid chemoreflex stimulation is the primary mechanism responsible for apnea-induced sympathetic activation during wakefulness and that it may contribute importantly to the sympathetic activation that accompanies sleep-disordered breathing.
Possible role of pulmonary blood volume in chronic hypoxic pulmonary hypertension
Authors: Ou L. C. , Sardella G. L. , Hill N. S. , Thron C. D.
Published: December 2017

Chronic hypoxia increases the total blood volume (TBV) and pulmonary arterial blood pressure (Ppa) and induces pulmonary vascular remodeling. The present study was undertaken to assess how the pulmonary blood volume (PBV) changes during hypoxia and the possible role of PBV in chronic hypoxic pulmonary hypertension. A novel method has been developed to measure the TBV, PBV, and Ppa in conscious rats. The method consists of chronic implantation of a loose ligature around the ascending aorta and pulmonary artery, so that when the ligature is drawn tightly, it traps the blood in the pulmonary vessels and left heart and simultaneously kills the rat. The pulmonary veins are then ligated to separate the left ventricular blood volume from the PBV. This surgical approach, together with chronic catheterization of the pulmonary artery and the use of 51Cr-labeled red blood cells, allows measurement of TBV, PBV, and Ppa. This method has been used to analyze the relationships between TBV and PBV and between Ppa or right ventricular hypertrophy and PBV in two rat strains with markedly different TBV and Ppa responses to chronic hypoxia. PBV per given lung weight did not increase and even decreased during hypoxia despite marked increases in TBV. There was a close correlation between Ppa or right ventricular hypertrophy and PBV in the two strains of chronically hypoxic animals, suggesting that a greater PBV plays a significant role in the development of severe chronic hypoxic pulmonary hypertension in the altitude-susceptible Hilltop rats.
Blood pressure, hemodynamic, and thermal responses after cycling exercise
Authors: Brown S. P. , Li H. , Chitwood L. F. , Anderson E. R. , Boatwright D.
Published: December 2017

Seated recovery [at 5, 15, 20, 40, and 60 min (R5,15,20,40,60)] body temperature (T) and blood pressure were examined after 45 min of cycling exercise (54 +/- 5% maximal O2 uptake) in 12 normotensive males to study the relationship between postexercise thermal and hemodynamic responses. Data were analyzed with a repeated-measures analysis of variance. Systolic (SBP, R15,20,40; P < 0.01) and mean arterial (MAP, R15,20; P < 0.05) blood pressures were significantly lower, but diastolic blood pressure (DBP) was unchanged. Heart rate (R5,15,20, P < 0.001) was above that measured at rest. Decreases in mean skin T (Tsk, R15,20,60; P < 0.01) and increases in core T (Tc, R5,15,20; P < 0.01) were found. Significant negative correlations averaging -0.68 (R15,20,40) and -0.69 (R15,20,40) were demonstrated for Tsk and SBP and MAP, respectively. Increases in thigh Tsk (R5,15,20; P < 0.00001) and decreases in calf (R15,20,40,60; P < 0.00001) and chest (Tchest, R5,15,20,40; P < 0.00001) Tsk were found. Significant negative correlations averaging -0.67 (R5,15,20,40) and -0.71 (R20,40,60) were demonstrated for Tchest and SBP and MAP, respectively. Inverse relationships between various regional Ts and blood pressure and the increased R Tc suggest a vasodilatory response in the visceral organs and/or lower limbs leading to a pooling of blood and transient decreases in blood pressure by a reduced venous return, although not affecting stroke volume and cardiac output.
Nocturnal pituitary hormone and renin profiles during chronic heat exposure
Authors: Saini J. , Brandenberger G. , Libert J. P. , Follenius M.
Published: December 2017

To establish the principal endocrine systems involved in the initial adaptation to chronic passive heat exposure, responses of the hydromineral and pituitary systems were compared. Nocturnal plasma profiles of growth hormone, prolactin, thyrotropin, and plasma renin activity were determined during a period of prolonged heat exposure designed to simulate a hot climate. Two groups of six male subjects (G1 and G2) were kept for 11 days in a climatically controlled apartment. The G1 group was exposed to 20 degrees C throughout the study, and the G2 group was exposed to 20 degrees C for 5 days and to 35 degrees C for the following 6 days. Blood was collected continuously during the 1st and 10th nights from 2300 to 0700 h and was sampled in 10-min aliquots for hormone analysis. Heat exposure increased the nocturnal mean core temperature (P < 0.02) and stimulated plasma renin activity (P < 0.01) but had little effect on the pituitary hormones except for a small increase in prolactin (P < 0.05). For the G1 group there was no change in hormone profiles. These results demonstrate that the principal initial endocrine system involved in acclimatization to passive heat exposure is the renin-angiotensin system, reflecting counteractive measures against salt and water losses. In contrast, 5 days of continuous heat exposure does not provoke metabolic changes, indicated by the small effect on pituitary hormone profiles.
Differential susceptibility of diaphragm muscle fibers to neuromuscular transmission failure
Authors: Johnson B. D. , Sieck G. C.
Published: December 2017

The pattern of glycogen utilization was used to determine whether various muscle fiber types in the rat diaphragm are differentially susceptible to neuromuscular transmission failure. Muscle segments from the midcostal region were repetitively stimulated directly or via the phrenic nerve at 10 or 75 Hz. Muscle fiber types were classified histochemically as type I, IIa, or IIb. The amount of muscle fiber glycogen depletion with direct stimulation depended on stimulation rate (75 Hz > 10 Hz) and fiber type (IIb > IIa > I). However, with nerve stimulation, muscle fiber glycogen depletion did not display the same dependency on stimulation rate (10 Hz > 75 Hz), although with stimulation at 10 Hz, the same rank order of fiber depletion was observed (IIb > IIa > I). This rank order of depletion was reversed (I > IIa > IIb) during repetitive stimulation of the nerve at 75 Hz. By intermittently stimulating the muscle directly during continuous nerve stimulation, we determined that neuromuscular transmission failure contributed significantly to the force decline after 2 min of stimulation at 75 Hz but relatively little to the force decline after 2 min of stimulation at 10 Hz. A significantly greater fraction of the force decline could be attributed to neuromuscular transmission failure with repetitive bouts of stimulation at 10 Hz. We conclude that neuromuscular transmission failure causes a significant portion of the force decline after 8 min of stimulation at 10 and 75 Hz, that all diaphragm fiber types are susceptible to neuromuscular transmission failure, but that type IIb fibers are particularly susceptible at higher frequencies of stimulation.
Skeletal muscle size: relationship to muscle function in heart failure
Authors: Minotti J. R. , Pillay P. , Oka R. , Wells L. , Christoph I. , Massie B. M.
Published: December 2017

Abnormalities of skeletal muscle function and metabolism are common in patients with congestive heart failure (CHF) and appear to contribute to systemic exercise limitation. Although the mechanism for these differences is unclear, one possibility is skeletal muscle atrophy. In 21 CHF patients and 12 sex- and age-matched sedentary control subjects, we quantified muscle size as maximal cross-sectional area (MCSA) of thigh muscles measured by magnetic resonance imaging and determined the relationship between muscle size and muscle function. Muscle strength was measured as maximum force developed during isometric contractions, and muscle endurance was quantified as the decline in force during 15 consecutive isokinetic knee extensions (measured as ratio of mean peak torque of last 3 and first 3 extensions). MCSAs of thigh muscles (141 +/- 28 vs. 167 +/- 47 cm2, P < 0.05) and knee extensors (62 +/- 13 vs. 75 +/- 13 cm2; P < 0.05) were both significantly smaller in patients than in control subjects. These differences persisted after normalization for body size. Isometric strength was less, but not significantly so, in patients (126 +/- 39 vs. 135 +/- 43 Nm; P = NS), but muscle endurance was markedly impaired (endurance ratio 0.67 +/- 0.14 vs. 0.83 +/- 0.11; P < 0.05). A strong correlation was found between isometric strength (r = 0.76) and MCSA of knee extensors, but only a weak correlation between dynamic endurance and MCSA was seen. We conclude that muscle size is smaller in CHF patients but that maximal force generated per area of muscle is not impaired.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute pulmonary response to intravenous histamine at fixed lung volume in dogs
Authors: Bates J. H. , Peslin R.
Published: December 2017

We measured tracheal pressure (Ptr), tracheal flow, and two alveolar pressures in five open-chest anesthetized and paralyzed dogs. The lungs were maintained at a fixed volume for 50 s while small amplitude oscillations in flow at 6 Hz were applied at the tracheal opening. The measurements of alveolar pressure showed that the resulting oscillations in Ptr were virtually entirely determined by airway resistance (Raw) and consequently gave accurate estimates of the same. A 20-mg bolus of histamine was given intravenously at the start of this period when Ptr was 0.5 kPa. After approximately 10 s the mean Ptr increased sharply by approximately 40% and plateaued after approximately 25 s. Raw, in contrast, continued to increase throughout the oscillation period. Furthermore, the increases in mean Ptr were virtually identical in all dogs, whereas the increases in Raw were highly variable among the dogs. Our results suggest that the increases in mean Ptr caused by histamine were due to contraction of distal elements in the lung, whereas the changes in Raw were due mainly to constriction of more central airways.
Muscle sympathetic nerve responses to graded leg cycling
Authors: Saito M. , Tsukanaka A. , Yanagihara D. , Mano T.
Published: December 2017

The aim of this study was to clarify the relationship between sympathetic outflow to skeletal muscle and oxygen uptake during dynamic exercise. Muscle sympathetic nerve activity (MSNA) was recorded from the right median nerve microneurographically in eight healthy volunteers during leg cycling at four different intensities in a seated position for a 16-min bout. Work loads selected were 20, 40, 60, and 75% of maximal oxygen uptake (VO2max). Heart rate and blood pressure were measured during each exercise test. MSNA burst frequency was suppressed by 28% during cycling at 20% VO2max (23 vs. 33 bursts/min for control). Thereafter, it increased in a linear fashion with increasing work rate, with a significantly higher burst frequency during 60% VO2max than the control value. Both heart rate and mean blood pressure rose significantly during 20% VO2max from the control value and increased linearly with increased exercise intensity. During light exercise, MSNA was suppressed by arterial and cardiopulmonary baroreceptors as a result of the hemodynamic changes associated with leg muscle pumping. The baroreflex inhibition may overcome the muscle metaboreflex excitation to induce MSNA suppression during light exercise. These results suggest that during light exercise MSNA is inhibited, perhaps due to loading of the cardiopulmonary and arterial baroreflexes, and that during heavier exercise the increase in MSNA occurs as muscle metaboreflexes are activated.
Changes in resistance and ventilatory timing that accompany apnea in premature infants
Authors: Miller M. J. , Petrie T. G. , Difiore J. M.
Published: December 2017

To characterize the changes in respiratory mechanics and ventilatory timing that accompany apnea in premature infants, we evaluated 36 apneas in 13 premature infants (birth weight, 1,200 +/- 350 g, postconceptional age at study 34 +/- 3 wk). Apnea was defined as a ventilatory pause > or = 10s accompanied by a decrease in heart rate of 20 beats/min. Nasal airflow was recorded with a pneumotachometer, and esophageal, pharyngeal, and nasal mask pressures were continuously measured. Inspiratory time (TI), expiratory time (TE), tidal volume (VT), and VT/TI were determined over five breaths before and after apnea. In addition, total pulmonary resistance (RT) and supraglottic resistance (Rs) were measured over the same epochs in inspiration and expiration. Before apnea, TE and RT increased (P < 0.05 and < 0.01, respectively); however, Rs did not change. Immediately after apnea, prolongation of TI occurred and both RT and Rs were increased (P < 0.01), consistent with continued upper airway instability. However, within two breaths after resolution of the apnea, RT and Rs returned to normal, reflecting rapid recovery of upper airway and total pulmonary resistance. The ventilatory changes that precede and follow apnea closely resemble those occurring during periodic breathing.
Effect of insulin-like factors on glucose transport activity in unweighted rat skeletal muscle
Authors: Henriksen E. J. , Ritter L. S.
Published: December 2017

We have previously demonstrated that mechanical unweighting of the soleus muscle by hindlimb suspension leads to increases in insulin receptor binding, muscle/fat-specific glucose transporter (GLUT-4) protein levels, and insulin-stimulated glucose transport activity. The present study used a novel approach to further evaluate the potential role of postreceptor binding mechanisms in this enhanced insulin effect after unweighting. Insulin-like growth factor I (IGF-I), vanadate, and phospholipase C were used to stimulate glucose transport activity independently of insulin receptor binding. Soleus glucose transport activity (assessed by 2-deoxyglucose uptake) was evaluated in vitro with soleus strips (approximately 18 mg). Progressively increased responses to maximally effective doses of insulin or IGF-I were observed after 3 and 6 days of unweighting compared with weight-matched control strips. Enhanced maximal responses to vanadate (6 days only) and phospholipase C (3 and 6 days) for 2-deoxyglucose uptake were also observed. The results of this study 1) provide evidence that post-insulin receptor binding mechanisms also play a role in the enhanced response of the insulin-dependent pathway for stimulation of glucose transport in unweighted skeletal muscle and 2) indicate that IGF-I action on glucose transport is included in this enhanced response in unweighted muscle.
Effects of prenatal undernutrition on developing rat diaphragm
Authors: Prakash Y. S. , Fournier M. , Sieck G. C.
Published: December 2017

The effects of maternal nutritional deprivation (ND) on the proportions and cross-sectional areas (CSAs) of type I and II fibers in the developing rat diaphragm (Dia) were examined. In addition, the effects of ND on in vitro contractile and fatigue properties were also studied. Compared with in the control (CTL) group (from pups of well-nourished mothers), proportions of type II fibers were significantly lower in the ND group during the first 3 postnatal wk. However, this difference did not persist into adulthood. CSAs of type I and II fibers were larger in ND Dia than in CTL Dia during early postnatal development, but in adults type I and II fiber CSAs were larger in CTL than in ND Dia. Interstitial space comprised a smaller fraction of total muscle area in ND Dia throughout postnatal development and persisted in adults. Estimated fiber density (no. of fibers/CSA muscle) was lower in ND groups at all ages. In addition, the total number of fibers was significantly lower in ND Dia at all ages. Optimal muscle fiber length for peak twitch and maximum isometric force generation was shorter in ND Dia at all ages. At postnatal days 7 and 14, specific force (maximum tetanic force in N/cm2) of ND Dia was significantly lower than that of CTL Dia. At day 21, Dia specific force was comparable between the two groups but was significantly lower in adult ND compared with adult CTL Dia. Except for days 0 and 14, ND Dia was more fatigue resistant than CTL Dia.(ABSTRACT TRUNCATED AT 250 WORDS)
Maximal lactic capacity at altitude: effect of bicarbonate loading
Authors: Kayser B. , Ferretti G. , Grassi B. , Binzoni T. , Cerretelli P.
Published: December 2017

The aim of the present study was to test the hypothesis that the net maximal blood lactate accumulation ([La]max) during heavy exercise in lowlanders acclimatized to chronic hypoxia may be limited by the reduced bicarbonate stores. Six men [age 32 +/- 4 (SD) yr] performed supramaximal exercise until voluntary exhaustion at sea level (204 +/- 54 W) and after sojourning for 1 mo at 5,050 m (175 +/- 23 W), without (C) and with (B) oral sodium-bicarbonate loading (0.3 g/kg body wt). Exhaustion time, arterial blood lactate concentration, arterial pH (pHa), arterial PCO2, and intramuscular pH were measured at rest and after exercise. At sea level, exhaustion time increased from 6.5 +/- 2.8 min in C to 7.5 +/- 2.7 min in B (P < 0.05). At altitude, exhaustion times were similar to the sea level C values and the same in C and B. At sea level, resting pHa increased from 7.41 +/- 0.02 in C to 7.46 +/- 0.03 in B (P < 0.001); the corresponding values at altitude were 7.46 +/- 0.04 and 7.55 +/- 0.03 (P < 0.001). Postexercise pHa at sea level was 7.22 +/- 0.02 in C and 7.25 +/- 0.08 in B (NS). After exercise at altitude, pHa was 7.32 +/- 0.04 and 7.44 +/- 0.03 in C and B, respectively (P < 0.001). [La]max increased from 12.86 +/- 1.45 mM in C to 16.63 +/- 1.76 mM in B (P < 0.01) at sea level and from 6.85 +/- 1.40 mM in C to 7.95 +/- 1.74 mM in B (NS) at altitude.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin-converting enzyme preferentially hydrolyzes trans isomer of proline-containing substrate
Authors: Merker M. P. , Dawson C. A. , Bongard R. D. , Roerig D. L. , Haworth S. T. , Linehan J. H.
Published: December 2017

An analysis of the hydrolysis kinetics of the synthetic angiotensin-converting enzyme (ACE) substrate benzoyl-phenylalanyl-alanyl-proline (BPAP) in the intact lung suggested that 12–15% of the BPAP was in a form that could not be hydrolyzed by ACE in the time course of a single pass through the lungs [C. A. Dawson et al. Am. J. Physiol. 257 (Heart Circ. Physiol. 26): H853-H865, 1989]. BPAP has been found to exist as a mixture of cis and trans isomers in a ratio of approximately 14:86 in aqueous solution at equilibrium. Thus, one possible explanation for the incomplete hydrolysis of BPAP on passage through the intact lung is that the trans form is the preferred substrate for ACE. To examine this hypothesis, we measured BPAP hydrolysis by ACE in vitro over a range of ACE concentrations and in the presence and absence of the peptidyl-prolyl cis-trans isomerase cyclophilin. In the presence of a sufficient concentration of ACE and in the absence of cyclophilin, hydrolysis of [3H]BPAP by ACE followed biexponential progress curves, consistent with the hypothesis that the rate of hydrolysis of the majority (approximately 87%) of the substrate is proportional to ACE concentration, whereas the hydrolysis rate of the remaining substrate fraction is independent of enzyme concentration. The addition of cyclophilin resulted in an increase in the ACE-independent rate constant, an effect that was reversed by the cyclophilin inhibitor cyclosporin A. These results suggest that the enzyme-independent rate constant represents the rate of cis-trans isomerization and that the enzyme-dependent rate constant represents the hydrolysis of the trans isomer.(ABSTRACT TRUNCATED AT 250 WORDS)
ANF decreases active sodium transport and increases alveolar epithelial permeability in rats
Authors: Olivera W. , Ridge K. , Wood L. D. , Sznajder J. I.
Published: December 2017

Previous studies reported that atrial natriuretic factor (ANF) decreased lung edema in guinea pigs. To determine whether ANF protects against lung edema by increasing active Na+ transport and lung edema clearance, ANF (10(-7) M) was instilled into the air spaces (n = 5) or perfused through the pulmonary circulation (n = 5) of isolated perfused liquid-filled rat lungs. These animals were compared with five control rats and four rats having amiloride (10(-5) M) instilled into the air space. Amiloride reduced lung edema clearance by 65%, perfused ANF reduced lung edema clearance by 32%, and instilled ANF did not change edema clearance compared with responses in control rats after 70 min of experimental protocol. Passive Na+ movement increased by 91% with perfused ANF and by 52% with instilled ANF compared with that in control rats. Albumin flux from the perfusate into the air space increased in ANF-perfused lungs compared with control lungs (P < 0.05) but not when ANF or amiloride was instilled into the air spaces. These results suggest that ANF instilled into rat air spaces or perfused through the pulmonary circulation increases lung epithelial permeability and that ANF perfused through the pulmonary circulation decreases lung edema clearance due to impaired active Na+ transport. Conceivably, the previously observed protective effect of ANF was due to reduced pressures across the pulmonary circulation, which resulted in less edema formation.
Elevated interstitial fluid volume in soleus muscles unweighted by spaceflight or suspension
Authors: Henriksen E. J. , Tischler M. E. , Woodman C. R. , Munoz K. A. , Stump C. S. , Kirby C. R.
Published: December 2017

Recent evidence by Kandarian et al. (J. Appl. Physiol. 71: 910#x2013;914, 1991) indicates that prolonged (28 days) unweighting of the rat soleus by hindlimb suspension results in a substantial increase in interstitial fluid volume (IFV), as defined by the inulin space. The lack of any significant difference in absolute IFV values between unweighted and control groups suggested that this elevated IFV was a consequence of muscle atrophy. Using young female rats, we directly tested this hypothesis by comparing the early responses of soleus muscle weight and IFV with unweighting by tail-cast suspension or actual exposure to microgravity during spaceflight. Significant differences from control were first observed after 3 days of suspension unweighting for soleus wet weight (-14%; P < 0.01) and IFV (+35%; P < 0.01) and increased further after 6 days (-32% and +53%, respectively; both P < 0.001). After 5.4 days of spaceflight, soleus wet weight was 38% less and IFV was 52% greater than control (both P < 0.001). A highly significant negative correlation between soleus wet weight and IFV for all groups was observed (r = -0.70, P < 0.001). These data indicate that elevated soleus IFV develops at an early time point during unweighting and that there is a direct relationship between the magnitude of this increase in IFV and the extent of muscle atrophy. This relationship also exists in soleus muscles unweighted by exposure to a microgravity environment.