Gastrointestinal osmoreceptors and renal sodium excretion in humans

The hypothesis that natriuresis can be induced by stimulation of gastrointestinal osmoreceptors was tested in eight supine subjects on constant sodium intake (150 mmol NaCl/day). A sodium load equivalent to the amount contained in 10% of measured extracellular volume was administered by a nasogastric tube as isotonic or hypertonic saline (850 mM). In additional experiments, salt loading was replaced by oral water loading (3.5% of total body water). Plasma sodium concentration increased after hypertonic saline (+3.1 +/- 0.7 mM), decreased after water loading (-3.8 +/- 0.8 mM), and remained unchanged after isotonic saline. Oncotic pressure decreased by 9.4 +/- 1.2, 3.7 +/- 1.2, and 10.7 +/- 1.3%, respectively. Isotonic saline induced an increase in renal sodium excretion (104 +/- 15 to 406 +/- 39 micromol/min) that was larger than seen with hypertonic saline (85 +/- 15 to 325 +/- 39 micromol/min) and water loading (88 +/- 11 to 304 +/- 28 micromol/min). Plasma ANG II decreased to 22 +/- 6, 35 +/- 6, and 47 +/- 5% of baseline after isotonic saline, hypertonic saline, and water loading, respectively. Plasma atrial natriuretic peptide (ANP) concentrations and urinary excretion rates of endothelin-1 were unchanged. In conclusion, stimulation of osmoreceptors by intragastric infusion of hypertonic saline is not an important natriuretic stimulus in sodium-replete subjects. The natriuresis after intragastric salt loading was independent of ANP but can be explained by inhibition of the renin-angiotensin system.     

Responses of celiac and cervical vagal afferents to infusions of lipids in the jejunum or ileum of the rat

Multiunit celiac and single-unit cervical recordings of vagal afferents were performed before and during infusions of fatty acids, triglycerides, or saline into either the ileum or jejunum of the rat. In multiunit recordings, lipids increased activity of vagal afferents to a greater extent than saline. The greatest increases in vagal afferent activity resulted from infusions of linoleic acid, conjugated linoleic acid, or oleic acid. The triglycerides, corn oil or Intralipid, were less effective than the fatty acids in affecting vagal afferent activity. Ileal pretreatment with the hydrophobic surfactant Pluronic L-81 significantly attenuated the response of celiac vagal afferents to ileal infusion of linoleic acid. Single-unit recordings of cervical vagal afferents supported the multiunit data in showing lipid-induced increased vagal afferent activity in approximately 50% of ileal units sampled and 100% of a limited number of jejunal units sampled. These data demonstrate that free fatty acids can activate ileal and jejunal vagal afferents in the rat, and this effect can be attenuated by pretreatment with a chylomicron inhibitor. These data are consistent with the view that lipid-induced activation of vagal afferents could be a potential substrate for the inhibitory effects of intestinal lipids on gastrointestinal function, food intake, and body weight gain.     

Ileal short-chain fatty acids inhibit gastric motility by a humoral pathway

The aim of this study was to evaluate the nervous and humoral pathways involved in short-chain fatty acid (SCFA)-induced ileal brake in conscious pigs. The role of extrinsic ileal innervation was evaluated after SCFA infusion in innervated and denervated Babkin's ileal loops, and gastric motility was measured with strain gauges. Peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) concentrations were evaluated in both situations. The possible involvement of absorbed SCFA was tested by using intravenous infusion of acetate. Ileal SCFA infusion in the intact terminal ileum decreased the amplitude of distal and terminal antral contractions (33 +/- 1.2 vs. 49 +/- 1.2% of the maximal amplitude recorded before infusion) and increased their frequency (1.5 +/- 0.11 vs. 1.3 +/- 0.10/min). Similar effects were observed during SCFA infusion in ileal innervated and denervated loops (amplitude, 35 +/- 1.0 and 34 +/- 0. 8 vs. 47 +/- 1.3 and 43 +/- 1.2%; frequency, 1.4 +/- 0.07 and 1.6 +/- 0.06 vs. 1.1 +/- 0.14 and 1.0 +/- 0.12/min). Intravenous acetate did not modify the amplitude and frequency of antral contractions. PYY but not GLP-1 concentrations were increased during SCFA infusion in innervated and denervated loops. In conclusion, ileal SCFA inhibit distal gastric motility by a humoral pathway involving the release of an inhibiting factor, which is likely PYY.     

Experimental muscle pain reduces initial motor unit discharge rates during sustained submaximal contractions.

The aim of this human study was to investigate the effect of experimentally induced muscle pain on the modifications of motor unit discharge rate during sustained, constant-force contractions. Intramuscular and multichannel surface electromyographic (EMG) signals were collected from the right and left tibialis anterior muscle of 11 volunteers. The subjects performed two 4-min-long isometric contractions at 25% of the maximal dorsiflexion torque, separated by a 20-min rest. Before the beginning of the second contraction, hypertonic (painful; right leg) or isotonic (nonpainful; left leg) saline was injected into the tibialis anterior. Pain intensity scores did not change significantly in the first 150 s of the painful contraction. Exerted torque and its coefficient of variation were the same for the painful and nonpainful contractions. Motor unit discharge rate was higher in the beginning of the nonpainful contraction than the painful contraction on the right side [means +/- SE, 11.3 +/- 0.2 vs. 10.6 +/- 0.2 pulses/s (pps); P < 0.01] whereas it was the same for the two contractions on the left side (11.6 +/- 0.2 vs. 11.5 +/- 0.2 pps). The decrease in discharge rate in 4 min was smaller for the painful (0.4 +/- 0.1 pps) than for the control contractions (1.3 +/- 0.1 pps). Initial value and decrease in motor unit conduction velocity were not different in the four contractions (right leg, 4.0 +/- 0.1 m/s with decrease of 0.6 +/- 0.1 m/s in 4 min; left leg, 4.1 +/- 0.1 m/s with 0.7 +/- 0.1 m/s decrease). In conclusion, stimulation of nociceptive afferents by injection of hypertonic saline did not alter motor unit conduction velocity but reduced the initial motor unit discharge rates and the difference between initial and final discharge rates during sustained contraction.     

Vagal afferent and reflex responses to changes in surface osmolarity in lower airways of dogs.

In anesthetized dogs we examined the sensitivity of afferent vagal endings in the lungs to changes in airway fluid osmolarity. Injection of 0.25-0.5 ml/kg water or hyperosmotic sodium chloride solutions (1,200-2,400 mmol/l) into a lobar bronchus caused bradycardia, arterial hypotension, apnea followed by rapid shallow breathing, and contraction of tracheal smooth muscle. All effects were abolished by vagotomy. We examined the sensory mechanisms initiating these effects by recording afferent vagal impulses arising from the lung lobe into which the liquids were injected. Water stimulated pulmonary and bronchial C-fibers and rapidly adapting receptors; isosmotic saline and glucose solutions were ineffective. Hyperosmotic saline (1,200-9,600 mmol/l, 0.25-1 ml/kg) stimulated these afferents in a concentration-dependent manner. Stimulation began 1-10 s after the injection and sometimes continued for several minutes. Responses of slowly adapting stretch receptors varied. Our results suggest that non-isosmotic fluid in the lower airways initiates defense reflexes by stimulating pulmonary and bronchial C-fibers and rapidly adapting receptors. Conceivably, stimulation of these afferents as a result of evaporative water loss from airway surface liquid could contribute to exercise-induced asthma.     

Natriuresis induced by mild hypernatremia in humans

The hypothesis that increases in plasma sodium induce natriuresis independently of changes in body fluid volume was tested in six slightly dehydrated seated subjects on controlled sodium intake (150 mmol/day). NaCl (3.85 mmol/kg) was infused intravenously over 90 min as isotonic (Iso) or as hypertonic saline (Hyper, 855 mmol/l). After Hyper, plasma sodium increased by 3% (142.0 +/- 0.6 to 146.2 +/- 0.5 mmol/l). During Iso a small decrease occurred (142.3 +/- 0.6 to 140.3 +/- 0.7 mmol/l). Iso increased estimates of plasma volume significantly more than Hyper. However, renal sodium excretion increased significantly more with Hyper (291 +/- 25 vs. 199 +/- 24 micromol/min). This excess was not mediated by arterial pressure, which actually decreased slightly. Creatinine clearance did not change measurably. Plasma renin activity, ANG II, and aldosterone decreased very similarly in Iso and Hyper. Plasma atrial natriuretic peptide remained unchanged, whereas plasma vasopressin increased with Hyper (1.4 +/- 0.4 to 3.1 +/- 0.5 pg/ml) and decreased (1.3 +/- 0.4 to 0.6 +/- 0.1 pg/ml) after Iso. In conclusion, the natriuretic response to Hyper was 50% larger than to Iso, indicating that renal sodium excretion may be determined partly by plasma sodium concentration. The mechanism is uncertain but appears independent of changes in blood pressure, glomerular filtration rate, the renin system, and atrial natriuretic peptide.     

Secretin activates vagal primary afferent neurons in the rat: evidence from electrophysiological and immunohistochemical studies

In this study, we evaluated the vagal afferent response to secretin at physiological concentrations and localized the site of secretin's action on vagal afferent pathways in the rat. The discharge of sensory neurons supplying the gastrointestinal tract was recorded from nodose ganglia. Of 91 neurons activated by electrical vagal stimulation, 19 neurons showed an increase in firing rate in response to intestinal perfusion of 5-HT (from 1.5 +/- 0.2 to 25 +/- 4 impulses/20 s) but no response to intestinal distension. A close intra-arterial injection of secretin (2.5 and 5.0 pmol) elicited responses in 15 of these 19 neurons (from 1.5 +/- 0.2 impulses/20 s at basal to 21 +/- 4 and 43 +/- 5 impulses/20 s, respectively). Subdiaphragmatic vagotomy and perivagal application of capsaicin, but not supranodose vagotomy, completely abolished the secretin-elicited vagal nodose neuronal response. In a separate study, 9 tension receptor afferents among 91 neurons responded positively to intestinal distension but failed to respond to luminal 5-HT. These nine neurons also showed no response to administration of secretin. As expected, immunohistochemical studies showed that secretin administration significantly increased the number of Fos-positive neurons in vagal nodose ganglia. In conclusion, we demonstrated for the first time that vagal sensory neurons are activated by secretin at physiological concentrations. A subpopulation of secretin-sensitive vagal afferent fibers is located in the intestinal mucosa, many of which are responsive to luminal 5-HT.     

Changes of deep cervical lymph flow following the infusion of isotonic, hypotonic, and hypertonic NaCl in rabbit.

Isotonic, hypotonic, or hypertonic saline was infused in anesthetized rabbits in order to test the effects of osmolality in cerebral vessels on lymph flow. The jugular lymph trunk was cannulated by PE tubing in a headward direction. Either a hypo-(100 mosmol), iso-(310 mosmol), or hypertonic (605 mosmol) NaCl solution was infused into the internal carotid artery (ICA) or the right lateral ventricle (RIV). Lymph was continuously collected at slight negative pressure, and measured over a 90 min preinfusion period, as well as during saline infusion and intermittent recovery periods. Mean peak flow rates for the first 30 min infusion of hypertonic saline via ICA and RLV were 5.1 +/- 1.2 and 6.7 +/- 1.6 microliters/min, respectively, or a significant increase of 38% and 40% over those of isotonic saline (3.7 +/- 0.9 microliters/min via ICA; 4.8 +/- 1.0 microliters/min via RLV). Conversely, for hypotonic saline, lymph flow rates were significantly reduced by 19% (2.9 +/- 0.6 microliters/min) and 23% (3.7 +/- 0.7 microliters/min) for the first 30 min infusion via ICA and RLV, respectively. Increases in arterial and intracranial pressures, as well as an enhancement of respiratory movements following hypertonic saline infusion, augmented lymph formation. The results suggest that the observed changes in jugular lymph flow following saline infusion can be correlated to the resulting increase in intracranial pressure and respiratory movements, and changes in the osmolality and blood pressure of cerebral vessels.     

Role of cAMP in activation of ischemically sensitive abdominal visceral afferents

A number of metabolites produced during abdominal ischemia can stimulate and/or sensitize visceral afferents. The precise mechanisms whereby these metabolites act are uncertain. Other studies have shown that the adenylate cyclase-cAMP system may be involved in the activation of sensory neurons. Therefore, we hypothesized that cAMP contributes to the activation of ischemically sensitive abdominal visceral afferents. Single-unit activity of abdominal visceral C fibers was recorded from the right thoracic sympathetic chain in anesthetized cats before and during 7 min of abdominal ischemia. Forty-six percent of ischemically sensitive C fibers responded to intra-arterial injection of 8-bromo-cAMP (0.35-1. 0 mg/kg), an analog of cAMP, with responses during ischemia increasing from 0.50 +/- 0.06 to 0.84 +/- 0.08 impulses/s (P < 0.05, n = 11 C fibers). Conversely, an inhibitor of adenylate cyclase, 2', 5'-dideoxyadenosine (DDA; 0.1 mg/kg iv), attenuated ischemia-induced increase in activity of afferents from 0.66 +/- 0.10 to 0.34 +/- 0. 09 impulses/s (P < 0.05; n = 8). Furthermore, whereas exogenous PGE(2) (3-4 microg/kg ia) augmented the ischemia-induced increase in activity of afferents (P < 0.05, n = 10), treatment with DDA (0.1 mg/kg iv) substantially reduced the increase in discharge activity of afferents during ischemia, which was augmented by PGE(2) (1.45 +/- 0.24 vs. 0.70 +/- 0.09 impulses/s, -DDA vs. +DDA; P < 0.05) in six fibers. A time control group (n = 4), however, demonstrated similar increases in the activity of afferents with repeated administration of PGE(2). These data suggest that cAMP contributes to the activation of abdominal visceral afferents during ischemia, particularly to the action of PGs on activation and/or sensitization of these endings.     

Vagal modulation of intestinal afferent sensitivity to systemic LPS in the rat

The central nervous system modulates inflammation in the gastrointestinal tract via efferent vagal pathways. We hypothesized that these vagal efferents receive synaptic input from vagal afferents, representing an autonomic feedback mechanism. The consequence of this vagovagal reflex for afferent signal generation in response to LPS was examined in the present study. Different modifications of the vagal innervation or sham procedures were performed in anesthetized rats. Extracellular mesenteric afferent nerve discharge and systemic blood pressure were recorded in vivo before and after systemic administration of LPS (6 mg/kg iv). Mesenteric afferent nerve discharge increased dramatically following LPS, which was unchanged when vagal efferent traffic was eliminated by acute vagotomy. In chronically vagotomized animals, to eliminate both vagal afferent and efferent traffic, the increase in afferent firing 3.5 min after LPS was reduced to 3.2 +/- 2.5 impulses/s above baseline compared with 42.2 +/- 2.0 impulses/s in controls (P < 0.001). A similar effect was observed following perivagal capsaicin, which was used to eliminate vagal afferent traffic only. LPS also caused a transient hypotension (<10 min), a partial recovery, and then persistent hypertension that was exacerbated by all three procedures. Mechanosensitivity was increased 15 min following LPS but had recovered at 30 min in all subgroups except for the chronic vagotomy group. In conclusion, discharge in capsaicin-sensitive mesenteric vagal afferents is augmented following systemic LPS. This activity, through a vagovagal pathway, helps to attenuate the effects of septic shock. The persistent hypersensitivity to mechanical stimulation after chronic vagal denervation suggests that the vagus exerts a regulatory influence on spinal afferent sensitization following LPS.     

Detection of inspiratory resistive loads in double-lung transplant recipients.

The afferent pathways mediating respiratory load perception are still largely unknown. To assess the role of lung vagal afferents in respiratory sensation, detection of inspiratory resistive loads was compared between 10 double-lung transplant (DLT) recipients with normal lung function and 12 healthy control (Nor) subjects. Despite a similar unloaded and loaded breathing pattern, the DLT group had a significantly higher detection threshold (2.91 +/- 0.5 vs. 1.55 +/- 0.3 cmH(2)O. l(-1). s) and Weber fraction (0.50 +/- 0.1 vs. 0.30 +/- 0.1) compared with the Nor group. These results suggest that inspiratory resistive load detection occurs in the absence of vagal afferent feedback from the lung but that lung vagal afferents contribute to inspiratory resistive load detection response in humans. Lung vagal afferents are not essential to the regulation of resting breathing and load compensation responses.     

Activation of Na<Superscript>+</Superscript>/H<Superscript>+</Superscript> exchange by protein phosphatase inhibitors in red blood cells of the frog<Emphasis Type="Italic"> Rana ridibunda</Emphasis>

The present study was designed to evaluate the role of protein phosphatases in regulation of sodium transport in the marsh frog erythrocytes using 22Na as a tracer. For this purpose the cells were treated with several known inhibitors of protein phosphatases. In standard isotonic medium, exposure of the cells to 10 mmol l(-1) NaF, 20 nmol l(-1) calyculin A or 0.1 mmol l(-1) cantharidin resulted in a significant (1.7-fold) increase in unidirectional ouabain-insensitive Na+ influx. The Na+ influx in frog red cells was progressively activated as the medium osmolality was increased by addition of 100, 200 or 300 mmol l(-1) sucrose to standard isotonic medium. The stimulatory effect of protein phosphatase blockers on Na+ influx was much higher in hypertonic medium containing 100 or 200 mmol l(-1) sucrose than that in isotonic medium. Stimulation of Na+ transport enhanced with increasing concentrations of calyculin A, and half-maximal activation (EC50) was obtained at 16 nmol l(-1). However, Na+ influx induced by strong hypertonic treatment (+300 mmol l(-1) sucrose) was not altered further in the presence of protein phosphatase inhibitors. The changes in Na+ influx evoked by protein phosphatase inhibitors and hypertonic treatment were associated with a rise in the intracellular Na+, but not K+, content. Enhancement in Na+ influx after addition of protein phosphatase blockers to cell suspension in isotonic or hypertonic media was almost completely inhibited by Na+/H+ exchange inhibitors, amiloride and ethyl-isopropyl-amiloride. The basal Na+ influx in frog erythrocytes in isotonic medium was relatively low (1.7 mmol/l cells/h) and not affected by 1 mmol l(-1) amiloride. Thus, the data obtained clearly indicate that Na+/H+ exchanger in the marsh frog red blood cells is under tight regulatory control, in all likelihood via protein phosphatases of types PP-1 and PP-2A.     

Stimulation of vagal pulmonary C-fibers by a single breath of cigarette smoke in dogs

Inhalation of cigarette smoke into the lower airway via a tracheostomy evokes immediate apnea, bradycardia, and systemic hypotension in dogs. These responses can still be evoked when conduction in myelinated vagal fibers is blocked preferentially by cooling but are abolished by vagotomy, suggesting that they are mediated by afferent vagal C-fibers. To examine this possibility, we recorded impulses in pulmonary C-fibers in anesthetized, open-chest dogs and delivered 120 ml cigarette smoke to the lungs in a single ventilatory cycle. Pulmonary C-fibers were stimulated within 1 or 2 s of the delivery of smoke generated by high-nicotine cigarettes, activity increasing from 0.3 +/- 0.1 to a peak of 12.6 +/- 1.3 (SE) impulses/s, (n = 60); the evoked discharge usually lasted 3-5 s. Smoke generated by low-nicotine cigarettes evoked a milder stimulation in 33% of pulmonary C-fibers but did not significantly affect the overall firing frequency (peak activity = 2.2 +/- 1.1 impulses/s, n = 36). Hexamethonium (0.7-1.2 mg/kg iv) prevented C-fiber stimulation by high-nicotine cigarette smoke (n = 12) but not stimulation by right atrial injection of capsaicin. We conclude that pulmonary C-fibers are stimulated by a single breath of cigarette smoke and that nicotine is the constituent responsible.     

P2 antagonist PPADS attenuates responses of thin fiber afferents to static contraction and tendon stretch

Injection into the arterial supply of skeletal muscle of pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), a P2 receptor antagonist, has been shown previously to attenuate the reflex pressor responses to both static contraction and to tendon stretch. In decerebrated cats, we tested the hypothesis that PPADS attenuated the responses of groups III and IV muscle afferents to static contraction as well as to tendon stretch. We found that injection of PPADS (10 mg/kg) into the popliteal artery attenuated the responses of both group III (n = 16 cats) and group IV afferents (n = 14 cats) to static contraction. Specifically, static contraction before PPADS injection increased the discharge rate of the group III afferents from 0.1 +/- 0.05 to 1.6 +/- 0.5 impulses/s, whereas contraction after PPADS injection increased the discharge of the group III afferents from 0.2 +/- 0.1 to only 1.0 +/- 0.5 impulses/s (P < 0.05). Likewise, static contraction before PPADS injection increased the discharge rate of the group IV afferents from 0.3 +/- 0.1 to 1.0 +/- 0.3 impulses/s, whereas contraction after PPADS injection increased the discharge of the group IV afferents from 0.2 +/- 0.1 to only 0.3 +/- 0.1 impulses/s (P < 0.05). In addition, PPADS significantly attenuated the responses of group III afferents to tendon stretch but had no effect on the responses of group IV afferents. Our findings suggest that both groups III and IV afferents are responsible for evoking the purinergic component of the exercise pressor reflex, whereas only group III afferents are responsible for evoking the purinergic component of the muscle mechanoreflex that is evoked by tendon stretch.     

Fluid volume and osmoregulation in humans after a week of head-down bed rest

Body fluid homeostasis was investigated during chronic bed rest (BR) and compared with that of acute supine conditions. The hypothesis was tested that 6 degrees head-down BR leads to hypovolemia, which activates antinatriuretic mechanisms so that the renal responses to standardized saline loading are attenuated. Isotonic (20 ml/kg body wt) and hypertonic (2.5%, 7.2 ml/kg body wt) infusions were performed in eight subjects over 20 min following 7 and 10 days, respectively, of BR during constant sodium intake (200 meq/day). BR decreased body weight (83.0 +/- 4.8 to 81.8 +/- 4.4 kg) and increased plasma osmolality (285.9 +/- 0.6 to 288.5 +/- 0.9 mosmol/kgH(2)O, P < 0.05). Plasma ANG II doubled (4.2 +/- 1.2 to 8.8 +/- 1.8 pg/ml), whereas other endocrine variables decreased: plasma atrial natriuretic peptide (42 +/- 3 to 24 +/- 3 pg/ml), urinary urodilatin excretion rate (4.5 +/- 0.3 to 3.2 +/- 0.1 pg/min), and plasma vasopressin (1.7 +/- 0.3 to 0.8 +/- 0.2 pg/ml, P < 0.05). During BR, the natriuretic response to the isotonic saline infusion was augmented (39 +/- 8 vs. 18 +/- 6 meq sodium/350 min), whereas the response to hypertonic saline was unaltered (32 +/- 8 vs. 29 +/- 5 meq/350 min, P < 0.05). In conclusion, BR elicits antinatriuretic endocrine signals, but it does not attenuate the renal natriuretic response to saline stimuli in men; on the contrary, the response to isotonic saline is augmented.     

Prolonged hypobaric hypoxemia attenuates vasopressin secretion and renal response to osmostimulation in men.

Effects of hypobaric hypoxemia on endocrine and renal parameters of body fluid homeostasis were investigated in eight normal men during a sojourn of 8 days at an altitude of 4,559 m. Endocrine and renal responses to an osmotic stimulus (5% hypertonic saline, 3.6 ml/kg over 1 h) were investigated at sea level and on day 6 at altitude. Several days of hypobaric hypoxemia reduced body weight (-2.1 +/- 0.4 kg), increased plasma osmolality (+5.3 +/- 1.4 mosmol/kgH(2)O), elevated blood pressure (+12 +/- 1 mmHg), reduced creatinine clearance (122 +/- 6 to 96 +/- 10 ml/min), inhibited the renin system (19.5 +/- 2.0 to 10.9 +/- 0.9 mU/l) and plasma vasopressin (1.14 +/- 0.16 to 0.38 +/- 0.06 pg/ml), and doubled circulating levels of norepinephrine (103 +/- 16 to 191 +/- 35 pg/ml) and endothelin-1 (3.0 +/- 0.2 to 6.3 +/- 0.6 pg/ml), whereas urodilatin excretion rate decreased from day 2 (all changes P < 0.05 compared with sea level). Plasma arginine vasopressin response and the antidiuretic response to hypertonic saline loading were unchanged, but the natriuretic response was attenuated. In conclusion, chronic hypobaric hypoxemia 1) elevates the set point of plasma osmolality-to-plasma vasopressin relationship, possibly because of concurrent hypertension, thereby causing hypovolemia and hyperosmolality, and 2) blunts the natriuretic response to hypertonic volume expansion, possibly because of elevated circulating levels of norepinephrine and endothelin, reduced urodilatin synthesis, or attenuated inhibition of the renin system.     

Hypertonic sodium resuscitation after hemorrhage improves hemodynamic function by stimulating cardiac, but not renal, sympathetic nerve activity

Small volume hypertonic saline resuscitation can be beneficial for treating hemorrhagic shock, but the mechanism remains poorly defined. We investigated the effects of hemorrhagic resuscitation with hypertonic saline on cardiac (CSNA) and renal sympathetic nerve activity (RSNA) and the resulting cardiovascular consequences. Studies were performed on conscious sheep instrumented with cardiac (n=7) and renal (n=6) sympathetic nerve recording electrodes and a pulmonary artery flow probe. Hemorrhage (20 ml/kg over 20 min) caused hypotension and tachycardia followed by bradycardia, reduced cardiac output, and abolition of CSNA and RSNA. Resuscitation with intravenous hypertonic saline (1.2 mol/l at 2 ml/kg) caused rapid, dramatic increases in mean arterial pressure, heart rate, and CSNA, but had no effect on RSNA. In contrast, isotonic saline resuscitation (12 ml/kg) had a much delayed and smaller effect on CSNA, less effect on mean arterial pressure, no effect on heart rate, but stimulated RSNA, although the plasma volume expansion was similar. Intracarotid infusion of hypertonic saline (1 ml/min bilaterally, n=5) caused similar changes to intravenous administration, indicating a cerebral component to the effects of hypertonic saline. In further experiments, contractility (maximum change in pressure over time), heart rate, and cardiac output increased significantly more with intravenous hypertonic saline (2 ml/kg) than with Gelofusine (6 ml/kg) after hemorrhage; the effects of hypertonic saline were attenuated by the β-receptor antagonist propranolol (n=6). These results demonstrate a novel neural mechanism for the effects of hypertonic saline resuscitation, comprising cerebral stimulation of CSNA by sodium chloride to improve cardiac output by increasing cardiac contractility and rate and inhibition of RSNA.     

NMDA channels control meal size via central vagal afferent terminals

The N-methyl-D-aspartate (NMDA) ion channel blocker MK-801 administered systemically or as a nanoliter injection into the nucleus of the solitary tract (NTS), increases meal size. Furthermore, we have observed that ablation of the NTS abolishes increased meal size following systemic injection of dizocilpine (MK-801) and that MK-801-induced increases in intake are attenuated in rats pretreated with capsaicin to destroy small, unmyelinated, primary afferent neurons. These findings led us to hypothesize that NMDA receptors on central vagal afferent terminals or on higher-order NTS neurons innervated by these vagal afferents might mediate increased food intake. To evaluate this hypothesis, we examined 15% sucrose intake after 50-nl MK-801 injections ipsilateral or contralateral to unilateral nodose ganglion removal (ganglionectomy). On the side contralateral to ganglionectomy, vagal afferent terminals would be intact and functional, whereas ipsilateral to ganglionectomy vagal afferent terminals would be absent. Three additional control preparations also were included: 1) sham ganglionectomy and 2) subnodose vagotomy either contralateral or ipsilateral to NTS cannula placement. We found that rats with subnodose vagotomies increased their sucrose intake after injections of MK-801 compared with saline, regardless of whether injections were made contralateral (12.6 +/- 0.2 vs. 9.6 +/- 0.3 ml) or ipsilateral (14.2 +/- 0.6 vs. 9.7 +/- 0.4 ml) to vagotomy. Rats with NTS cannula placements contralateral to nodose ganglionectomy also increased their intake after MK-801 (12.2 +/- 0.9 and 9.2 +/- 1.1 ml for MK-801 and saline, respectively). However, rats with placements ipsilateral to ganglionectomy did not respond to MK-801 (8.0 +/- 0.5 ml) compared with saline (8.3 +/- 0.4 ml). We conclude that central vagal afferent terminals are necessary for increased food intake in response to NMDA ion channel blockade. The function of central vagal afferent processes or the activity of higher-order NTS neurons driven by vagal afferents may be modulated by NMDA receptors to control meal size.     

Effects of changes in plasma hepatic-portal and systemic osmolality on plasma concentrations of arginine vasopressin in conscious newborn calves

Systemic plasma concentrations of arginine vasopressin (AVP) were studied in three groups of 10-15 day-old conscious newborn calves. Animals in the first group (control group) and in the second group (systemic-hypertonic-injected group) received respectively isotonic and hypertonic (8 mmol NaCl/kg body weight) saline injection into the right jugular vein. Animals in the third group were fitted with chronic mesenteric and hepatic-portal catheters and received a 1 h-hypertonic saline infusion (2 mmol NaCl/kg body weight) into the main mesenteric vein. In animals in the second group there were parallel increases in systemic plasma concentration of Na+ (from 148.0 +/- 2.6 to 177 +/- 8 mmol/l; P less than 0.01), osmolality (from 289 +/- 2 to 319 +/- 4 mOsmol/kg H2O; P less than 0.01) and systemic plasma concentrations of AVP (from 4.2 +/- 0.4 to 11.1 +/- 0.6 pmol/l; P less than 0.01) 10 min after the injection. There were no significant changes in control animals. Hypertonic saline infusion into the main mesenteric vein in the third group induced an increase in concentration of Na+ (from 147.3 +/- 2.0 to 165.0 +/- 5.0 mmol/l; P less than 0.01) and osmolality (from 288 +/- 5 to 315 +/- 10 mOsmol/kg H2O; P less than 0.01) in hepatic-portal vein plasma but did not alter systemic plasma osmolality or concentrations of Na+ and AVP. This study demonstrates that the relationship between plasma concentrations of AVP and systemic osmolality is operative in the newborn calf but does not support the hypothesis that hepatic portal osmo-receptors sensitive to hyperosmolality influence AVP release.     

Enhancement of antral contractions and vagal afferent signaling with synchronized electrical stimulation

Gastric filling activates vagal afferents involved in peripheral signaling to the central nervous system (CNS) for food intake. It is not known whether these afferents linearly encode increasing contractions of the antrum during antral distension (AD). The aim of this study was to investigate effects of AD and electrically enhanced antral contractions on responses of vagal afferents innervating the antrum. Single-fiber recordings were made from the vagal afferents in anesthetized male Long-Evans rats. Antral contractions were measured with a solid-state probe placed in the antrum. A nonexcitatory electrical stimulation (NES) inducing no smooth muscle contractions was applied during the ascending phase of antral contractions to enhance subsequent antral contractions. Fifty-six fibers identified during AD (1 ml for 30 s) were studied through different types of mechanical stimuli. Under normal conditions, one group of fibers exhibited rhythmic firing in phase with antral contractions. Another group of fibers had nonrhythmic spontaneous firing. Responses of 15 fibers were tested with NES during multiple-step distension (MSD). NES produced a mean increase in antral contraction amplitude (177.1 +/- 35.3%) and vagal afferent firing (21.6 +/- 2.6%). Results show that both passive distension and enhanced antral contractions activate distension-sensitive vagal afferents. Responses of these fibers increase linearly to enhanced antral contraction induced by NES or MSD up to a distending volume of 0.6 ml. However, responses reached a plateau at a distending volume >0.8 ml. We concluded that enhanced contraction of the antrum can activate vagal afferents signaling to the CNS.