Intravenous Infusion Of Hypertonic Saline Research Articles

Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with H1N1 Infection

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is related to several conditions. However, there are few reports associated with H1N1 virus infection. We describe a 36 year old patient with SIADH admitted to our department if internal medicine with fever, cough and myalgias. The labooratory analysis showed serum hypo-osmolar hyponatremia and high level of urinary sodium concentration. All other biological analysis were within normal range. Moreover, All bacterial and fungal cultures, blood and urine cultures were all negative for any microbial pathogen. The thoraco-abdominal CT scan was normal. Rapid flu test was positive for influenza type A 15 days after. The patient recovered with intravenous infusion of hypertonic saline and fluid restriction and he did not received any anti-viral drug. Despite a strong relationship betwwen H1N1 virus infection and SIADH needs to be established, physicians should be aware of this potential seroius effect and should monitor the serum sodium closely.
 Keywords : H1N1 infection, inappropriate secretion of antidiuretic hormone, hyponatremia

Ageing attenuates the effect of extracellular hyperosmolality on whole-body heat exchange during exercise-heat stress.

In humans, hypohydration attenuates sweat secretion and attenuates whole-body heat loss, probably to mitigate further fluid losses and thereby support blood pressure regulation. Recently, however, we demonstrated that the hypohydration-mediated reduction in net whole-body heat exchange (evaporative heat loss-dry heat gain) was blunted in middle-aged compared to younger men during moderate exercise in dry heat; albeit, the underpinning mechanisms could not be determined. Here we evaluated the hypothesis that those findings stemmed from a diminished influence of extracellular hyperosmolality on net whole-body heat exchange in middle-aged-to-older compared to young men. Consistent with that hypothesis, extracellular hyperosmolality induced by an intravenous infusion of hypertonic saline (3% NaCl) reduced net heat exchange and augmented rectal temperature to a greater extent in the young compared to middle-aged-to-older men. Thus, age-related differences in the influence of hypohydration on thermoregulatory function appear to be due to blunted sensitivity to hyperosmolality with ageing. We recently demonstrated that sweating-induced hypohydration attenuated whole-body heat dissipation to a greater extent in young compared to middle-aged men during exercise-heat stress. Here, we evaluated whether this divergent response stemmed from an attenuated influence of extracellular hyperosmolality on heat exchange with ageing. To achieve this, ten young (mean(SD): 25(5)years) and ten middle-aged-to-older (61(5)years) men completed two trials involving a 90-min intravenous infusion of isosmotic saline (0.9% NaCl; ISO) or hyperosmotic saline (3.0% NaCl; HYP) followed by 60min of cycling at a fixed metabolic heat production of 250W/m2 (∼50% peak aerobic power) in dry heat (40°C, ∼17% relative humidity). Whole-body net heat exchange (evaporative heat loss-dry heat gain) was measured via direct calorimetry. Rectal temperature was monitored continuously. Heat exchange was attenuated in HYP compared to ISO in the young (233(20) vs. 251(17)W/m2 ; P=0.002) but not older group (229(16) vs. 227(20)W/m2 ; P=0.621). Further, heat exchange was lower in the middle-aged-to-older vs. young men in ISO (P=0.034) but not in HYP (P=0.623). Similarly, end-exercise rectal temperature was greater in HYP relative to ISO in the young (38.3(0.4)°C vs. 37.9(0.3)°C; P=0.015) but not the middle-aged-to-older men (38.3(0.3)°C vs. 38.2(0.2)°C; P=0.652). Compared to the young, rectal temperature was greater in the middle-aged-to-older during ISO (P=0.035) whereas no between-group difference was observed in HYP (P=0.746). Our findings indicate that ageing blunts the effect of extracellular hyperosmolality on thermoregulatory function during exercise-heat stress.

Hyponatremia-Induced Seizures Secondary to Magnesium Citrate Colon Cleansing Agent

Mild and clinically insignificant electrolyte disturbances are a well-recognised complication of all bowel preparation. Seizure as a complication is very rare. Magnesium citrate, a hyperosmolar substance, is often used for bowel preparation before colonoscopy and colon surgery. We report a 74-years-old female, with no prior history of seizures, who had her first seizure associated with hyponatremia following ingestion of magnesium citrate for bowel preparation. A careful correction of serum sodium must be undertaken. The patient improved her mental status to baseline after intravenous infusion of hypertonic saline. The other causes of hyponatremia and seizure were ruled out. This case highlights the association between magnesium citrate bowel preparations with significant hyponatremia and seizure. The physicians in the ED and general practice need to be aware of this serious complication of magnesium citrate bowel preparation to diagnose them early and initiate timely management.

Do the carotid body chemoreceptors mediate cardiovascular and sympathetic adjustments induced by sodium overload in rats?

Acute plasma hypernatremia induces several cardiovascular and sympathetic responses. It is conceivable that these responses contribute to rapid sodium excretion and restoration of normal conditions. Afferent pathways mediating these responses are not entirely understood. The present study analyses the effects of acute carotid chemoreceptor inactivation on cardiovascular and sympathetic responses induced by infusion of hypertonic saline (HS). All experiments were performed on anesthetized male Wistar rats instrumented for recording of arterial blood pressure (ABP), renal blood flow (RBF) and renal sympathetic nerve activity (RSNA). Animals were subjected to sham surgery or carotid chemoreceptor inactivation by bilateral ligation of the carotid body artery (CBA). In sham rats (n=8), intravenous infusion of HS (3 M NaCl, 1.8 ml/kg b.wt.) elicited a transient increase (9±2mmHg) in ABP, and long lasting (30 min) increases in RBF (138±5%) and renal vascular conductance (RVC) (128±5%) with concurrent decrease in RSNA (-19±4%). In rats submitted to CBA ligation (n=8), the pressor response to HS was higher (24±2mmHg; p<0.05). However, RBF and RVC responses to HS infusion were significantly reduced (113±5% and 93±4%, respectively) while RSNA was increased (13±2%). When HS (3M NaCl, 200μl) was administrated into internal carotid artery (ICA), distinct sympathetic and cardiovascular responses were observed. In sham-group, HS infusion (3M NaCl, 200μl) into ICA promoted an increase in ABP (26±8mmHg) and RSNA (29±13%). In CBA rats, ABP (-3±5.6mmHg) remained unaltered despite sympathoinhibition (-37.6±5.4%). These results demonstrate that carotid body chemoreceptors play a role in the development of hemodynamic and sympathetic responses to acute HS infusion.

Employment of vasopressin receptor antagonists in management of hyponatraemia and volume overload in some clinical conditions.

Hyponatraemia, the most common electrolyte imbalance occurring in hospitalized subjects, is usually classified as hypovolaemic, euvolaemic or hypervolaemic. Hyponatraemia is a predictor of death among subjects with chronic heart failure and cirrhosis. The inappropriate secretion of the antidiuretic hormone (AVP) seems to be of pivotal importance in the decline of serum sodium concentration in these clinical conditions. The objective of this review was to summarize recent progress in management of hyponatraemia in SIADH, cirrhosis and heart failure. Literature searches were conducted on the topics of hyponatraemia and vasopressin receptor antagonists, using PubMed, pharmaceutical company websites and news reports. The information was evaluated for relevance and quality, critically assessed and summarized. The initial treatment of severe hyponatraemia is directed towards the prevention or management of neurological manifestations and consists of an intravenous infusion of hypertonic saline. Fluid restriction is indicated in oedematous states. Diuretics alone or in combination with other specific drugs remain the main strategy in the management of volume overload in heart failure. In resistant cases, ultrafiltration can lead to effective removal of isotonic fluid preventing new episodes of decompensation; however, aquapheresis is associated with increased costs and other limits. In several trials, the efficacy of vasopressin receptor antagonists in euvolaemic patients (inappropriate antidiuretic hormone secretion) or in hypervolaemic hyponatraemia (chronic heart failure, cirrhosis) has been evaluated. It was found that vaptans, which promote aquaresis, were superior to a placebo in raising and maintaining serum sodium concentrations in these subjects. Combined with conventional therapy, vasopressin receptor antagonists (AVP-R antagonists) are able to increase the excretion of electrolyte-free water and the sodium concentration. Further studies are needed to assess efficacious outcomes of aquaresis compared with aquapheresis and with conventional therapy.

Hyponatremia management in critically ill: Food (protein) for thought.

Sir, Hyponatremia is one of the most common disorder of body fluid and electrolyte balance encountered in critically ill patients and associated with increased morbidity and mortality. A wide range of conditions can cause hyponatremia and, as a result, it is being managed by clinicians from a variety of backgrounds with a variety of approaches to its diagnosis and management. Adding to the complexity is the available treatment options, which includes normal saline, hypertonic saline, fluid restriction, drugs (demeclocycline and vaptans) and increasing intake of solutes like urea/protein. Treatment decision is based on multiple factors like severity and symptoms of hyponatremia, onset of hyponatremia, underlying disease, and associated illness. Rate of correction and overcorrection are important factors to consider. The decision to administer normal saline or hypertonic saline to patient with hyponatremia is quite clear and easy to practice. Except the use of saline and vaptans, rest of the treatment options are infrequently practiced, sometimes difficult to apply in critically ill patients especially with regard to fluid restriction. Management of the hyponatremia should ensure patient management rather than simply looking at the sodium level. If hyponatremia is serious and symptomatic, it is life-threatening. In this situation, the first line of treatment will be prompt intravenous infusion of hypertonic saline. For patients with reduced circulating volume, extracellular volume should be replaced with intravenous infusion of 0.9% saline. If the cause is apparent, reversing it may lead to correction as restricting water intake in psychogenic polydipsia, giving glucocorticoid/thyroid replacement in deficient, stopping hypotonic fluids or medications like selective serotonin reuptake inhibitors, nonsteroidal anti-inflammatory drugs, thiazides or desmopressin and optimization of Congestive heart failure (CHF), hepatic or renal failure. For patients with the syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH), which constitutes about 40% of hyponatremia cases and with moderate or profound hyponatremia, first-line treatment is fluid restriction. Equal second-line treatments are increasing solute intake. For moderate or profound hyponatremia, there is no recommendation for the use of lithium, demeclocycline, and even vasopressin receptor antagonist. Overcorrection is major reasons against vaptans.[1] There are not good outcome data either, with vaptans in form of improved survival or improved quality of life.[2] The lack of outcome data also applies to other treatments of hyponatremia. There are a vast majority of hyponatremic patients in the Intensive Care Unit (ICU) who are neither volume deficient nor they have profound and symptomatic hyponatremia. There are also patients in critical care unit where it is difficult to implement fluid restriction. Many patients develop hyponatremia during the course of their ICU management. Such groups of patients can be easily managed by increasing their dietary protein intake. Because of fixed urinary osmolarity in SIADH, increasing the dietary osmoles by increasing their dietary protein intake will lead to increase in urinary output and improvement in hyponatremia.[3] Moreover, increasing protein intake in critically ill will leads to better patient outcome. Studies have suggested that the use of higher protein concentration in nutritional therapy for critically ill patients may help to reduce mortality.[4,5]

Efferent pathways in sodium overload-induced renal vasodilation in rats.

Hypernatremia stimulates the secretion of oxytocin (OT), but the physiological role of OT remains unclear. The present study sought to determine the involvement of OT and renal nerves in the renal responses to an intravenous infusion of hypertonic saline. Male Wistar rats (280–350 g) were anesthetized with sodium thiopental (40 mg. kg−1, i.v.). A bladder cannula was implanted for collection of urine. Animals were also instrumented for measurement of mean arterial pressure (MAP) and renal blood flow (RBF). Renal vascular conductance (RVC) was calculated as the ratio of RBF by MAP. In anesthetized rats (n = 6), OT infusion (0.03 µg • kg−1, i.v.) induced renal vasodilation. Consistent with this result, ex vivo experiments demonstrated that OT caused renal artery relaxation. Blockade of OT receptors (OXTR) reduced these responses to OT, indicating a direct effect of this peptide on OXTR on this artery. Hypertonic saline (3 M NaCl, 1.8 ml • kg−1 b.wt., i.v.) was infused over 60 s. In sham rats (n = 6), hypertonic saline induced renal vasodilation. The OXTR antagonist (AT; atosiban, 40 µg • kg−1 • h−1, i.v.; n = 7) and renal denervation (RX) reduced the renal vasodilation induced by hypernatremia. The combination of atosiban and renal denervation (RX+AT; n = 7) completely abolished the renal vasodilation induced by sodium overload. Intact rats excreted 51% of the injected sodium within 90 min. Natriuresis was slightly blunted by atosiban and renal denervation (42% and 39% of load, respectively), whereas atosiban with renal denervation reduced sodium excretion to 16% of the load. These results suggest that OT and renal nerves are involved in renal vasodilation and natriuresis induced by acute plasma hypernatremia.

Severe Hyponatremia Following Radioactive Iodine Therapy in Patients with Differentiated Thyroid Cancer

Symptomatic hyponatremia in association with radioactive iodine (RAI) therapy for differentiated thyroid cancer has rarely been reported. Due to the increasing incidence of thyroid cancer worldwide, more patients are now receiving postoperative RAI therapy. We report two cases of life-threatening severe hyponatremia in association with RAI therapy. Two elderly female patients who had bilateral thyroidectomies for their thyroid cancer underwent a low-iodine diet and levothyroxine withdrawal for two weeks prior to RAI therapy. Upon admission, the patients were given 130 mCi (4810 MBq) and 150 mCi (5550 MBq) of (131)I respectively, and oral hydration (two to three liters of water daily) to increase the frequency of emptying the bladder of RAI. Both patients completed their RAI therapy without significant complications and were discharged from hospital. Two days after discharge, both patients were admitted to the emergency room with complaints of severe nausea and dizziness. Initial laboratory tests revealed that they were in a hypothyroid state and had severe hyponatremia with a serum sodium level of 108 mEq/L. The symptomatic hyponatremia responded to intravenous hypertonic saline infusion and thyroid hormone replacement, and the patients made a full recovery. The low-iodine diet and hypothyroid state with overzealous hydration in the setting of RAI therapy may have provoked severe hypotonic hyponatremia. Hypothyroid patients after undergoing RAI therapy, especially the elderly, are at an increased risk for serious hyponatremia and should be monitored closely.

Involvement of catecholaminergic medullary pathways in cardiovascular responses to acute changes in circulating volume

Water deprivation and hypernatremia are major challenges for water and sodium homeostasis. Cellular integrity requires maintenance of water and sodium concentration within narrow limits. This regulation is obtained through engagement of multiple mechanisms and neural pathways that regulate the volume and composition of the extracellular fluid. The purpose of this short review is to summarize the literature on central neural mechanisms underlying cardiovascular, hormonal and autonomic responses to circulating volume changes, and some of the findings obtained in the last 12 years by our laboratory. We review data on neural pathways that start with afferents in the carotid body that project to medullary relays in the nucleus tractus solitarii and caudal ventrolateral medulla, which in turn project to the median preoptic nucleus in the forebrain. We also review data suggesting that noradrenergic A1 cells in the caudal ventrolateral medulla represent an essential link in neural pathways controlling extracellular fluid volume and renal sodium excretion. Finally, recent data from our laboratory suggest that these structures may also be involved in the beneficial effects of intravenous infusion of hypertonic saline on recovery from hemorrhagic shock.

Cardiovascular adjustments induced by hypertonic saline in hemorrhagic rats: Involvement of carotid body chemoreceptors

The peripheral hyperosmolarity elicited by intravenous infusion of hypertonic saline brings potential benefits to the treatment of hemorrhage. The neural mechanisms involved in these beneficial effects remain unknown. The present study examines the role of carotid chemoreceptors in cardiovascular responses induced by hypertonic saline after hypovolemic hemorrhage in rats. Male Wistar rats (300–400g) were anesthetized with thiopental, and instrumented for recording of mean arterial pressure. Arterial pressure was reduced to 60mm Hg by withdrawal of arterial blood over 10min, and maintained at this level for 60min by withdrawal or infusion of blood. In control rats (n=8) with intact chemoreceptors, the subsequent intravenous infusion of hypertonic saline (3M NaCl, 1.8mlkg−1 body weight, in 2min) restored blood pressure (pressure increased from 61±4 to 118±5mm Hg). In experimental rats (n=8), the carotid body arteries were tied, 30min after the beginning of the hypotensive phase, leaving the carotid chemoreceptors ischemic. In these rats, hypertonic saline failed to restore blood pressure (pressure increased from 55±1 to 70±6mm Hg). These findings suggest that the restoration of blood pressure after hypovolemic hemorrhage induced by hypertonic saline depends on intact carotid chemoreceptors.

Influence of increased plasma osmolality on sympathetic outflow during apnea.

Animal models have shown that peripheral chemoreceptors alter their firing patterns in response to changes in plasma osmolality, which, in turn, may modulate sympathetic outflow. The purpose of this study was to test the hypothesis that increases in plasma osmolality augment muscle sympathetic nerve activity (MSNA) responses to chemoreceptor activation. MSNA was recorded from the peroneal nerve (microneurography) during a 23-min intravenous hypertonic saline infusion (3% NaCl; HSI). Chemoreceptor activation was elicited by voluntary end-expiratory apnea. MSNA responses to end-expiratory apnea were calculated as the absolute increase from the preceding baseline period. Plasma osmolality significantly increased from pre- to post-HSI (284 ± 1 to 290 ± 1 mOsm/kg H(2)O; P < 0.01). There was a significant overall effect of osmolality on sympathetic activity (P < 0.01). Duration of the voluntary end-expiratory apnea was not different after HSI (pre = 40 ± 5 s; post = 41 ± 4 s). MSNA responses to end-expiratory apnea were not different after HSI, expressed as an absolute change in burst frequency (n = 11; pre = 8 ± 2; post = 11 ± 1 burst/min) and as a percent increase in total activity (pre = 51 ± 4% AU; post = 53 ± 4% AU). A second group of subjects (n = 8) participated in 23-min volume/time-control intravenous isotonic saline infusions (0.9% NaCl). Isotonic saline volume-control infusions yielded no change in plasma osmolality or MSNA at rest. Furthermore, MSNA responses to apnea following isotonic saline infusion were not different. In summary, elevated plasma osmolality increased MSNA at rest and during apnea, but contrary to the hypothesis, MSNA responsiveness to apnea was not augmented. Therefore, this study does not support a neural interaction between plasma osmolality and chemoreceptor stimulation.

Renal vasodilation induced by hypernatraemia: Role of α-adrenoceptors in the median preoptic nucleus

1. The renal vasodilation induced by infusion of hypertonic saline (HS) in anaesthetized rats has been shown to depend on the integrity of the median preoptic nucleus (MnPO), as well as noradrenergic afferents to this nucleus. In the present study, we sought to determine the role of alpha(1) and alpha(2)-adrenoceptors in the MnPO in cardiovascular responses induced by intravenous HS infusion (3 mol/L NaCl; 1.8 mL/kg, i.v., over 1 min). 2. Male Wistar rats (320-360 g) were anaesthetized with urethane (1.2 g/kg, i.v.) and instrumented for recording of mean arterial pressure (MAP), renal blood flow (RBF) and vascular conductance (RVC). In one experimental group, rats were injected with yohimbine, prazosin or saline (control) 20 min before HS infusion. In another experimental group, rats were injected with yohimbine or prazosin 20 min after HS infusion. 3. In control rats (n = 7), HS infusion 20 min after saline nanoinjection produced a transient hypertension. Ten minutes after HS infusion, RBF and RVC increased to 159 +/- 14% and 145 +/- 11% of baseline, respectively. Nanoinjection of the alpha(1)-adrenoceptor antagonist prazosin (0.25 mmol/L; n = 6) into the MnPO 20 min before HS infusion increased the HS-induced pressor response. However, HS-induced increases in RBF and RVC were significantly reduced (130 +/- 11% and 105 +/- 6% of baseline, respectively, 10 min after HS). Nanoinjection of the alpha(2)-adrenoceptor antagonist yohimbine (0.23 mmol/L; n = 5) into the MnPO 20 min before HS infusion increased the duration of the pressor response and reduced the increases in RBF and RVC induced by HS (117 +/- 10% and 97 +/- 11% of baseline, respectively, 10 min after HS). 4. We also observed that nanoinjections of the prazosin into the MnPO 60 min after HS infusion resulted in a gradual return of RBF and RVC to baseline values. However nanoinjection of yohimbine 60 min after HS failed to reduce renal vasodilatation induced by hypernatremia. 5. The results of the present study demonstrate that the integrity of adrenergic neurotransmission in the MnPO is essential for the renal vasodilation that follows acute increases in blood sodium concentration.

AFFERENT PATHWAYS INVOLVED IN CARDIOVASCULAR ADJUSTMENTS INDUCED BY HYPERTONIC SALINE RESUSCITATION IN RATS SUBMITTED TO HEMORRHAGIC SHOCK

The peripheral hyperosmolarity elicited by intravenous infusion of hypertonic saline (HS) can be beneficial in treating hemorrhagic shock. However, the neural mechanisms involved in this resuscitation remain unknown. The present study sought to determine the effects of selective baroreceptor denervation on arterial blood pressure response during HS resuscitation in rats submitted to hemorrhagic shock. Male Wistar rats (280-320 g) were anesthetized with thiopental sodium (40 mg/kg, i.v.), and the femoral artery and jugular vein were cannulated for MAP and heart rate recording and HS infusion (3 mol/L NaCl; 0.18 mL/100 g body weight, >2 min). Hemorrhagic shock was obtained by withdrawing blood over 30 min until a MAP of 60 mmHg was obtained. This level of MAP was maintained for a further 30 min through subsequent blood withdrawal or reinfusion. Next, animals were divided into selective aortic and/or carotid denervation or sham groups before infusing HS. Results showed that in the sham group (n = 12), HS infusion increased MAP to levels close to baseline (from 65 +/- 3 to 112 +/- 5 mmHg, 10 min after HS). In the aortic denervated group (n = 10), HS infusion also increased MAP (from 54 +/- 3 to 112 +/- 5 mmHg, 10 min after HS). In contrast, in the carotid denervation group (n = 8), the increase in MAP induced by HS infusion was abolished (from 53 +/- 3 to 73 +/- 12 mmHg, 10 min after HS). These results indicate that in hemorrhaged rats, HS infusion produces a pressor effect that is likely to be mediated through carotid rather than aortic baroreceptors.

Neural Reflex Hypotension Induced by Very Small Dose of Hypertonic NaCl Solution in Rats

Although the precise mechanisms of transient hypotension after intravenous infusion of hypertonic saline (HTS) are not yet clarified, a rapid infusion of HTS is widely used as the initial therapy of hypovolemia. We investigated the effect of the intravenous infusion of a small dose of 0.97-9.7% NaCl solutions in anesthetized rats. Intravenous infusion of HTS at a rate of 0.3 ml/kg/min for 1 min produced the transient hypotension lasting for several minutes. The depressor response to HTS was not abolished by bilateral cervical vagotomy. The HTS infusion into the femoral vein evoked the depressor response with a larger magnitude and a shorter latency than that into the aortic arch. While the arterial baroreceptor pressure was kept constant at the baseline level of systemic arterial pressure, HTS-induced hypotension was significantly augmented. The gain factor of the arterial baroreflex was reduced by intravenous HTS. Pretreatment with bretylium tosylate completely abolished the depressor response without affecting the baseline level of arterial pressure. These results suggest that the depressor response to the very small dose of intravenous HTS is the sympathosympathetic neural reflex with cardiopulmonary afferents and vasomotor efferents.

Time course of synergistic interaction between DOCA and salt on blood pressure: roles of vasopressin and hepatic osmoreceptors

In DOCA-salt rats, the time course of the synergistic interaction between osmolality and DOCA to produce hypertension is unknown. Therefore, in rats 2 wk after implantation of subcutaneous silicone pellets containing DOCA (65 mg) or no drug (sham), we determined blood pressure (BP) and heart rate (HR) responses, using telemetric pressure transducers, during 2 wk of excess salt ingestion (1% NaCl in drinking water). BP was unaltered in sham rats after increased salt, but in DOCA rats BP increased within 4 h. The initial hypertension of 30-35 mmHg stabilized within 2 days, followed approximately 5 days later by a further increment of approximately 30 mmHg. HR first decreased during the dark phase; the second phase was linked to an abrupt increase in HR and BP variability and decreased HR variability. Pressor responses to acute intravenous hypertonic saline infusion were doubled in DOCA-treated rats via vasopressin and nonvasopressin mechanisms. Only in DOCA-treated rats, portal vein hypertonic saline infusion increased BP, which was prevented by V(1) vasopressin blockade. After 2 wk of DOCA-salt, oral ingestion of water rapidly decreased BP. Intraportal infusion of water did not lower BP in DOCA-salt rats, suggesting that hepatic osmoreceptors were not involved. In summary, the hypertension of DOCA-treated rats consuming excess salt exhibits multiple phases and can be rapidly reversed. Hypertonicity-induced vasopressin and nonvasopressin pressor mechanisms that are augmented by DOCA, and hepatic osmoreceptors may contribute to the initial developmental phase. With time, combined DOCA-salt induces marked changes in the regulation of the autonomic nervous system, which may favor hypertension development.

Sympathetic neural responses to increased osmolality in humans

The purpose of this study was to examine the relationship between osmolality and efferent sympathetic outflow in humans. We hypothesized that increased plasma osmolality would be associated with increases in directly measured sympathetic outflow. Muscle sympathetic outflow was successfully recorded in eight healthy subjects during a 60-min intravenous hypertonic saline infusion (HSI; 3% NaCl) on one day and during a 60-min intravenous isotonic saline (ISO) infusion (0.9% NaCl) on a different day. The HSI provides an osmotic and volume stimulus, whereas the ISO infusion provides a volume-only stimulus. Muscle sympathetic nerve activity was quantified using the technique of peroneal microneurography. Plasma osmolality increased during the HSI but not during the ISO infusion (ANOVA, P < 0.05). Sympathetic outflow differed between the trials (ANOVA, P < 0.05); during the HSI burst, frequency initially increased from 14.6 +/- 2.5 to 18.1 +/- 1.9 bursts/min; during the ISO infusion, burst frequency initially declined from 14.7 +/- 2.5 to 12.0 +/- 2.1 bursts/min. Plasma norepinephrine concentration was greater at the end of the HSI compared with the end of the ISO infusion (HSI: 297 +/- 64 vs. ISO: 202 +/- 49 pg/ml; ANOVA, P < 0.05). We conclude that HSI-induced increases in plasma osmolality are associated with increases in sympathetic activity in humans.

Urinary aquaporin-2 excretion in dogs: a marker for collecting duct responsiveness to vasopressin

In humans, the urinary aquaporin-2 (U-AQP2) excretion closely parallels changes in vasopressin (VP) action and has been proposed as a marker for collecting duct responsiveness to VP. This report describes the development of a radioimmunoassay for the measurement of U-AQP2 excretion in dogs. In addition, the localization of AQP2 in the canine kidney was investigated by immunohistochemistry. Basal U-AQP2 excretion was highly variable among healthy dogs. Two hours after oral water loading, the mean U-AQP2/creatinine ratio decreased significantly from (231±30)×10 −9 to (60±15)×10 −9 ( P=0.01), while the median plasma VP concentration decreased from 4.2 pmol/l (range 2.2–4.8 pmol/l) to 1.2 pmol/l (range 1.0–1.9 pmol/l). Subsequent intravenous administration of desmopressin led to a significantly increased mean U-AQP2/creatinine ratio of (258±56)×10 −9 ( P=0.01). Two hours of intravenous hypertonic saline infusion (20% NaCl, 0.03 ml/kg body weight/min) significantly increased the mean U-AQP2/creatinine ratio from (86±6)×10 −9 to (145±23)×10 −9 ( P=0.045), while the median plasma VP concentration increased significantly from 2.2 pmol/l (range 1.1–6.3 pmol/l) to 17.1 pmol/l (range 8.4–67 pmol/l) ( P<0.001). Immunohistochemistry revealed extensive labeling for AQP2 in the kidney collecting duct cells, predominantly localized in the apical and subapical region. As in humans, U-AQP2 excretion in dogs closely reflects changes in VP exposure. Urinary AQP2 excretion may become a diagnostic tool in dogs for the differentiation of polyuric conditions such as (partial) central or nephrogenic diabetes insipidus, primary polydipsia, and inappropriate VP release.

The role of nitric oxide in morphine dependence and withdrawal excitation of rat oxytocin neurons.

Magnocellular oxytocin neurons develop morphine dependence after intracerebroventricular infusion for 5 days as revealed by their profound excitation following naloxone-induced withdrawal. Oxytocin neurons strongly express nitric oxide synthase (NOS) and nitric oxide (NO) inhibits their activity. This study investigated whether excitation of oxytocin neurons during morphine withdrawal involves reduced activity of NOS and NO. Neuron activity was measured in urethane-anaesthetized rats with blood sampling for oxytocin radioimmunoassay and extracellular single unit firing rate recording of supraoptic nucleus oxytocin neurons. To compare morphine-dependent and -naive rats oxytocin secretion was measured during stimulation by intravenous hypertonic saline infusion. Prior treatment with Nomega-nitro-l-arginine methyl ester, a NOS inhibitor, facilitated osmotically stimulated oxytocin secretion in both morphine-dependent and -naive rats. The facilitation was not different between these groups when corrected for the slower responses observed in morphine-dependent rats. Treatment of morphine-dependent rats with Nomega-nitro-l-arginine methyl ester also enhanced oxytocin secretion during naloxone-precipitated withdrawal. Oxytocin neurons excited by withdrawal were recorded during microdialysis application to the supraoptic nucleus of the NO donor sodium nitroprusside alone and in combination with the GABAA antagonist bicuculline. Sodium nitroprusside inhibited oxytocin neurons during naloxone-precipitated morphine withdrawal and, while bicuculline alone increased firing rate, it did not reduce the inhibition by sodium nitroprusside, in contrast with previous findings in naive rats. Together, these findings indicate that NO restraint of oxytocin secretion is not curtailed during morphine dependence and remains a potent inhibitor of withdrawal excitation despite reduced effectiveness on GABA innervation of the supraoptic nucleus. Hence there is no evidence that changes in NO regulation underlie excitation of oxytocin neurons during opiate withdrawal in morphine dependence.

Glutamatergic input in the PVN is important in renal nerve response to elevations in osmolality.

Elevations in plasma osmolality elicit reflex humoral and neural responses. The hypothalamic paraventricular nucleus (PVN) is important in humoral responses. We have investigated whether the PVN contributed to the renal nerve reduction that is normally elicited by increased plasma osmolality in the conscious rabbit. Renal sympathetic nerve activity (RSNA) was monitored after an intravenous infusion of hypertonic saline (1.7 M NaCl, 2 ml/min for 7 min). The responses were examined in animals microinjected with muscimol (10 nmol) into, and outside, the PVN to acutely inhibit neuronal function or with kynurenate (25 nmol) to block glutamate receptors. Compared with vehicle, the maximum reduction in RSNA elicited by hypertonic saline was significantly less with muscimol or kynurenate pretreatment into the PVN. A similar study with kynurenate was also performed in sinoaortically denervated rabbits, and similar effects were observed. The effect was specific to the PVN because microinjections of the drugs outside the PVN had no effect on the response. The findings suggest that excitatory inputs into the PVN may be important in the neural responses elicited by elevations in plasma osmolality.

Responses of Magnocellular Neurons to Osmotic Stimulation Involves Coactivation of Excitatory and Inhibitory Input: An Experimental and Theoretical Analysis

How does a neuron, challenged by an increase in synaptic input, display a response that is independent of the initial level of activity? Here we show that both oxytocin and vasopressin cells in the supraoptic nucleus of normal rats respond to intravenous infusions of hypertonic saline with gradual, linear increases in discharge rate. In hyponatremic rats, oxytocin and vasopressin cells also responded linearly to intravenous infusions of hypertonic saline but with much lower slopes. The linearity of response was surprising, given both the expected nonlinearity of neuronal behavior and the nonlinearity of the oxytocin secretory response to such infusions. We show that a simple computational model can reproduce these responses well, but only if it is assumed that hypertonic infusions coactivate excitatory and inhibitory synaptic inputs. This hypothesis was tested first by applying the GABA(A) antagonist bicuculline to the dendritic zone of the supraoptic nucleus by microdialysis. During local blockade of GABA inputs, the response of oxytocin cells to hypertonic infusion was greatly enhanced. We then went on to directly measure GABA release in the supraoptic nucleus during hypertonic infusion, confirming the predicted rise. Together, the results suggest that hypertonic infusions lead to coactivation of excitatory and inhibitory inputs and that this coactivation may confer appropriate characteristics on the output behavior of oxytocin cells. The nonlinearity of oxytocin secretion that accompanies the linear increase in oxytocin cell firing rate reflects frequency-facilitation of stimulus-secretion coupling at the neurohypophysis.