Hyponatremia in the rat in the absence of positive water balance.
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The purpose of this report is to determine the mechanisms that lead to hyponatremia when isotonic saline was the only fluid infused into rats given antidiuretic hormone (ADH), and what might minimize the degree of this hyponatremia. Normal rats were deprived of food and water for the 24-hr study period. They received an infusion of isotonic saline to expand their extracellular fluid (ECF) volume with and without exogenous ADH administration (N = 8 in each of the four groups). Similar studies were also carried out in 32 rats fed a low electrolyte diet for 72 hr before the experiment. An additional control group was fed the low electrolyte diet supplemented with sodium (Na), potassium (K), and chloride (Cl). Hyponatremia developed over 24 hr in rats fed their usual diet if treated with ADH and isotonic saline (fall, 13 +/- 2 mM, P < 0.01). The hyponatremia was caused by negative balance for Na + K salts. Hyponatremia did not develop after the saline + ADH treatment if rats were pretreated for 3 days with a low electrolyte diet. Two factors were required to develop this hyponatremia--generation of electrolyte-free water as a result of the excretion of a large quantity of Na + K salts at a high concentration in the urine, and prevention of the excretion of this electrolyte-free water by ADH. Increasing the avidity for Na reabsorption by the kidney prevented this type of hyponatremia from developing. (+info)
The studies presented here were performed to determine the effect of agonist stimulation on the cytosolic free Ca2+ concentration ([Ca2+]i) in single smooth muscle cells, freshly isolated from afferent arterioles and interlobular arteries averaging between 10 to 40 microns in diameter. Microvessels were obtained from male Sprague-Dawley rats using an iron oxide collection technique followed by collagenase digestion. Freshly isolated microvascular smooth muscle cells (MVSMC) were loaded with fura 2 and studied using fluorescence photometry techniques. The resting [Ca2+]i averaged 67 +/- 3 nM (N = 82 cells). Increasing the extracellular K+ concentration significantly increased [Ca2+]i dose-dependently (P < 0.05). Involvement of extracellular Ca2+ in the response to KCl-induced depolarization was also evaluated. Resting [Ca2+]i increased approximately 132% from 40 +/- 5 nM to 93 +/- 26 nM in response to 90 mM extracellular KCl. This change was abolished in nominally Ca(2+)-free conditions and markedly attenuated by diltiazem. Inhibition of K+ channels with charybdotoxin or tetraethylammonium chloride produced a modest transient increase in [Ca2+]i during the response to 30 mM K+ and had no detectable effect on responses to 90 mM K+. Studies were also performed to establish whether freshly isolated renal MVSMC exhibit appropriate responses to receptor-dependent physiological agonists. Angiotensin II (100 nM) increased cell Ca2+ from 97 +/- 10 nM to 265 +/- 47 nM (N = 12 cells). Similarly, 100 microM ATP increased MVSMC [Ca2+]i from a control level of 71 +/- 14 nM to 251 +/- 47 nM (N = 11 cells). Norepinephrine administration caused [Ca2+]i to increase from 63 +/- 4 nM to 212 +/- 47 nM (N = six cells), and vasopressin increased [Ca2+]i from 86 +/- 10 nM to 352 +/- 79 nM (N = five cells). These data demonstrate that receptor-dependent and -independent vasoconstrictor agonists increase [Ca2+]i in MVSMC, freshly isolated from rat preglomerular vessels. Furthermore, the ability to measure [Ca2+]i in responses to physiological stimuli in these single cells permits investigation of signal transduction mechanisms involved in regulating renal microvascular resistance. (+info)
Vasopressin and urinary concentrating activity in diabetes mellitus.
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In diabetes mellitus (DM), the high urine flow rate suggests that urinary concentrating capacity is impaired. However, several studies have shown that vasopressin is elevated in DM and the consequences of this elevation have not yet been characterized. This study reevaluated renal function and water handling in male Wistar rats with Streptozotocin-induced DM, and in control rats. During five weeks after induction of DM, urine was collected in metabolic cages and a blood sample was drawn during the third week. Control rats (CONT) were studied in parallel. On week 3, urine flow rate was tenfold higher in DM than in CONT rats and urinary osmolality was reduced by half along with a markedly higher osmolar excretion (DM/CONT = 5.87), due for a large part to glucose but also to urea (DM/CONT = 2.49). Glucose represented 52% of total osmoles (90.3 +/- 6.5 mmol/d out of 172 +/- 14 mosm/d). Free water reabsorption was markedly higher in DM rats compared to CONT (326 +/- 24 vs 81 +/- 5 ml/d). In other rats treated in the same way, urinary excretion of vasopressin was found to be markedly elevated (15.1 +/- 4.1 vs 1.44 +/- 0.23 ng/d). In DM rats, glucose concentration in urine was 17 fold higher than in plasma, and urea concentration 14 fold higher. Both urine flow rate and free water reabsorption were positively correlated with the sum of glucose and urea excretions (r = 0.967 and 0.653, respectively) thus demonstrating that the urinary concentrating activity of the kidney increased in proportion to the increased load of these two organic solutes. These results suggest that vasopressin elevation in DM contributes to increase urinary concentrating activity and thus to limit water requirements induced by the metabolic derangements of DM. The possible deleterious consequences of sustained high level of vasopressin in DM are discussed. (+info)
Vasopressin stimulates sodium transport in A6 cells via a phosphatidylinositide 3-kinase-dependent pathway.
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The enzyme phosphatidylinositide 3-kinase (PI3K) phosphorylates the D-3 position of the inositol ring of inositol phospholipids and produces 3-phosphorylated inositides. These novel second messengers are thought to mediate diverse cellular signaling functions. The fungal metabolite wortmannin covalently binds to PI3K and selectively inhibits its activity. The role of PI3K in basal and hormone-stimulated transepithelial sodium transport was examined using this specific inhibitor. Wortmannin, 50 nM, did not affect basal, aldosterone-stimulated, or insulin-stimulated transport in A6 cells. Wortmannin completely inhibits vasopressin stimulation of transport in these cells. Vasopressin stimulates PI3K activity in A6 cells. Vasopressin stimulation of transport is also blocked by 5 microM LY-294002, a second inhibitor of PI3K. One-hour preincubation with wortmannin blocked vasopressin stimulation of protein kinase A activity in the cells. Sodium transport responses to exogenous cAMP and forskolin, which directly activates adenylate cyclase, were not affected by wortmannin. These results indicate that wortmannin inhibits vasopressin stimulation of Na(+) transport at a site proximal to activation of adenylate cyclase. The results suggest that PI3K may be involved in receptor activation by vasopressin. (+info)
Troglitazone and pioglitazone attenuate agonist-dependent Ca2+ mobilization and cell proliferation in vascular smooth muscle cells.
(45/2313)
1. The effects of troglitazone and pioglitazone on agonist-induced Ca2+ mobilization and cell proliferation were studied using fluorescent Ca2+ indicator fura-2 AM and incorporation of [3H]-thymidine in rat aortic smooth muscle cells. The patch clamp techniques were also employed. 2. Vasopressin and platelet-derived growth factor-BB (PDGF) caused a transient elevation in [Ca2+]i by Ca2+ mobilization from intracellular stores, followed by a sustained rise due to Ca2+ entry. Nicardipine partly inhibited the sustained phase, but La3+ completely abolished it. 3. Troglitazone and pioglitazone did not significantly affect the transient rise elicited by these agonists, but preferentially inhibited the sustained phase of [Ca2+]i. 4. Under voltage clamp conditions, troglitazone and pioglitazone inhibited voltage-dependent L-type Ca2+ current (ICa.L). They also inhibited nonselective cation channels (Icat) elicited by vasopressin in a concentration-dependent manner. The half maximal inhibitory concentrations of troglitazone on ICa.L and Icat were 4.6 and 5.7 microM, respectively. On the other hand, nifedipine and nicardipine did not inhibit Icat. 5. Vasopressin and PDGF increased incorporation of [3H]-thymidine, and nifedipine and nicardipine partly suppressed it. However, the inhibitory effects of La3+ and exclusion of extracellular Ca2+ were more potent than the Ca2+ blocking agents. Troglitazone and pioglitazone also inhibited it concentration-dependently. 6. These results suggest that troglitazone and pioglitazone preferentially inhibited agonist (vasopressin and PDGF)-induced Ca2+ entry and proliferation in rat vascular smooth muscle cells, where the inhibitory effects of thiazolidinediones on ICa.L and Icat might be partly involved. Thus, thiazolidinediones may exert hypotensive and antiatherosclerotic effects. (+info)
Changes in urinary water and electrolyte excretion in sodium-loaded sheep in response to intravenous infusion of arginine vasopressin.
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Mature sheep receiving supplements of sodium chloride into the rumen were given intravenous infusions of arginine vasopressin at rates varying from 4-6-23 pmol/min (2-10 mU/min). Infusion of the hormone led to an increase in urine flow and to increases in the amounts of sodium and chloride excreted, the effect on flow was, however, the greater so that the osmolality of the urine fell during the infusions. In sheep given intravenous infusions of a hypertonic sodium chloride solution addition of vasopressin to the infusate led to the formation of a larger volume of urine containing a higher proportion of the infused salt load compared to when the salt solution alone was given. As before the effect on flow was the greater and hence the osmolality of the urine was lower when the hormone was given. In other experiments intravenous infusion of a hypertonic sodium chloride solution at rates providing 2-8 mmol NaCl/min led to increases in urine flow and increases in sodium and chloride excretion, the size of these increases being proportional to infusion rate. Plasma vasopressin levels markedly increased during these infusions, the levels seen being similar to those seen in sheep given vasopressin in amounts which increased both urine flow and electrolyte excretion. This suggests that during hypertonic salt loading vasopressin probably contributes directly to the increases in urine flow and the increases in electrolyte excretion which are seen. Further evidence in support of this was obtained in experiments in which a greater natriuretic response was seen in sheep given a hypertonic sodium chloride solution into the carotid artery as opposed to the given a hypertonic sodium chloride solution into the carotid artery as opposed to the jugular vein and where it was shown that plasma vasopressin levels were indeed higher when the solution was given into the artery. (+info)
Direct actions of nitric oxide on rat neurohypophysial K+ channels.
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1. Nitric oxide (NO) has been shown to modulate neuropeptide secretion from the posterior pituitary. Here we show that NO activates large-conductance Ca2+-activated K+ (BK) channels in posterior pituitary nerve terminals. 2. NO, generated either by the photolysis of caged-NO or with chemical donors, irreversibly enhanced the component of whole-terminal K+ current due to BK channels and increased the activity of BK channels in excised patches. NO also inhibited the transient A-current. The time courses of these effects on K+ current were very different; activation of BK channels developed slowly over several minutes whereas inhibition of A-current immediately followed NO uncaging. 3. Activation of BK channels by NO occurred in the presence of guanylyl cyclase inhibitors and after removal of ATP or GTP from the pipette solution, suggesting a cGMP-independent signalling pathway. 4. The sulfhydryl alkylating agent N-ethyl maleimide (NEM) increased BK channel activity. Pretreatment with NEM occluded NO activation. 5. NO activation of BK channels occurred independently of voltage and cytoplasmic Ca2+ concentration. In addition, NO removed the strict Ca2+ requirement for channel activation, rendering channels highly active even at nanomolar Ca2+ levels. 6. These results suggest that NO, or a reactive nitrogen byproduct, chemically modifies nerve terminal BK channels or a closely associated protein and thereby produces an increase in channel activity. Such activation is likely to inhibit impulse activity in posterior pituitary nerve terminals and this may explain the inhibitory action of NO on secretion. (+info)
Neuroendocrine activation in heart failure is modified by endurance exercise training.
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OBJECTIVES: The purpose of this study was to determine whether endurance exercise training could buffer neuroendocrine activity in chronic heart failure patients. BACKGROUND: Neuroendocrine activation is associated with poor long-term prognosis in heart failure. There is growing consensus that exercise may be beneficial by altering the clinical course of heart failure, but the mechanisms responsible for exercise-induced benefits are unclear. METHODS: Nineteen heart failure patients (ischemic disease; New York Heart Association [NYHA] class II or III) were randomly assigned to either a training group or to a control group. Exercise training consisted of supervised walking three times a week for 16 weeks at 40% to 70% of peak oxygen uptake. Medications were unchanged. Neurohormones were measured at study entry and after 16 weeks. RESULTS: The training group (n = 10; age = 61 +/- 6 years; EF = 30 +/- 6%) and control group (n = 9; age = 62 +/- 7 years; EF = 29 +/- 7%) did not differ in clinical findings at study entry. Resting levels of angiotensin II, aldosterone, vasopressin and atrial natriuretic peptide in the training and control groups did not differ at study entry (5.6 +/- 1.3 pg/ml; 158 +/- 38 pg/ml; 6.1 +/- 2.0 pg/ml; 37 +/- 8 pg/ml training group vs. 4.8 +/- 1.2; 146 +/- 23; 4.9 +/- 1.1; 35 +/- 10 control group). Peak exercise levels of angiotensin II, aldosterone, vasopressin and atrial natriuretic peptide in the exercise and control groups did not differ at study entry. After 16 weeks, rest and peak exercise hormone levels were unchanged in control patients. Peak exercise neurohormone levels were unchanged in the training group, but resting levels were significantly (p < 0.001) reduced (angiotensin -26%; aldosterone -32%; vasopressin -30%; atrial natriuretic peptide -27%). CONCLUSIONS: Our data indicate that 16 weeks of endurance exercise training modified resting neuroendocrine hyperactivity in heart failure patients. Reduction in circulating neurohormones may have a beneficial impact on long-term prognosis. (+info)