Bicarbonate and chloride secretion in Calu-3 human airway epithelial cells.
(25/2149)
Serous cells are the predominant site of cystic fibrosis transmembrane conductance regulator expression in the airways, and they make a significant contribution to the volume, composition, and consistency of the submucosal gland secretions. We have employed the human airway serous cell line Calu-3 as a model system to investigate the mechanisms of serous cell anion secretion. Forskolin-stimulated Calu-3 cells secrete HCO-3 by a Cl-offdependent, serosal Na+-dependent, serosal bumetanide-insensitive, and serosal 4,4'-dinitrostilben-2,2'-disulfonic acid (DNDS)-sensitive, electrogenic mechanism as judged by transepithelial currents, isotopic fluxes, and the results of ion substitution, pharmacology, and pH studies. Similar studies revealed that stimulation of Calu-3 cells with 1-ethyl-2-benzimidazolinone (1-EBIO), an activator of basolateral membrane Ca2+-activated K+ channels, reduced HCO-3 secretion and caused the secretion of Cl- by a bumetanide-sensitive, electrogenic mechanism. Nystatin permeabilization of Calu-3 monolayers demonstrated 1-EBIO activated a charybdotoxin- and clotrimazole- inhibited basolateral membrane K+ current. Patch-clamp studies confirmed the presence of an intermediate conductance inwardly rectified K+ channel with this pharmacological profile. We propose that hyperpolarization of the basolateral membrane voltage elicits a switch from HCO-3 secretion to Cl- secretion because the uptake of HCO-3 across the basolateral membrane is mediated by a 4,4 '-dinitrostilben-2,2'-disulfonic acid (DNDS)-sensitive Na+:HCO-3 cotransporter. Since the stoichiometry reported for Na+:HCO-3 cotransport is 1:2 or 1:3, hyperpolarization of the basolateral membrane potential by 1-EBIO would inhibit HCO-3 entry and favor the secretion of Cl-. Therefore, differential regulation of the basolateral membrane K+ conductance by secretory agonists could provide a means of stimulating HCO-3 and Cl- secretion. In this context, cystic fibrosis transmembrane conductance regulator could serve as both a HCO-3 and a Cl- channel, mediating the apical membrane exit of either anion depending on basolateral membrane anion entry mechanisms and the driving forces that prevail. If these results with Calu-3 cells accurately reflect the transport properties of native submucosal gland serous cells, then HCO-3 secretion in the human airways warrants greater attention. (+info)
Hyperuricaemia in patients with right or left heart failure.
(26/2149)
Based on the clinical observation that patients with right or left heart failure often present with hyperuricaemia, the relation between serum urate values and haemodynamic variables was studied in patients with primary pulmonary hypertension (PPH) as well as in patients with advanced ischaemic heart disease or dilated cardiomyopathy. The study was a retrospective analysis of 39 patients with PPH and 36 patients with left heart disease, examining serum urate levels in association with haemodynamic variables. Elevated urate concentrations were found in 79% of the PPH patients. There was no association between serum urate levels and mean pulmonary artery pressures, but a significant correlation was found between urate levels and the cardiac index (r=0.48; p=0.0021) and an even stronger correlation between serum urate levels and mean right atrial pressures (r=0.83; p<0.0001). A similar association was found in a subgroup of 21 PPH patients not receiving diuretics. In 36 patients with ischaemic heart disease or dilated cardiomyopathy, hyperuricaemia was present in 78% and was significantly associated with elevated right atrial pressures (r=0.40; p=0.031) and even more so with elevated left atrial pressures (r=0.55; p=0.0005) but not with the cardiac index (r=0.034; p=0.86). The data show that hyperuricaemia in patients with cardiac dysfunction is closely related to elevated right or left atrial filling pressures. (+info)
Sodium depletion and aldosterone decrease dopamine transporter activity in nucleus accumbens but not striatum.
(27/2149)
Motivated behaviors, including sodium (Na) appetite, are correlated with increased dopamine (DA) transmission in the nucleus accumbens (NAc). DA transporter (DAT) modulation affects DA transmission and may play a role in motivated behaviors. In vivo Na depletion, which reliably induces Na appetite, was correlated with robust decreases in DA uptake via the DAT in the rat NAc with rotating disk electrode voltammetry [1,277 +/- 162 vs. 575 +/- 89 pmol. s-1. g-1; Vmax of transport for control vs. Na-depleted tissue]. Plasma aldosterone (Aldo) levels increase after in vivo Na depletion and contribute to Na appetite. Decreased DAT activity in the NAc was observed after in vitro Aldo treatment (428 +/- 28 vs. 300 +/- 25 pmol. s-1. g-1). Neither treatment affected DAT activity in the striatum. These results suggest that a direct action of Aldo is one possible mechanism by which Na depletion induces a reduction in DAT activity in the NAc. Reduced DAT activity may play a role in generating increased NAc DA transmission during Na appetite, which may underlie the motivating properties of Na for the Na-depleted rat. (+info)
Roles of aldosterone and angiotensin in maturation of sodium appetite in furosemide-treated rats.
(28/2149)
When rats are treated with furosemide, there is a rapid natriuresis. However, increased sodium appetite does not occur until some time later. One hypothesis to explain this delay is that increased circulating levels of the hormones of sodium depletion prime or sensitize the brain circuits involved in sodium appetite, perhaps by induction of target gene(s). In the present study, we describe the time course of the temporal maturation of sodium appetite after furosemide treatment and the associated changes in plasma levels of ANG II and aldosterone and in plasma volume. Sodium appetite is modest 3 h after furosemide treatment, is increased after 12 h, and is still larger after 24 h. This pattern is evident with repeated testing. Plasma levels of aldosterone and plasma renin activity are substantially increased 3 h after furosemide treatment, and so the NaCl appetite cannot result simply from progressively increasing levels of these hormones. Furthermore, activation of the subfornical organ and the ventral lamina terminalis, assessed with c-Fos immunocytochemistry, did not differ across these three times. Metyrapone, an inhibitor of adrenal steroid synthesis, was used to examine sodium appetite in the absence of elevations in aldosterone after furosemide treatment. Although metyrapone effectively blocked the increase in aldosterone, it was without effect on the appetite 3 or 24 h after furosemide treatment. Furthermore, elevations of plasma aldosterone by the use of minipumps for several days before furosemide treatment did not prime or potentiate but instead tended to inhibit the induced sodium appetite, despite achieving levels of aldosterone and plasma renin activity typically associated with a robust sodium appetite. Infusions of DOCA gave a similar result. Lastly, minipump infusions of ANG II also did not potentiate sodium appetite. Thus neither addition nor subtraction of these hormones alone influenced sodium appetite under these conditions. (+info)
Mechanisms of the therapeutic effect of astragalus membranaceus on sodium and water retention in experimental heart failure.
(29/2149)
OBJECTIVE: To investigate the therapeutic effect of Astragali on sodium and water retention in aortocaval fistula-caused experimental congestive heart failure and its involved mechanisms. METHODS: In aortocaval fistula-caused chronic (5 wk), heart failure rats treated with and without Astragali 1.0 g/day intraperitoneally, changes of cardiac and renal function, renal response to atrial natriuretic peptide (ANP) were examined. Dot blot analysis was used to determine the effect of Astragali on hypothalamic arginine vasopresin (AVP) mRNA expression, and mRNA expressions of aortic and renal AVP V1a receptor, renal AVP V2 receptor and aquaporin-2 (AQP2) were simultaneously detected by RT-PCR method. RESULTS: Rats with aortocaval fistula impaired cardiac and renal functions evidenced by higher right atrial pressure (RAP), left ventricular end-diastolic pressure (LVEDP), lower + dP/dtmax of left ventricle, glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume (UV), urinary sodium excretion (UNaV) and free water clearance (CH2O) compared with sham-operated control (P < 0.05). There was no change in serum sodium, hematocrit and plasma osmolality. Astragali could remarkably improve the cardiac and renal functions. Dot blot analysis demonstrated upregulated hypothalamic AVP mRNA expression in this experimental heart failure. The AVP V1a receptor mRNA level of aortic arch and renal medulla were reduced, while in renal cortex it was elevated. The mRNA expressions of AVP V2 receptor and AQP2 were increased in renal cortex while decreased in medulla. Astragali could partially or completely correct those abnormal mRNA expressions. Analysis on plasma atrial natriuretic peptide (ANP), urinary cyclic guanidino monophosphate excretion (UcGMP V), urinary cyclic guanidino monophosphate excretion/plasma atrial natriuretic peptide (UcGMP V/pANP), and further correlation and linear regression analysis between UcGMP V and plasma ANP showed that there was blunted renal response to ANP in heart failure rat, and astragali could improve the renal reaction to ANP significantly. CONCLUSION: Chinese herb, astragali have therapeutic effects on sodium and water retention in aortocaval fistula-induced heart failure, the mechanisms of which might be the improvement of cardiac and renal functions, partly correction of abnormal mRNA expressions of AVP system and AQP2, and amelioration of blunted renal response to ANP. (+info)
Mannitol and frusemide in the treatment of diuretic resistant oedema in nephrotic syndrome.
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Three children (two girls aged 7 and 9 years, and one boy aged 4 years) with diuretic resistant oedema in steroid resistant nephrotic syndrome were treated with a combination of intravenous mannitol and frusemide. All three responded with loss of oedema of 10% to 30% of body weight over one week. There were no complications of hypertension or hypovolaemia. Mannitol-frusemide combination is a safe, inexpensive, and effective treatment for diuretic resistant oedema. Its use in other conditions and in developing countries (where the availability and purity of 20% albumin is limited) needs to be explored. (+info)
Treatment of nephrogenic diabetes insipidus with hydrochlorothiazide and amiloride.
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Nephrogenic diabetes insipidus (NDI) is characterised by the inability of the kidney to concentrate urine in response to arginine vasopressin. The consequences are severe polyuria and polydipsia, often associated with hypertonic dehydration. Intracerebral calcification, seizures, psychosomatic retardation, hydronephrosis, and hydroureters are its sequelae. In this study, four children with NDI were treated with 3 mg/kg/day hydrochlorothiazide and 0.3 mg/kg/day amiloride orally three times a day for up to five years. While undergoing treatment, none of the patients had signs of dehydration or electrolyte imbalance, all showed normal body growth, and there was no evidence of cerebral calcification or seizures. All but one had normal psychomotor development and normal sonography of the urinary tract. However, normal fluid balance was not attainable (fluid intake, 3.8-7.7 l/m2/day; urine output, 2.2-7.4 l/m2/day). The treatment was well tolerated and no side effects could be detected. Prolonged treatment with hydrochlorothiazide/amiloride appears to be more effective and better tolerated than just hydrochlorothiazide. Its efficacy appears to be similar to that of hydrochlorothiazide/indomethacin but without their severe side effects. (+info)
Diabetes and cardiovascular events in hypertensive patients.
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To determine the relation of self-reported history of diabetes as well as baseline and in-treatment blood sugar to subsequent cardiovascular disease (CVD) in treated hypertensive patients, we assessed the experience of 6886 participants in a systematic treatment program. The presence or absence of a history of diabetes was known for all patients, who were then stratified into 3 groups according to blood sugar at baseline and in treatment (<6.11, 6.11 to 7.74, and >/=7.75 mmol/L). Some 7.4% of all patients reported history of diabetes, and the overall prevalence of blood sugar >/=7. 75 mmol/L was 7.7% and 10.4% at baseline and in treatment, respectively. Patients with a history of diabetes were 10 or 8 times as likely to have blood sugar >/=7.75 mmol/L at baseline (47.2% versus 4.5%) or in treatment (55.0% versus 6.8%), as were patients without history. During an average 6.3 years of follow-up, patients with history of diabetes had a cardiovascular event incidence 2-fold higher than those without history (20.8 versus 8.6/1000 person-years). Age-gender-adjusted CVD incidence rate but not non-CVD was twice as high in the highest compared with the lowest blood sugar stratum (baseline 16.6 versus 8.4/1000 person-years; in treatment 15.2 versus 8.2). Three separate models of Cox multivariate analysis revealed that history of diabetes (with no history as reference) had a greater association with CVD events (hazard ratio 2.37, 95% confidence interval 1.80 to 3.11) than did baseline (1.75, 1.31 to 2.33) or in-treatment blood sugar (1.55, 1. 19 to 2.02). Furthermore, in the presence of history of diabetes (2. 15, 1.58 to 2.92), neither baseline nor in-treatment blood sugar was independently associated with CVD risk. In the elevated (>/=7.75 mmol/L) in-treatment blood sugar group, the age-gender-adjusted rate of CVD events in frequent diuretic users (30.79/1000 person-years) was significantly higher than in moderate (13.34, P=0.004) and rare users (13.25, P=0.008). These data affirm that the coincidence of diabetes and hypertension is common, that evidence of diabetes substantially increases CVD risk, that self-reported history is a more powerful predictor of CVD events than any measure of blood sugar, and that CVD increases in hypertensive diuretic users who develop hyperglycemia even when blood pressure is well controlled. (+info)