Maintenance Of Extracellular Fluid Volume Research Articles

The heart as an endocrine organ

The concept of the heart as an endocrine organ arises from the observation that the atrial cardiomyocytes in the mammalian heart display a phenotype that is partly that of endocrine cells. Investigations carried out between 1971 and 1983 characterised, by virtue of its natriuretic properties, a polypeptide referred to atrial natriuretic factor (ANF). Another polypeptide isolated from brain in 1988, brain natriuretic peptide (BNP), was subsequently characterised as a second hormone produced by the mammalian heart atria. These peptides were associated with the maintenance of extracellular fluid volume and blood pressure. Later work demonstrated a plethora of other properties for ANF and BNP, now designated cardiac natriuretic peptides (cNPs). In addition to the cNPs, other polypeptide hormones are expressed in the heart that likely act upon the myocardium in a paracrine or autocrine fashion. These include the C-type natriuretic peptide, adrenomedullin, proadrenomedullin N-terminal peptide and endothelin-1. Expression and secretion of ANF and BNP are increased in various cardiovascular pathologies and their levels in blood are used in the diagnosis and prognosis of cardiovascular disease. In addition, therapeutic uses for these peptides or related substances have been found. In all, the discovery of the endocrine heart provided a shift from the classical functional paradigm of the heart that regarded this organ solely as a blood pump to one that regards this organ as self-regulating its workload humorally and that also influences the function of several other organs that control cardiovascular function.

Angiotensin II Induces Modulation of Calcium Channel Currents in Osteoblasts

Angiotensin II (Ang II) plays a major role in the maintenance of extracellular fluid volume and blood pressure. In addition to its well-established role in circulatory homeostasis, it has been implicated in the process of bone formation. Osteoblasts play a major role in bone formation, employing intracellular Ca(2+) as a second messenger to modulate hormonal responses and as a cofactor for mineralization. Voltage-dependent Ca(2+) channels (VDCCs) mediate the influx of Ca(2+) in response to membrane depolarization. The purpose of this study was to investigate the effects of Ang II on VDCC currents in osteoblasts using a patch-clamp recording method. To our knowledge, the data presented here demonstrate for the first time that Ang II facilitates VDCCs in osteoblasts.

Abstract 338: Kidney-specific SPAK Inhibits Activity of the Na-K-2Cl Cotransporter

The WNK-SPAK/OSR1 pathway has been shown to play a critical role in the regulation of ion homeostasis, and the maintenance of extracellular fluid volume and blood pressure. SPAK and OSR1, members of the MAP kinase family, phosphorylate and activate the cation chloride cotransporters NKCC1, NKCC2 and NCC. SPAK and OSR1 are themselves phosphorylated and activated by members of the WNK kinase family. We recently identified a kidney-specific (KS-) SPAK isoform (KS-SPAK) which inhibits phosphorylation of the N-terminus of NKCC2 by SPAK or OSR1 in vitro . Since changes in NKCC2 phosphorylation status have been reported to incompletely correlate with changes in NKCC2 activity, we tested the ability of KS-SPAK to inhibit the activity of NKCC2 in Xenopus oocytes. First, 86 Rubidium ( 86 Rb, equivalent to potassium) uptake experiments were performed under hypertonic (300mOsM) conditions, to maximally activate endogenous SPAK and OSR1 in oocytes. KS-SPAK decreased 86 Rb uptake to 38% of that of oocytes injected with NKCC2 alone, and this inhibition required the conserved carboxy-terminus of SPAK, which interacts with cation cotransporters and WNK kinases. We next tested the ability of KS-SPAK to inhibit the activity of endogenous NKCC1, and observed a 67% reduction in 86 Rb uptake compared with water-injected oocytes, similar to the 73% reduction observed with the NKCC1/NKCC2 inhibitor bumetanide. This inhibition likely involves effects on endogenous SPAK or OSR1, since under hypotonic (160mOSM) conditions, when SPAK is relatively inactive, KS-SPAK did not inhibit endogenous NKCC1 activity, whereas bumetanide still inhibited 86 Rb uptake by water-injected oocytes by 50%. Co-injection of KS-SPAK with SPAK only reversed KS-SPAK inhibition of endogenous NKCC2 activity by 50%, despite a co-injection ratio of SPAK:KS-SPAK of 15:1, suggesting the mechanism of KS-SPAK inhibition may not be simple competition for NKCC2 binding. Another SPAK isoform, SPAK2, which has been proposed to be kinase-inactive, did not inhibit activity of co-injected NKCC2 or endogenous NKCC1 at any tonicity. Together, these data show that KS-SPAK is a potent inhibitor of both NKCC1 and NKCC2 activity, whereas the other putative inhibitory isoform SPAK2 had no effect on their activity.

Angiotensin II and the glomerulus: focus on diabetic kidney disease.

The renin-angiotensin system plays a key role in the progression of kidney disease, in addition to its well-described role in the maintenance of extracellular fluid volume and blood pressure. Recent studies have shown that blockade of the renin-angiotensin system at the level of the angiotensin II type 1 receptor can have important effects on proteinuria and the rate of progression of kidney disease in patients with type 2 diabetes mellitus. This review first discusses recent experimental studies relating angiotensin II to kidney function in diabetes mellitus and changes in glomerular permselectivity, and then focuses on recent clinical trials with angiotensin II receptor blockers in patients with type 2 diabetes mellitus.

Effect of mineralocorticoid deficiency on ion and urea transporters and aquaporin water channels in the rat

Mineralocorticoid deficiency is associated with impaired urinary concentration and dilution. The present investigation was undertaken to determine the effects of selective mineralocorticoid deficiency on renal sodium and urea transporters and aquaporin water channels and whether these perturbations can be reversed by maintenance of extracellular fluid volume. Mineralocorticoid deficiency was induced by bilateral adrenalectomies with glucocorticoid replacement. Mineralocorticoid deficient rats receiving plain drinking water (MDW) were compared with mineralocorticoid deficient rats receiving saline-drinking water (MDS) in order to maintain extracellular fluid volume, and with controls (CTL). In MDW rats, there was a significant decrease in renal outer medulla Na–K–2Cl co-transporter and outer medulla Na–K-ATPase as well as an increase in inner medulla aquaporins 2 and 3. There were no significant changes in aquaporin-1, aquaporin-4, or urea transporters. These alterations were reversed with maintenance of extracellular fluid volume in MDS rats. Our findings indicate that mineralocorticoid deficiency in the rat is associated with alterations in factors involved in the countercurrent concentrating mechanism (Na–K–2Cl, Na–K-ATPase) and osmotic water equilibration in the collecting duct (AQP2, AQP3). Maintenance of sodium balance and extracellular fluid volume is associated with normalization of these perturbations.

Angiotensin II stimulates calcineurin activity in proximal tubule epithelia through AT-1 receptor-mediated tyrosine phosphorylation of the PLC-gamma1 isoform.

Angiotensin II (AngII) contributes to the maintenance of extracellular fluid volume by regulating sodium transport in the nephron. In nonepithelial cells, activation of phospholipase C (PLC) by AT-1 receptors stimulates the generation of 1,4,5-trisphosphate (IP(3)) and the release of intracellular calcium. Calcineurin, a serine-threonine phosphatase, is activated by calcium and calmodulin, and both PLC and calcineurin have been linked to sodium transport in the proximal tubule. An examination of whether AngII activates calcineurin in a model of proximal tubule epithelia (LLC-PK1 cells) was performed; AngII increased calcineurin activity within 30 s. An examination of whether AngII activates PLC in proximal tubule epithelia was also performed after first showing that all three families of PLC isoforms are present in LLC-PK1 cells. Application of AngII increased IP(3) generation by 60% within 15 s, which coincided with AngII-induced tyrosine phosphorylation of the PLC-gamma1 isoform also observed at 15 s. AngII-induced tyrosine phosphorylation was blocked by the AT-1 receptor antagonist, Losartan. Subsequently, an inhibitor of tyrosine phosphorylation blocked the AngII-induced activation of calcineurin, as did coincubation with an inhibitor of PLC activity and with an antagonist of the AT-1 receptor. It is therefore concluded that AngII stimulates calcineurin phosphatase activity in proximal tubule epithelial cells through a mechanism involving AT-1 receptor-mediated tyrosine phosphorylation of the PLC isoform.

Hypertension and the kidney.

Hypertension and kidney function are intimately related, with each having significant influences on the other. Given the major role played by the kidney in maintenance of extracellular fluid volume and peripheral vascular resistance, the kidney is justifiably a target of investigation to determine its potential role in essential hypertension. Conversely, hypertension is associated with progressive renal failure, and hypertension-associated end-stage renal disease is the second leading cause of end-stage renal disease in the United States. It is therefore important that we continue to investigate the hypertension/renal relationship in an effort to better understand the determinants of essential hypertension and to prevent a major cause of end-stage renal disease.

Regulation of the sodium transporters NHE3, NKCC2 and NCC in the kidney.

The regulation of sodium transport in the kidney is important for maintenance of extracellular fluid volume and arterial blood-pressure regulation. The major sodium transporters and channels in individual renal tubule segments have been identified via physiological techniques, and complementary DNAs for all of the key sodium transporters and channels expressed along the renal tubule have been cloned. Complementary DNA probes and antibodies are now being used to investigate the molecular basis of renal tubule sodium-transport regulation. This review summarizes some of the major observations made in the past year that are relevant to the regulation of the major sodium transporters in the proximal tubule (the type 3 sodium-hydrogen exchanger, NHE3), the thick ascending limb of Henle (the bumetanide-sensitive sodium-potassium-chloride cotransporter, NKCC2), and the distal convoluted tubule (the thiazide-sensitive sodium-chloride cotransporter, NCC).

Concerted actions of renal endothelial and macula densa NO systems in the maintenance of extracellular fluid volume.

It is now clear that nitric oxide (NO) exerts a substantial influence on renal function and that the kidney has a high capacity to produce NO. However, there are at least two different NO systems in the kidney. The interplay between NO generated by the endothelium and by the macula densa is considered in this review. It seems that endothelial NO increases in response to an increase in perfusion pressure and an increase in distal delivery, whereas macula densa NO decreases upon a sustained increase in distal delivery. Furthermore, evidence is accumulating that macula densa NO may well mediate renin release. Though seemingly in contrast, both the response of the endothelial NO and of the macula densa NO system seem appropriate to restore a perturbation of fluid balance. The function of the tubuloglomerular feedback (TGF) mechanism is likely to be influenced by both sources of NO, because of the close proximity of these NO producing cells to the vascular smooth muscle cells of the afferent arteriole. The endothelial NO system seems to be responsible for short-term, dampening actions to increased afferent arteriolar tone elicited by activation of the TGF system. The macula densa NO system, on the other hand, is probably adapting TGF responses to sustained increases in distal delivery. The analysis presented in this paper is an attempt to integrate the function of the two NO systems into physiological regulation. The exact role of the medullary NOS enzymes remains to be further elucidated.

Relevance of the tubuloglomerular feedback mechanism in pathophysiology.

The balance between a high filtration rate and high reabsorption rate in the kidney is critical in the maintenance of extracellular fluid volume. One of the mechanisms that maintain this balance is the tubuloglomerular feedback (TGF) mechanism, which operates at the level of the macula densa assessing the load and/or solute concentration coming out of the loop of Henle and controlling this load by adjusting the GFR. This review discusses the potential role of the TGF system with respect to volume homeostasis in various conditions where GFR is maintained, decreased, or increased. In most of the states discussed, the TGF system seems to act appropriately regarding volume control; however, trade-off effects occasionally occur. After acetazolamide administration, during extracellular fluid volume contraction or expansion or acute hyperkalemia, the TGF mechanism responds appropriately with regard to volume balance. After a large reduction of renal mass, the system adjusts to function at a higher level of GFR and distal delivery. In chloride-depletion metabolic alkalosis, glomerulonephritis, diabetes mellitus, and acute renal failure, the adaptation of the TGF system appears to be appropriate with regard to volume control; however, it may lead to trade-off effects, such as maintenance of metabolic alkalosis, glomerular hypertension and sclerosis, or depression of GFR, respectively. Because the TGF mechanism often contributes to compensatory adjustments to or development of disease, it can be appreciated that any in-depth evaluation of the mechanisms responsible for various pathophysiologic conditions should include an assessment of the potential role of the TGF mechanism.

Fluid, Electrolyte, and Acid-Base Disorders.

SECTION I NORMAL WATER and ACID-BASE REGULATION: Regulation of Intra- And Extracellular Volume. Sodium Metabolism and Maintenance of Extracellular Fluid Volume. Edema-Forming States. Acid-Base Regulation: Cellular and Whole-Body. Classification of Acid-Base Disturbances. Metabolic Acidosis. Acid-Base Disturbances in Pulmonary Medicine. Disorders of Sodium Metabolism. Hyponatremia, Hypernatremia. Disorders of Postassium Metabolism. Hyperkalemia, Hypokalemia. Calcium Homeostasis and Disorders of Calcium Metabolism. Disorders of Magnesium Metabolism. Physiology of Phosphorus Metabolism and Pathophysiology of Hypo-And Hyperphosphatemia SECTION 2 SPECIFIC PATHOLOGIC STATES and SPECIAL CONSIDERATIONS: Clinical Manifestations of Electrolyte and Acid-Base Disorders. Total Parenteral Nutrition and Its Complications. Fluid and Electrolyte Therapy in Critically Ill Patients and Those Who Are Pre-, Post-, Or Intraoperative. Acute Renal Failure. Chronic Renal Failure. Metabolic Encephalopathy as a Complication of Acid-Base and Electrolyte Disorders. Fluid, Electrolyte, And Acid-Base Complications of Diabetic Emergencies. The Liver and Acid-Base Regulation in Health and Disease. Fluid, Electrolyte, And Acid-Base Complications of Dialysis. Metabolic Disorders Associated with Gastrointestinal Disease. Fluid and Electrolyte Metabolism in Normal and Abnormal Pregnancy. Fluid and Electrolyte Therapy in Infants and Children . Ageing and Renal Function

Concentration and molecular forms of active and inactive renin in human fetal kidney, amniotic fluid and adrenal gland: evidence for renin-angiotensin system hyperactivity in 2nd trimester of pregnancy.

In a study of 38 fetuses total kidney renin was significantly correlated with gestational age (r = 0.63). Although whole fetal kidney renin specific activity was found to decrease with gestational age (r = -0.65), the mean value of the specific activity was about 20 times greater than in normal adult cortex and double that in tissue from patients with renal artery stenosis, suggesting renin-angiotensin system hyperactivity. In approximately 40% of fetal kidneys examined, evidence for an inactive (trypsin-activatable) renin precursor was found. The molecular weight of this form was indistinguishable from active renin (45 000 daltons) by Sephadex chromatography. Amniotic fluid from nine cases (100%) contained angiotensin (ANG) 1, angiotensin converting enzyme (ACE), renin substrate, active and inactive renin (both 45 000 daltons). Five of the 38 (13%) fetal adrenal glands contained renin, but no evidence for trypsin-activatable forms. Aldosterone was present in low concentration in the earliest adrenals examined, and a positive correlation existed between total tissue aldosterone and gestational age (r = 0.73). These findings suggest that the fetal renin-angiotensin system has an important role to play in the maintenance of extracellular fluid volume and blood pressure in the developing fetus.