Control Of Fluid Volume Research Articles

Diuretic use in renal disease

Diuretics are agents commonly used in diseases characterized by excess extracellular fluid, including chronic kidney disease, the nephrotic syndrome, cirrhosis and heart failure. Multiple diuretic classes, including thiazide-type diuretics, loop diuretics and K(+)-sparing diuretics, are used to treat patients with these diseases, either individually or as combination therapies. An understanding of what determines a patient's response to a diuretic is a prerequisite to the correct use of these drugs. The response of patients with these diseases to diuretics, which is related to the dose, is best described by a sigmoid curve whose contour can become distorted by any of the several sodium-retaining states that are directly or indirectly associated with renal disease. Diuretic actions are of considerable importance to patients who have renal disease, as their effective use assists in extracellular fluid volume control, reducing excretion of protein in urine and lessening the risk of developing hyperkalemia. Diuretic-related adverse events that involve the uric acid, Na(+) and K(+) axes are not uncommon; therefore the clinician must be vigilant in looking for biochemical disturbances. As a result of diuretic-related adverse events, clinicians must be resourceful in the dose amount and frequency of dosing.

The importance of body composition and dry weight assessments in patients with chronic kidney disease (Review)

Chronic volume overload is the major cause of hypertension and other cardiovascular morbidity in dialysis patients. One of the most important goals of physicians who take care of patients with chronic renal failure is to obtain near euvolemia or "dry body weight" in order to maintain or normalize blood pressure and prevent further cardiovascular events. In clinical practice, exact estimation of dry weight in hemodialysis patients remains a major challenge. Alterations in body composition, particularly malnutrition, are common in patients receiving long-term hemodialysis and contribute to a high mortality rate. In contrast, obesity - a known risk factor for cardiovascular morbidity and mortality - is prevalent amongst kidney allograft recipients in - long term after renal transplantation. Several technological tools and biochemical markers for estimation of plasma volume and body composition are available for clinical use. Our aim was to highlight the importance of control of body fluid volume and body composition in patients with chronic kidney disease and to describe the different methods available for such measurements.

Molecular profiling of the human nasal epithelium: A proteomics approach

A comprehensive proteomic profiling of nasal epithelium (NE) is described. This study relies on simple subcellular fractionation used to obtain soluble- and membrane-enriched fractions followed by 2-dimensional liquid chromatography (2D-LC) separation and tandem mass spectrometry (MS/MS). The cells were collected using a brushing technique applied on NE of clinically evaluated volunteers. Subsequently, the soluble- and the membrane-protein enriched fractions were prepared and analyzed in parallel using 2D-LC-MS/MS. In a set of 1482 identified proteins, 947 (63.9%) proteins were found to be associated to membrane fraction. Grand average hydropathy value index (GRAVY) analysis, the transmembrane protein mapping and annotations of primary location deposited in the Human Protein Reference Database (HPRD) confirmed an enrichment of hydrophobic proteins on this dataset. Ingenuity Pathway Analysis (IPA) of soluble fraction revealed an enrichment of molecular and cellular functions associated with cell death, protein folding and drug metabolism while in membrane fraction showed an enrichment of functions associated with molecular transport, protein trafficking and cell-to-cell signaling and interaction. The IPA showed similar enrichment of functions associated with cellular growth and proliferation in both soluble and membrane subproteomes. This finding was in agreement with protein content analysis using exponentially modified protein abundance index (emPAI). A comparison of our data with previously published studies focusing on respiratory tract epithelium revealed similarities related to identification of proteins associated with physical barrier function and immunological defence. In summary, we extended the NE molecular profile by identifying and characterizing proteins associated to pivotal functions of a respiratory epithelium, including the control of fluid volume and ionic composition at the airways' surface, physical barrier maintenance, detoxification and immunological defence. The extent of similarities supports the applicability of a less invasive analysis of NE to assess prognosis and treatment response of lung diseases such as asthma, cystic fibrosis and chronic obstructive pulmonary disease.

The functional genomics of guanylyl cyclase/natriuretic peptide receptor‐A: Perspectives and paradigms

The cardiac hormones atrial natriuretic peptide and B-type natriuretic peptide (brain natriuretic peptide) activate guanylyl cyclase (GC)-A/natriuretic peptide receptor-A (NPRA) and produce the second messenger cGMP. GC-A/NPRA is a member of the growing family of GC receptors. The recent biochemical, molecular and genomic studies on GC-A/NPRA have provided important insights into the regulation and functional activity of this receptor protein, with a particular emphasis on cardiac and renal protective roles in hypertension and cardiovascular disease states. The progress in this field of research has significantly strengthened and advanced our knowledge about the critical roles of Npr1 (coding for GC-A/NPRA) in the control of fluid volume, blood pressure, cardiac remodeling, and other physiological functions and pathological states. Overall, this review attempts to provide insights and to delineate the current concepts in the field of functional genomics and signaling of GC-A/NPRA in hypertension and cardiovascular disease states at the molecular level.

Mechanisms of fluid production in smooth adhesive pads of insects

Insect adhesion is mediated by thin fluid films secreted into the contact zone. As the amount of fluid affects adhesive forces, a control of secretion appears probable. Here, we quantify for the first time the rate of fluid secretion in adhesive pads of cockroaches and stick insects. The volume of footprints deposited during consecutive press-downs decreased exponentially and approached a non-zero steady state, demonstrating the presence of a storage volume. We estimated its size and the influx rate into it from a simple compartmental model. Influx was independent of step frequency. Fluid-depleted pads recovered maximal footprint volumes within 15 min. Pads in stationary contact accumulated fluid along the perimeter of the contact zone. The initial fluid build-up slowed down, suggesting that flow is driven by negative Laplace pressure. Freely climbing stick insects left hardly any traceable footprints, suggesting that they save secretion by minimizing contact area or by recovering fluid during detachment. However, even the highest fluid production rates observed incur only small biosynthesis costs, representing less than 1 per cent of the resting metabolic rate. Our results show that fluid secretion in insect wet adhesive systems relies on simple physical principles, allowing for passive control of fluid volume within the contact zone.

The home dialysis first paradigm: suitability and transitioning

Patients with progressive renal insufficiency are faced with a multitude of decisions and choices during the continuum of their care. Those that choose to embark on the road to renal replacement therapy are faced with complicated decisions regarding modality choice and possibly transplantation. Others may proceed with palliative pre-dialysis care, without considering any further therapy. Empowerment of patient choice or autonomy is now felt to be central to medical decision making [1]. It seems evident that in the past, many patients with end-stage renal disease (ESRD) have reported that they did not receive all the information required to make an informed choice about dialytic modalities [2]. Lameire and colleagues introduced an integrated care approach to modality decision making more than 10 years ago [3]. Their approach was to intimately plan pre-dialysis care with timely referral to a renal multidisciplinary team, timely preparation for dialysis followed by timely initiation. Peritoneal dialysis (PD) was their focus of the initial modality of choice for suitable patients with timely transfer to in-center hemodialysis (HD) as a rescue therapy should PD be inadequate. Although this approach was a welcome one in regard to attempting to integrate or streamline pre-dialysis care, it had a number of shortcomings. Mendelssohn and Pierratos identified four important deficiencies with this approach including a lack of emphasis on the following: (1) decreasing the rate of progression of chronic kidney disease, (2) management of cardiovascular risk and other comorbidities, (3) consideration of home HD, pre-emptive transplant, and PD as the initial modality for suitable patients, and (4) empowerment of patient choice [4]. Mendelssohn and Pierratos indicated a number of reasons why home HD is a good initial modality [4]. The advantages listed in their 2001 editorial still hold today (and some are more robust with the supporting data that has accrued since then). Briefly, home HD has the following advantages: (1) improved extracellular fluid volume and blood pressure control, (2) liberalization of the diet, (3) patient independence and flexibility, (4) improved quality of life, (5) reduced erythropoietin-stimulating agent utilization, (6) possible survival benefits, (7) possibly comparable lifeexpectancy results as transplantation, and (8) more cost-effective than in-center HD (after approximately M. Benaroia Division of Nephrology, Grand River Hospital, 835 King Street, West, Kitchener, ON N2G 1G3, Canada

Mechanisms of Apical Fluid Volume Control in Airway Epithelia

Our objective is to use computer modeling to understand mechanisms of apical fluid volume control in an airway epithelium. We choose human bronchial epithelium (HBE) because of clinical importance. To build the model, we utilize published short and open circuit electrical and pharmacological data. We use a stochastic parametric search tool to establish parameters for transporters and channels in the tissue, namely permeabilities for Na, K, Cl and HCO3 and the HK pump in the apical membrane, and permeabilities for K and Cl, plus the NaK pump, NKCC, NBC, AE and the NHE in basolateral membrane. To complete the model, we postulate that the NKCC is sensitive to cell volume and the apical Pna permeability (ENaC) is sensitive to the apical volume. Important results include: a) with active regulation of cell and apical volumes by basolateral NKCC and apical ENaC the system assumes an oscillating steady state. Absent active regulation, the system drifts to “fluid catastrophe” either flooding or drying out, and b) if the apical Pcl is changed, the apical Pna necessary to maintain the apical fluid thickness varies such that the ratio of Pna/Pcl is maintained roughly constant. Supported by NIH 5PN2EY016570

Regulation of cardiac angiotensin-converting enzyme and angiotensin AT1 receptor gene expression in Npr1 gene-disrupted mice.

1. Understanding of the regulatory mechanisms of gene expression in the control of blood pressure and fluid volume is a key issue in cardiovascular medicine. Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) signalling antagonizes the physiological and pathophysiological effects mediated by the renin-angiotensin-aldosterone system (RAAS) in the regulation of cardiovascular homeostasis. 2. The targeted-disruption of the Npr1 gene (coding for GC-A/PRA) leads to activation of the cardiac RAAS involved in the hypertrophic remodelling process, which influences cardiac size, expression of pro-inflammatory cytokine genes and the behaviour of various hypertrophy marker genes. The Npr1 gene-knockout (Npr1(-/-)) mice exhibit 35-40 mmHg higher systolic blood pressure and a significantly greater heart weight to bodyweight ratio than wild-type (Npr1(+/+)) mice. 3. The expression of both angiotensin-converting enzyme (ACE) and angiotensin II AT(1a) receptors are significantly increased in hearts from Npr1(-/-) mice compared with hearts from Npr1(+/+) mice. In parallel, the expression of interleukin-6 and tumour necrosis factor-alpha is also markedly increased in hearts from Npr1(-/-) mice. 4. These findings indicate that disruption of NPRA/cGMP signalling leads to augmented expression of the cardiac RAAS in conjunction with pro-inflammatory cytokines in Npr1-null mutant mice, which promotes the development of cardiac hypertrophy and remodelling.

The Epithelial Sodium Channel α subunit (α ENaC) alternatively spliced form "b" in Dahl rats: What's next?

BackgroundThe amiloride-sensitive Epithelial Sodium Channel (ENaC) is critical in maintaining Na+ balance, extracellular fluid volume and long term blood pressure control. ENaC is composed of three main subunits α, β, & γ. While α ENaC is critical for channel functionality, β & γ ENaC maximize channel function. To date, there are four alternatively spliced forms of the α subunit of ENaC (α ENaC-a, -b, -c, & -d) that have been published in rats, in addition to the major α ENaC transcript. While α ENaC-a, -c & -d transcripts are low abundance transcripts compared to full-length α ENaC, α ENaC-b is a higher abundance and salt-sensitive transcript compared to full-length α ENaC.Presentation of the hypothesisα ENaC-b protein, which is preferentially produced in Dahl R rats, to a greater extent on high salt diet, exerts a dominant negative effect on full-length α ENaC subunit by physically binding to and trapping full-length α ENaC subunit in the endoplasmic reticulum, and finally accelerating full-length α ENaC proteolytic degradation in a dose-dependent manner.Testing the hypothesis1) To examine the mRNA and protein abundance of α ENaC-b relative to α ENaC full-length in kidney, lung, and taste tissues of Dahl rats. 2) To compare the expression (mRNA and protein) of α ENaC-b in kidneys of Dahl S and R rats on regular and high salt diet. 3) To examine the putative binding of α ENaC-b proteins to full-length α ENaC in vitro and to determine the impact of such binding on full-length α ENaC expression in vitro.Implications of the hypothesisOur studies will be the first to demonstrate the over-expression of salt-sensitive α ENaC-b spliced form in kidney tissues of Dahl R rats at the expense of full-length α ENaC. The current proposal will provide highly novel insights into the putative mechanisms leading to ENaC hypoactivity in high-salt-fed Dahl R rats. Finally, findings from the present proposal will uncover a new mechanism by which alternative splicing may control the regulation of ENaC expression/function.

A timely characterization of vasopressin-sensitive adenylyl cyclase isoforms in the mouse inner medullary collecting duct

second messenger signaling in the kidney mediates several of the organ's basic physiological functions including the regulation of blood pressure, control of fluid volume, and maintenance of the body's water homeostasis in times of duress. Tight regulation of the second messenger cAMP is critical

Sorting out Lysosomal Trafficking of the Thiazide-Sensitive Na-Cl Co-transporter

The aldosterone-sensitive distal nephron is a key site for regulated renal sodium reabsorption and, hence, plays a critical role in the long-term control of arterial BP and extracellular fluid volume. Coupled Na+ and Cl− transport across the luminal surface of the most proximal portion of the aldosterone-sensitive distal nephron, the distal convoluted tubule, occurs through the thiazide-sensitive Na-Cl co-transporter (NCC). NCC bears a similar structure to other members of the SLC12 family of electroneutral cation chloride co-transporters, containing 12 transmembrane domains flanked by large cytoplasmic amino and carboxyl termini and two sites for N-linked glycosylation.1 It exists functionally as a homodimer at the apical surface of the distal convoluted tubule, where it reabsorbs 5 to 10% of the filtered sodium chloride load.1 NCC is the molecular target of thiazides and thiazide-like diuretics, which, because of their cardiovascular benefits, are recommended first-line agents for patients with newly diagnosed essential hypertension. Given the relevance of NCC function in human hypertension, it is not surprising that the co-transporter has become the subject of intense investigation in recent years. The greatest impetus that stimulated the recent explosion of NCC research is the seminal discovery in 2001 that familial hyperkalemic hypertension (FHHt; also known as PHA-2, or Gordon syndrome), a Mendelian syndrome of NCC overactivity, is caused by mutations in the with-no-lysine (WNK) …

NT-proBNP, fluid volume overload and dialysis modality are independent predictors of mortality in ESRD patients

N-terminal fragment of B-type natriuretic peptide (NT-proBNP) is a marker of both fluid volume overload and myocardial damage, and it has been useful as a predictor of mortality in patients with end-stage renal disease (ESRD). It has been suggested that continuous ambulatory peritoneal dialysis (CAPD), automated peritoneal dialysis (APD) and haemodialysis (HD) may have different effects on fluid volume and blood pressure control; however, whether the independent predictive value of NT-proBNP for mortality is preserved when analysed in conjunction with fluid overload and dialysis modality is not clear. A prospective multicentre cohort of 753 prevalent adult patients on CAPD, APD and HD was followed up for 16 months. Plasmatic levels of NT-proBNP, extracellular fluid volume/total body water ratio (ECFv/TBW) and traditional clinical and biochemical markers for cardiovascular damage risk were measured, and their role as predictors of all-cause and cardiovascular mortality was analysed. NT-proBNP level, ECFv/TBW and other cardiovascular damage risk factors were not evenly distributed among the different dialysis modalities. NT-proBNP levels and ECFv/TBW were correlated with several inflammation, malnutrition and myocardial damage markers. Multivariate analysis showed that NT-proBNP levels and ECFv/TBW were predictors of both all-cause and cardiovascular mortality, independently of dialysis modality and the presence of other known clinical and biochemical risk factors. NT-proBNP is a reliable predictor of death risk independently of the effect of dialysis modality on fluid volume control, and the presence of other clinical and biochemical markers recognized as risk factors for all-cause and cardiovascular mortality. NT-pro-BNP is a good predictor of mortality independently of fluid volume overload and dialysis modality.

Expression of aquaporin-1,3,8,9 mRNA in human amniotic membranes in polyhydranmios

Objective To determine the expression of aquaporin-1,3,8,9 mRNA (AQP-1,3,8, 9) in amniotic membranes in pregnant women with polyhydramnios. Methods Amniotic membranes were collected from women who presented with either polyhydramnios (n= 5)or normal amniotic fluid volume (control, n= 5) underwent elective cesarean sections at term. The AQP-1,3,8,9 mRNA expression were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Results The expression of AQP-9 mRNA on fetal membranes were significantly higher in polyhydramnios groups (1. 1403±0. 0831) than that of control (0. 5903±0. 1909) (P = 0. 002), although the expression of AQP-1, 3 and 8 showed no significant difference between the two groups (P= 0. 972, 0. 242,0. 608, respectively). Conclusions AQP-9 may play an important role in maintaining the volume and the balance of different components of amniotic fluid in polyhydramnios cases. Key words: Aquaporins; Gene expression; Polyhydramnios; Extraembryonic membranes

Beyond The Current Paradigm: Recent Advances in The Understanding of Sodium Handling – Guest Editors: Stanley Shaldon and Joerg Vienken: Water‐Free Sodium Accumulation

The widely accepted concept of body fluid and electrolyte homeostasis is that Na(+) is restricted mainly to the extracellular fluid and K(+) to the intracellular space, where both ions act to hold water and thereby control the extracellular and intracellular fluid volume by their osmotic activity. Na(+) accumulation thus inevitably leads to water retention. The constancy of the extracellular volume is the task of the kidneys, which control the total body Na(+) content. More recent data have questioned this traditional view, suggesting that large amounts of Na(+) can be accumulated without accompanying water retention by osmotically inactive Na(+) retention, or by osmotically neutral Na(+)/K(+) exchange. Besides the control of the body Na(+) content by the kidneys, redistribution of body electrolytes hence provides an extrarenal regulatory alternative in the maintenance of body fluid volume and blood pressure control.

Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC)

The aldosterone-sensitive distal nephron (ASDN) includes the late distal convoluted tubule 2, the connecting tubule (CNT) and the collecting duct. The appropriate regulation of sodium (Na(+)) absorption in the ASDN is essential to precisely match urinary Na(+) excretion to dietary Na(+) intake whilst taking extra-renal Na(+) losses into account. There is increasing evidence that Na(+) transport in the CNT is of particular importance for the maintenance of body Na(+) balance and for the long-term control of extra-cellular fluid volume and arterial blood pressure. Na(+) transport in the CNT critically depends on the activity and abundance of the amiloride-sensitive epithelial sodium channel (ENaC) in the luminal membrane of the CNT cells. As a rate-limiting step for transepithelial Na(+) transport, ENaC is the main target of hormones (e.g. aldosterone, angiotensin II, vasopressin and insulin/insulin-like growth factor 1) to adjust transepithelial Na(+) transport in this tubular segment. In this review, we highlight the structural and functional properties of the CNT that contribute to the high Na(+) transport capacity of this segment. Moreover, we discuss some aspects of the complex pathways and molecular mechanisms involved in ENaC regulation by hormones, kinases, proteases and associated proteins that control its function. Whilst cultured cells and heterologous expression systems have greatly advanced our knowledge about some of these regulatory mechanisms, future studies will have to determine the relative importance of the various pathways in the native tubule and in particular in the CNT.

CFTR structure and function: is there a role in the kidney?

Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). Mutations in the CFTR gene may result in a defective protein processing that leads to changes in function and regulation of this chloride channel. Despite of the expression of CFTR in the kidney, patients with CF do not present major renal dysfunction, but it is known that both the urinary excretion of proteins and renal capacity to concentrate and dilute urine are altered in these patients. CFTR mRNA is expressed in all nephron segments of rat and human, and this abundance is more prominent in renal cortex and outer medulla renal areas. CFTR protein was detected in apical surface of both proximal and distal tubules of rat kidney but not in the outer medullary collecting ducts. Studies have demonstrated that CFTR does not only transport Cl- but also ATP. ATP transport by CFTR could be involved in the control of other ion transporters such as Na+ (ENaC) and K+ (renal outer medullary potassium) channels, especially in TAL and CCD. In the kidney, CFTR also might be involved in the endocytosis of low-molecular-weight proteins by proximal tubules. This review is focused on the CFTR function and structure, its role in the renal physiology, and its modulation by hormones involved in the control of extracellular fluid volume.

Responses of Amniotic Fluid Volume and Its Four Major Flows to Lung Liquid Diversion and Amniotic Infusion in the Ovine Fetus

We designed experiments to allow direct measurement of amniotic fluid volume and continuous measurement of lung liquid production, swallowing, and urine production in fetal sheep. From these values, the rate of intramembranous absorption was calculated. Using this experimental design, the contribution of lung liquid to the control of amniotic fluid volume was examined. Fetuses were assigned to 1 of 4 protocols, each protocol lasting 3 days: control, isovolemic replacement of lung liquid, supplementation of amniotic fluid inflow by 4 L/day, and supplementation of amniotic inflow during isovolemic replacement of lung liquid. We found no effect of lung liquid replacement on any of the known flows into and out of the amniotic fluid. Although intramembranous absorption increased greatly during supplementation, the amniochorionic function curves were not altered by isovolemic lung liquid replacement. We conclude that lung liquid does not appear to contain a significant regulatory substance for amniotic fluid volume control.

Regulation of the epithelial sodium channel [ENaC] in kidneys of salt-sensitive Dahl rats: insights on alternative splicing.

The epithelial sodium channel [ENaC] is critical for the maintenance of sodium balance, extracellular fluid volume and long term blood pressure control. Monogenic disorders causing ENaC hyperactivity have led to a severe form of hereditary hypertension in humans, known as Liddle's syndrome. Similarly, in animal models, ENaC hyperactivity has been well documented in kidneys of salt-sensitive [S] Dahl rats [a genetic model of salt-sensitive hypertension] versus their normotensive control [Dahl salt-resistant [R] rats]. The purpose of the present review is to highlight the differential regulation of ENaC in kidneys of Dahl S versus R rats. A systematic overview of the putative role of alternative splicing of the main α subunit of ENaC [α ENaC] in modulating ENaC expression in kidneys of Dahl rats will be discussed. Finally, a better understanding of the meaningful contribution of ENaC in the pathogenesis of salt-sensitive hypertension will be achieved upon completion of this review.

Associação entre perfil glicêmico materno e o índice de líquido amniótico em gestações complicadas pelo Diabetes mellituspré-gestacional

to study the relation between amniotic fluid volume and glycemic control in pregnancies complicated by diabetes mellitus type 1 and 2, followed in a specialized multidisciplinary prenatal care service. This descriptive study was performed between January 2001 and December 2004. Inclusion criteria were: simple pregnancy, diagnosis of pregestational diabetes, beginning of prenatal care before the 26th week and absence of fetal anomaly. Cases with newborns small for gestational age were excluded. The amniotic fluid index (AFI) was measured weekly, beginning at the 27th week of gestation and continued until delivery and the maternal glycemic profile was obtained a week before ultrasound assessment. This profile consisted of the glycemic level averages and percentages of the abnormal high values. Correlation between the glycemic profile and the AFI was shown by the Spearman correlation test. Sixty pregnant women were assessed and 659 correlations between the AFI and glycemic profile were obtained. No correlation was observed in any of the gestational weeks studied. The mean glycemic value was 103.69 mg/dl (SD=13.69) in the group with AFI pound18 cm, and the 103.67 mg/dl (SD=11.46) in the group with AFI < 18 cm and no significant difference was detected. This study showed no correlation between AFI and maternal glycemic profile during the third trimester in type 1 and 2 diabetic pregnant women, undergoing standardized treatment and rigorous metabolic control.

Functional Domains of Aquaporin-1: Keys to Physiology, and Targets for Drug Discovery

Aquaporins (AQPs) are expressed in physiologically essential tissues and organs in which edema and fluid imbalances are of major concern. Potential roles in brain water homeostasis and edema, angiogenesis, cell migration, development, neuropathological diseases, and cancer suggest that this family of membrane proteins is an attractive set of novel drug targets. A problem in pursuing therapeutic and basic research strategies for dissecting contributions of AQPs to cell and tissue functions is that little is known regarding the pharmacology of AQP channels; currently defined agents such as tetraethylammonium and phloretin as blockers for aquaporins suffer from a lack of specificity and potency. Subtypes of AQPs modulated by signaling pathways could enable discrete localized control of fluid homeostasis, volume and morphology in cells and intracellular organelles, and might be found to participate in many different aspects of physiology, such as the control of paracellular permeability, process extension, growth, migration, and other responses involving changes in cell shape or surface to volume ratios. Recognizing that AQP1 is a water channel and, under permissive conditions, also a cGMP-gated cation channel, evidence in various tissues for a coupling of the cGMP signaling cascade to a physiological outcome that might involve AQP1 dual ion-and-water channel functions is of interest. Groundbreaking advances in defining aquaporin gating mechanisms suggest conformational changes are important elements in regulation and gating across classes of aquaporins. With a rapidly expanding knowledge of aquaporin structure and functional regulation, new avenues for manipulation of aquaporin channels are likely to be discovered. In parallel, a discovery for novel compounds with specificity and potency for aquaporins is a compelling goal. The need for pharmacological agents to dissect the roles of aquaporins in physiological and pathological processes is a clear call for further research in the field.