Clinical Research - Osmolality
Hyperosmolal vaginal lubricants markedly reduce epithelial barrier properties in a three-dimensional vaginal epithelium model.
Seyoum Ayehuniea, Ying-YingWang, Timothy Landry, Stephanie Bogojevic, and Richard A. Cone. Toxicology Reports (2018).
The osmolality of healthy vaginal fluid is 370 ± 40 mOsm/Kg in women with Nugent scores 0–3, and that a well-characterized three-dimensional human vaginal epithelium tissue model demonstrated that vaginal lubricants with osmolality greater than 4 times that of vaginal fluid (>1500 mOsm/Kg) markedly reduce epithelial barrier properties and showed damage in tissue structure. Four out of four such lubricants caused disruption in the parabasal and basal layers of cells as observed by histological analysis and reduced barrier integrity as measured by trans-epithelial electrical resistance (TEER). No epithelial damage to these layers was observed for hypo- and iso-osmolal lubricants with osmolality of <400 mOsm/Kg. The results confirm extensive reports of safety concerns of hyperosmolal lubricants.
Mucosal irritation potential of personal lubricants relates to product osmolality as detected by the slug mucosal irritation assay.
Els Adriaens and Jean Paul Remon. Journal of the American Sexually Transmitted Diseases Association (2008).
Five commercial lubricants with an osmolality range were evaluated using the previously validated slug mucosal irritation assay. Specifically, arion lusitanicus were treated with lubricants over 5 days to quantify mucus production and tissue damage, allowing assignment of each product into an irritation potency category (none, mild, moderate, or severe). Commonly used personal lubricants show a full range of mucosal irritation potential, which is related to product osmolality, with iso-osmotic lubrication products causing no change in vaginal mucous production or irritation.
Treating vulvovaginal atrophy/genitourinary syndrome of menopause: how important is vaginal lubricant and moisturizer composition?
D. Edwards and N. Panay. Climacteric (2015).
Personal lubricants and moisturizers are effective treatment options in the management of vaginal dryness with a variety of causes. However, differences exist between commercially available products. Given that non-physiological pH and osmolality, and the presence of excipients such as parabens and microbicides, are associated with a variety of proven or potential detrimental effects, the recommended safe values for pH and osmolality should be carefully ensured when choosing or prescribing a personal lubricant. This provides a stimulus for both regulatory authorities and manufacturers to work together in reformulating preparations to be more patient-friendly.
Global Consultation on Personal Lubricants
Lubricants are widely used for sexual intercourse by men, women, and transgender individuals around the world. Some reports suggest that personal lubricant used for rectal sex by men who have sex with men (MSM) is greater than 90% among MSM communities in the USA. Used in combination with condoms, personal lubricants help to reduce friction, improve comfort, and may help to reduce breakage in some situations, providing greater protection against unintended pregnancy, HIV, and other STIs. However, there are concerns about the safety of these products, as research has shown users are experiencing irritation, burning, and damaging effects to vaginal and rectal tissue. The Global Consultation on Personal Lubricants, held 8–10 November 2016 in Bangkok, Thailand, was convened to study these issues and examine ways to produce, procure, and distribute safer products for all. Hosted by the United Nations Population Fund (UNFPA), the United States Agency for International Development (USAID), the World Health Organization (WHO), and the International Planned Parenthood Federation (IPPF), the meeting brought together more than 80 manufacturers, researchers and technical experts, sexual health advocates and educators, and international organizations that procure lubricants for governments or local organizations.
The Na/K pump, CI ion, and osmotic stabilization of cells
Clay M. Armstrong. Proceedings of the National Academy of Sciences of the United States of America (2003).
An equation for membrane voltage is derived that takes into account the electrogenicity of the Na/K pump and is valid dynamically, as well as in the steady state. This equation is incorporated into a model for the osmotic stabilization of cells. The results emphasize the role of the pump and membrane voltage in lowering internal Cl− concentration, thus making osmotic room for vital substances that must be sequestered in the cell.
The Structure and Function of the Na, K-ATPase Isoforms in Health and Disease
Michael V. Clausen, Florian Hilbers, and Hanne Poulsen. Frontiers in Physiology (2017).
The sodium and potassium gradients across the plasma membrane are used by animal cells for numerous processes, and the range of demands requires that the responsible ion pump, the Na,K-ATPase, can be fine-tuned to the different cellular needs. Therefore, several isoforms are expressed of each of the three subunits that make a Na,K-ATPase, the alpha, beta and FXYD subunits. This review summarizes the various roles and expression patterns of the Na,K-ATPase subunit isoforms and maps the sequence variations to compare the differences structurally. Mutations in the Na,K-ATPase genes encoding alpha subunit isoforms have severe physiological consequences, causing very distinct, often neurological diseases. The differences in the pathophysiological effects of mutations further underline how the kinetic parameters, regulation and proteomic interactions of the Na,K-ATPase isoforms are optimized for the individual cellular needs.
Excitation of skeletal muscle is a self-limiting process, due to run-down of Na+, K+ gradients, recoverable by stimulation of the Na+, K+ pumps
Torben Clausen. Physiological Reports (2015).
The general working hypothesis of this study was that muscle fatigue and force recovery depend on passive and active fluxes of Na+ and K+. This is tested by examining the time‐course of excitation‐induced fluxes of Na+ and K+ during 5–300 sec of 10–60 Hz continuous electrical stimulation in rat extensor digitorum longus (EDL) muscles in vitro and in vivo using 22Na and flame photometric determination of Na+ and K+. 60 sec of 60 Hz stimulation rapidly increases 22Na influx, during the initial phase (0–15 sec) by 0.53 μmol(sec)−1(g wet wt.)−1, sixfold faster than in the later phase (15–60 sec). These values agree with flame photometric measurements of Na+ content. The progressive reduction in the rate of excitation‐induced Na+ uptake is likely to reflect gradual loss of excitability due to accumulation of K+ in the extracellular space and t‐tubules leading to depolarization. This is in keeping with the concomitant progressive loss of contractile force previously demonstrated. During electrical stimulation rat muscles rapidly reach high rates of active Na+, K+‐transport (in EDL muscles a sevenfold increase and in soleus muscles a 22‐fold increase), allowing efficient and selective compensation for the large excitation‐induced passive Na+, K+‐fluxes demonstrated over the latest decades. The excitation‐induced changes in passive fluxes of Na+ and K+ are both clearly larger than previously observed. The excitation‐induced reduction in [Na+]o contributes considerably to the inhibitory effect of elevated [K+]o. In conclusion, excitation‐induced passive and active Na+ and K+ fluxes are important causes of muscle fatigue and force recovery, respectively.
Sodium pump current measured in cardia ventricular myocytes isolated from control and potassium depleted rabbits
Michael J. Shattock, Hiroshi Matsuura, and Jeremy P.T. Ward. Cardiovascular Research (1994).
Objective: The aim was to investigate cardiac muscle sodium pump function following chronic potassium depletion in rabbits. Methods: Sodium pump current was measured using the whole cell voltage clamp technique in ventricular myocytes from control rabbits or rabbits with chronic dietary potassium depletion, under conditions designed to minimise all other electrogenic channels, pumps, and exchangers. The effects of changes in external [K+] and intracellular [Na+] were investigated. Experiments were performed on ventricular myocytes enzymatically isolated from adult rabbits, average weight 2.5 kg, which were fed either a control (n = 6), or a potassium deficient diet (n = 8) for 25 d. Results: Potassium depletion significantly increased the sodium pump current density recorded with 10 mM extracellular [K+] and 50 mM [Na+] in the pipette (conditions which activate an estimated 98% of the maximally available pump current), from 1.53(SEM 0.05) pA·pF−1 (control, n = 4) to 1.74(0.06) pA·pF−1 (potassium depleted, n = 4; p < 0.05). The relationship between sodium pump current and extracellular [K+] (30 mM [Na+] in pipette) showed a significant leftward shift in myocytes from potassium depleted animals, such that the Km was reduced from 1.27(0.10) (control, n = 4) to 0.72(0.11) mM (potassium depleted, n = 4; p<0.05). The effect of varying pipette [Na+] on sodium pump current was examined in cells supervised with 5 mM [K+]. The Km was again reduced from 19.44 mM (control) to 16.91 mM (potassium depleted). The Hill coefficients for activation of the pump by potassium and sodium were essentially unchanged, as was the shape of the current-voltage relationship. Conclusions: These results suggest that chronic potassium depletion results in an adaptation of the cardiac sodium pump such that pump activity can be maintained, or even enhanced, despite a fall in plasma [K+]. This adaptation is achieved by both alterations in ionic sensitivity to potassium and sodium, and an increase in maximum activity. The latter may reflect an increase in sodium pump site density. These changes are likely to account for the preservation of intracellular [K+] in cardiac muscle during chronic potassium deficiency.
Gene Level Regualtion of Na, K-ATPase in the Renal Proximal Tubule Is Controlled by Two Independent but Interactig Regulatory Mechanisms Involving Salt Inducible Kinase 1 and CREB-Regulated Transcriptional Coactivators
Mary Taub. International Journal of Molecular Sciences (2018).
For many years, studies concerning the regulation of Na,K-ATPase were restricted to acute regulatory mechanisms, which affected the phosphorylation of Na,K-ATPase, and thus its retention on the plasma membrane. However, in recent years, this focus has changed. Na,K-ATPase has been established as a signal transducer, which becomes part of a signaling complex as a consequence of ouabain binding. Na,K-ATPase within this signaling complex is localized in caveolae, where Na,K-ATPase has also been observed to regulate Inositol 1,4,5-Trisphosphate Receptor (IP3R)-mediated calcium release. This latter association has been implicated as playing a role in signaling by G Protein Coupled Receptors (GPCRs). Here, the consequences of signaling by renal effectors that act via such GPCRs are reviewed, including their regulatory effects on Na,K-ATPase gene expression in the renal proximal tubule (RPT). Two major types of gene regulation entail signaling by Salt Inducible Kinase 1 (SIK1). On one hand, SIK1 acts so as to block signaling via cAMP Response Element (CRE) Binding Protein (CREB) Regulated Transcriptional Coactivators (CRTCs) and on the other hand, SIK1 acts so as to stimulate signaling via the Myocyte Enhancer Factor 2 (MEF2)/nuclear factor of activated T cell (NFAT) regulated genes. Ultimate consequences of these pathways include regulatory effects which alter the rate of transcription of the Na,K-ATPase β1 subunit gene atp1b1 by CREB, as well as by MEF2/NFAT