P2Y2 receptor agonists, like UTP and ATP, stimulate mucin secretion from goblet cells in vitro. Therefore, mucin stimulants could be good candidates for the treatment of dry eye syndrome because mucin increases the tear film stability and protects against desiccation of ocular surface. INS365 is a more stable P2Y2 receptor agonist than UTP. In the present study, we evaluated, in normal rabbit eyes, its effectiveness to release mucin from goblet cells and to protect the corneal damage induced by desiccation. For mucin secretion, impression cytology was performed following the instillation of INS365 solution or saline into the conjunctival sac. The specimens were stained with periodic acid and Schiff (PAS) reagent, and then the staining area was calculated using computer software. INS365 dose-dependently decreased the PAS staining area of conjunctival goblet cells from 2 to 15 min post-application. Furthermore, we utilized the rabbit short-term dry eye model to evaluate if INS365 eyedrops could protect against any of the damage produced by blockage of blinking with ocular speculum. INS365 significantly suppressed corneal damage at concentrations of more than 0.1% w/v. These results suggest that this P2Y2 agonist is a good candidate for the treatment of dry eye disease.
The purpose of the present study was to understand the mechanisms of action of diquafosol, a stable derivative of uridine 5′-triphosphate, on Cl– transport across the isolated rabbit conjunctiva. Rabbit conjunctivas were isolated and mounted in a modified Ussing chamber. Under short-circuit conditions, the effects were determined of mucosal (tear) side diquafosol application on the short-circuit current (Isc). Diquafosol rapidly and dose-dependently increased the Isc at concentrations ranging from 0.1 to 968 µM when added to the mucosal side of the conjunctiva. In the absence of the serosal Cl–, the Isc induced by 10 µM diquafosol was substantially reduced. On the contrary, in the absence of mucosal side Na+, the diquafosol-induced increases in Isc were unchanged. Following 45-min preincubation, the P2Y2 antagonist suramin inhibited the diquafosol-induced increases in the Isc whereas the P2Y1 antagonist pyridoxal-phosphate-6-azophenyl-2′4′-disulfonic acid had no effect. These studies suggest that diquafosol stimulates net Cl– secretion from the serosal to the mucosal side via stimulation of P2Y2 receptors in the rabbit conjunctiva.
These data indicate that activation of P2Y(2) receptor increases tear fluid secretion accompanied with some proteins in normal rabbits. The purinergic agonists, UTP and ATP, have potential therapeutic value in the treatment of dry eye.
BackgroundIn this study, we sought to investigate the 2‐year prognostic impact of B‐type natriuretic peptide (BNP) levels at discharge, following transcatheter aortic valve replacement.Methods and ResultsWe enrolled 1094 consecutive patients who underwent transcatheter aortic valve replacement between 2013 and 2016. Study patients were stratified into 2 groups according to survival classification and regression tree analysis (high versus low BNP groups). We evaluated the impact of high BNP on 2‐year mortality compared with that of low BNP using a multivariable Cox model, and assessed whether this stratification would improve predictive accuracy for determining 2‐year mortality by assessing time‐dependent net reclassification improvement and integrated discrimination improvement. The median age of patients was 85 years (quartile 82–88), and 29.2% of the study population were men. The median Society of Thoracic Surgeons score was 6.8 (4.7–9.5), and BNP at discharge was 186 (93–378) pg/mL. All‐cause mortality following discharge was 7.9% (95% CI, 5.8–9.9%) at 1 year and 15.4% (95% CI, 11.6–19.0%) at 2 years. The survival classification and regression tree analysis revealed that the discriminating BNP level to discern 2‐year mortality was 202 pg/mL, and that elevated BNP had a statistically significant impact on outcomes, with an adjusted hazard ratio of 2.28 (1.36–3.82, P=0.002). The time‐dependent net reclassification improvement (P=0.047) and integrated discrimination improvement (P=0.029) analysis revealed that the incorporation of BNP stratification with other clinical variables significantly improved predictive accuracy for 2‐year mortality.ConclusionsElevation of BNP at discharge is associated with 2‐year mortality after transcatheter aortic valve replacement.
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