Abstract. NIP-142 is a novel benzopyran compound that was shown to prolong the atrial effective refractory period and terminate experimental atrial fibrillation in the dog. In the present study, we examined the effects of NIP-142 on isolated guinea pig myocardium and on the Gprotein-coupled inwardly rectifying potassium channel current (acetylcholine-activated potassium current; I KACh ) expressed in Xenopus oocytes. NIP-142 (10 and 100 µM) concentration-dependently prolonged the refractory period and action potential duration in the atrium but not in the ventricle. E-4031 and 4-aminopyridine prolonged action potential duration in both left atrium and right ventricle. Prolongation by NIP-142 of the atrial action potential duration was observed at stimulation frequencies between 0.5 and 5 Hz. In contrast, the prolongation by E-4031 was not observed at higher frequencies. Tertiapin, a blocker of I KACh , prolonged action potential duration in the atrium but not in the ventricle. NIP-142 completely reversed the carbachol-induced shortening of atrial action potential duration. NIP-142 (1 to 100 µM), as well as tertiapin (0.1 to 100 nM), concentration-dependently blocked I KACh expressed in Xenopus oocytes; the blockade by NIP-142 was not affected by membrane voltage. In conclusion, NIP-142 was shown to prolong atrial refractory period and action potential duration through blockade of I KACh which may possiblly explain its previously described antiarrhythic activity. NIP-142 has pharmacological properties that are different from classical class III antiarrhythmic agents such as atria specificity and lack of reverse frequency dependence, and thus appears promising for the treatment of supraventricular arrhythmia.
Prostaglandin analogues have the potential to inhibit adipogenesis through FP receptor stimulation. Although these findings should be further analyzed in model systems more closely related to orbital fat, PG analogues may directly lead to reduced orbital fat by inhibiting adipogenesis.
to examine whether autotaxin (AtX) in the aqueous humor causes elevated intraocular pressure (iop) in patients with posner-Schlossman syndrome (pSS). AtX and transforming growth factor beta (tGf-β) in the aqueous humor were quantified in PSS patients. The expression of ATX and TGF-β in cytomegalovirus (cMV)-infected-human trabecular meshwork (htM) cells was examined. Biological changes in htM cells and monkey Schlemm's canal endothelial (Sce) cells cultured in the conditioned medium of cMV-infected htM cells were analyzed. the expression of AtX and tGf-β1 was upregulated in the aqueous humor of cMV-positive pSS patients, and the level of AtX in the aqueous humor was positively correlated with iop. cMV infection upregulated AtX and tGf-β1 in hTM cells. The conditioned medium induced fibrotic changes in hTM cells and reduced SCE permeability, which was attenuated by an AtX inhibitor, a lysophosphatidic acid receptor antagonist, and a Rho kinase inhibitor. AtX in the aqueous humor induced by cMV infection may trigger elevated iop. Modulating AtX activity may be a novel treatment modality for pSS.
The trabecular meshwork (TM) constitutes the main pathway for aqueous humor drainage and is exposed to complex intraocular pressure fluctuations. The mechanism of homeostasis in which TM senses changes in intraocular pressure and leads to normal levels of outflow resistance is not yet well understood. Previous reports have shown that Piezo1, a mechanically-activated cation channel, is expressed in TM and isolated TM cells. Therefore, we tested hypothesis that Piezo1 may function in response to membrane tension and stretch in TM. In human trabecular meshwork (hTM) cells, PIEZO1 was showed to be abundantly expressed, and Piezo1 agonist Yoda1 and mechanical stretch caused a Piezo1-dependent Ca2+ influx and release of arachidonic acid and PGE2. Treatment with Yoda1 or PGE2 significantly inhibited hTM cell contraction. These results suggest that mechanical stretch stimuli in TM activates Piezo1 and subsequently regulates TM cell contraction by triggering Ca2+ influx and release of arachidonic acid and PGE2. Thus, Piezo1 could acts as a regulator of intraocular pressure (IOP) within the conventional outflow pathway and could be a novel therapeutic strategy to modulate IOP in glaucoma patients.
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