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Verapamil reduces transepithelial sodium and potassium transport in H441 monolayers
Author(s) -
Han Dongyun,
Nie Hongguang,
Gu Xiu,
Ji Honglong
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.1023.2
Subject(s) - verapamil , amiloride , glibenclamide , chemistry , pharmacology , endocrinology , medicine , sodium , calcium , organic chemistry , diabetes mellitus
Verapamil‐induced noncardiogenic pulmonary edema is a common clinical disorder, the pathogenetic mechanisms remain unknown. In this study, we investigated the effects of verapamil on transepithelial short‐circuit currents (Isc) in confluent H441 monolayers and alveolar fluid clearance in vivo . Intratracheal administration of verapamil (100 μM) reduced alveolar fluid clearance by 41 ± 6% (P<0.05, n=4). The Ussing chamber studies showed that apical application of verapamil reduced amiloride‐sensitive Isc in a dose‐dependent manner (K i =26 μM). This inhibitory effect was also observed when 100 μM verapamil was added to the basolateral side of intact monolayers (from 20 ± 4 to 12 ± 2 μA/cm 2 , P<0.05, n=4). Further studies showed the direct inhibitory effects on transapical (from 41 ± 1 to 28 ± 3 μA/cm 2 , P<0.05, n=4) and transbasolateral Isc (61 ± 1 to 52 ± 2 μA/cm 2 , P<0.05, n=4) in permeabilized monolayers. The inhibitors of Kv (clofilium), K Ca (clotrimazole), and K ATP (glibenclamide) channels decreased amiloride‐sensitive Isc levels by 54 ± 5%, 32 ± 5%, and 21 ± 1%, respectively (P<0.05, n=4). In the presence of these K + channel inhibitors, verapamil‐inhibitable Isc fraction was significantly decreased. Importantly, the openers for Kv (pyrithione), K Ca (1‐EBIO), and K ATP channels (minoxidil) recovered verapamil‐induced decrease in Isc. Taken together, our results for the first time demonstrate that inhibition of K + channels may be a critical mechanism for the pathogenesis of verapamil‐induced lung edema.