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001-es BibID:BIBFORM096191
035-os BibID:(cikkazonosító)9499 (scopus)85114049778 (wos)000694373200001
Első szerző:Dienes Csaba (gyógyszerész)
Cím:Electrophysiological Effects of the Transient Receptor Potential Melastatin 4 Channel Inhibitor (4-Chloro-2-(2-chlorophenoxy)acetamido) Benzoic Acid (CBA) in Canine Left Ventricular Cardiomyocytes / Csaba Dienes, Tamás Hézső, Dénes Zsolt Kiss, Dóra Baranyai, Zsigmond Máté Kovács, László Szabó, János Magyar, Tamás Bányász, Péter P. Nánási, Balázs Horváth, Mónika Gönczi, Norbert Szentandrássy
Dátum:2021
ISSN:1661-6596 1422-0067
Megjegyzések:Transient receptor potential melastatin 4 (TRPM4) plays an important role in many tissues, including pacemaker and conductive tissues of the heart, but much less is known about its electrophysiological role in ventricular myocytes. Our earlier results showed the lack of selectivity of 9-phenanthrol, so CBA ((4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) was chosen as a new, potentially selective inhibitor. Goal: Our aim was to elucidate the effect and selectivity of CBA in canine left ventricular cardiomyocytes and to study the expression of TRPM4 in the canine heart. Experiments were carried out in enzymatically isolated canine left ventricular cardiomyocytes. Ionic currents were recorded with an action potential (AP) voltage-clamp technique in whole-cell configuration at 37 ?C. An amount of 10 mM BAPTA was used in the pipette solution to exclude the potential activation of TRPM4 channels. AP was recorded with conventional sharp microelectrodes. CBA was used in 10 ?M concentrations. Expression of TRPM4 protein in the heart was studied by Western blot. TRPM4 protein was expressed in the wall of all four chambers of the canine heart as well as in samples prepared from isolated left ventricular cells. CBA induced an approximately 9% reduction in AP duration measured at 75 and 90% of repolarization and decreased the short-term variability of APD90. Moreover, AP amplitude was increased and the maximal rates of phase 0 and 1 were reduced by the drug. In AP clamp measurements, CBA-sensitive current contained a short, early outward and mainly a long, inward current. Transient outward potassium current (Ito) and late sodium current (INa,L) were reduced by approximately 20 and 47%, respectively, in the presence of CBA, while L-type calcium and inward rectifier potassium currents were not affected. These effects of CBA were largely reversible upon washout. Based on our results, the CBA induced reduction of phase-1 slope and the slight increase of AP amplitude could have been due to the inhibition of Ito. The tendency for AP shortening can be explained by the inhibition of inward currents seen in AP-clamp recordings during the plateau phase. This inward current reduced by CBA is possibly INa,L, therefore, CBA is not entirely selective for TRPM4 channels. As a consequence, similarly to 9-phenanthrol, it cannot be used to test the contribution of TRPM4 channels to cardiac electrophysiology in ventricular cells, or at least caution must be applied.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
CBA
TRPM4
cardiac ionic currents
cardiac action potentials
canine myocytes
action potential voltage clamp
Megjelenés:International Journal Of Molecular Sciences. - 22 : 17 (2021), p. 9499. -
További szerzők:Hézső Tamás (1993-) (élettanász) Kiss Dénes Zsolt (1995-) (orvos, élettanász) Baranyai Dóra Kovács Zsigmond Máté (1995-) (orvos) Szabó László (1994-) (molekuláris biológus) Magyar János (1961-) (élettanász) Bányász Tamás (1960-) (élettanász) Nánási Péter Pál (1956-) (élettanász) Horváth Balázs (1981-) (élettanász) Gönczi Mónika (1974-) (élettanász) Szentandrássy Norbert (1976-) (élettanász)
Pályázati támogatás:NKFIH-K115397
Egyéb
NKFIH-K138090
Egyéb
NKFIH-FK128116
Egyéb
GINOP-2.3.2-15-2016-00040
GINOP
EFOP-3.6.2-16-2017-00006
EFOP
DE-SPACE(TKP-2020-NKA-04)
Egyéb
EFOP-3.6.3-VEKOP-16-2017-00009
EFOP
ÚNKP-20-3
Egyéb
ÚNKP-20-2
Egyéb
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