Characterization of SN-6, a novel Na+/Ca2+ exchange inhibitor in guinea pig cardiac ventricular myocytes.
We examined the effect of SN-6, a new benzyloxyphenyl Na(+)/Ca(2+) exchange (NCX) inhibitor on the Na(+)/Ca(2+) exchange current (I(NCX)) and other membrane currents in isolated guinea pig ventricular myocytes using the whole-cell voltage-clamp technique. SN-6 suppressed I(NCX) in a concentration-dependent manner. The IC(50) values of SN-6 were 2.3 microM and 1.9 microM for the outward and inward components of the bi-directional I(NCX), respectively. On the other hand, SN-6 suppressed the outward uni-directional I(NCX) more potently (IC(50) value of 0.6 microM) than the inward uni-directional I(NCX). SN-6 at 10 microM inhibited the uni-directional inward I(NCX) by only 22.4+/-3.1%. SN-6 and KB-R7943 suppressed I(NCX) more potently when intracellular Na(+) concentration was higher. Thus, both drugs inhibit NCX in an intracellular Na(+) concentration-dependent manner. Intracellular application of trypsin via a pipette solution did not change the blocking effect of SN-6 on I(NCX). Therefore, SN-6 is categorized as an intracellular-trypsin-insensitive NCX inhibitor. SN-6 at 10 microM inhibited I(Na), I(Ca), I(K) and I(K1) by about 13%, 34%, 33% and 13%, respectively. SN-6 at 10 microM shortened the action potential duration at 50% repolarization (APD(50)) by about 34%, and that at 90% repolarization (APD(90)) by about 25%. These results indicate that SN-6 inhibits NCX in a similar manner to that of KB-R7943. However, SN-6 at 10 microM affected other membrane currents less potently than KB-R7943.
Niu
Chun-Feng
CF
Department of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
Watanabe
Yasuhide
Y
Ono
Kyoichi
K
Iwamoto
Takahiro
T
Yamashita
Kanna
K
Satoh
Hiroshi
H
Urushida
Tuyoshi
T
Hayashi
Hideharu
H
Kimura
Junko
J
D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology; D001593:Benzyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D017136:Ion Transport / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000502:physiology; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; C487681:2-(4-(4-nitrobenzyloxy)benzyl)thiazolidine-4-carboxylic acid ethyl ester; D000889:Anti-Arrhythmia Agents; D001593:Benzyl Compounds; D019831:Sodium-Calcium Exchanger; D053778:Thiazolidines; C004717:diacetylmonoxime; D012964:Sodium; D014357:Trypsin; D013890:Thiourea; D003931:Diacetyl; D002118:Calcium