Inhibitory effects of AMP 579, a novel cardioprotective adenosine A1/A2A receptor agonist, on native IKr and cloned HERG current.
We investigated the effects of 1S-[1a,2b,3b,4a(S*)]-4-[7-[[1-[(3-chloro-2-thienyl)methylpropyl]propyl-amino]-3H-imidazo[4,5-b] pyridyl-3-yl]-N-ethyl-2,3-dihydroxycyclopentane carboxamide (AMP 579), a novel cardioprotective adenosine A(1)/A(2A) receptor agonist, on the rapid and slow components of the delayed rectifier K(+) current (I(Kr) and I(Ks)) in guinea-pig ventricular myocytes and on the human ether-a-go-go-related gene (HERG) channel expressed in human embryonic kidney (HEK 293) cells. Whole-cell current and membrane potential were recorded using patch-clamp techniques. In guinea-pig ventricular myocytes, AMP 579 inhibited I(Kr) in a concentration-dependent manner with IC(50) value of 15.2 microM, when I(Kr) was blocked by chromanol 293B. On the contrary, AMP 579 (10 microM) did not affect I(Ks) in the presence of the I(Kr) blocker E-4031. The former effect of AMP 579 was unaffected by either the selective adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine or the non-selective adenosine A(1)/A(2) receptor antagonist 8-sulphophenyltheophylline. Moreover, AMP 579-induced inhibition of I(Kr) was not voltage- and frequency-dependent. In HEK 293 cells expressing HERG channels, AMP 579 (10 microM) significantly blocked the HERG current at +10 mV by 34.9+/-7.0% (n=4, p<0.05), and the degree of inhibition was comparable with that observed in guinea-pig ventricular myocytes (36.8+/-6.0%, n=4). AMP 579 (10 microM) significantly inhibited the L-type Ca(2+) current (I(Ca)) by 41.0+/-6.8% (n=5, p<0.05), which was unaffected by 8-sulphophenyl-theophylline. Consequently, despite its inhibitory actions on I(Kr) or HERG current, the drug significantly shortened the action potential duration measured at 90% repolarization from 275.6+/-19.4 to 208.3+/-18.6 ms (n=4, p<0.05). Thus, AMP 579 inhibits both native I(Kr) and cloned HERG channels with additional inhibitory effect of I(Ca), and such inhibitory effects may at least partially underlie the observed antifibrillatory action of the drug during myocardial ischemia/reperfusion.
Saegusa
Noriko
N
Department of Pharmacology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan. tsato@faculty.chiba-u.jp
Sato
Toshiaki
T
Ogura
Takehiko
T
Komuro
Issei
I
Nakaya
Haruaki
H
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D003001:Cloning, Molecular; D051638:Ether-A-Go-Go Potassium Channels; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000502:physiology; D043705:Receptor, Adenosine A2A / Q000502:physiology
C113971:4-(7-((2-3-chloro-2-thienyl)-1-methyl-propylamino)-3H-imidazo(4,5-b)pyridyl-3-yl)cyclopentane carboxamide; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D002316:Cardiotonic Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A