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.