COMPARISON OF BINDING TO RAPIDLY ACTIVATING DELAYED RECTIFIER K-KR, AND EFFECTS ON MYOCARDIAL REFRACTORINESS FOR CLASS-III ANTIARRHYTHMIC AGENTS( CHANNEL, I)
Jj. Lynch et al., COMPARISON OF BINDING TO RAPIDLY ACTIVATING DELAYED RECTIFIER K-KR, AND EFFECTS ON MYOCARDIAL REFRACTORINESS FOR CLASS-III ANTIARRHYTHMIC AGENTS( CHANNEL, I), Journal of cardiovascular pharmacology, 25(2), 1995, pp. 336-340
Saturation binding studies in guinea pig ventricular myocytes with H-3
-dofetilide, a radioligand for the cardiac rapidly activating delayed
rectifier K+ I-Kr channel, indicated specific high-affinity binding wi
th a K-d of 83 nM and a B-max of 0.18 pmol/mg cellular protein (1.36 x
10(6) sites/cell). Using displacement of high-affinity H-3-dofetilide
binding as a measure of interaction with the I-Kr channel, potencies
(K-i values) for binding to the I-Kr channel in guinea pig myocytes fo
r six class III antiarrhythmic agents were characterized and compared
to indices of functional electrophysiologic activity in isolated guine
a pig papillary muscles [EC(25) values, concentration required to incr
ease effective refractory period (ERP) 25% above baseline]. Dofetilide
, E-4031, sematilide, and d-sotalol, which have been characterized pre
viously as selective I-Kr blockers, displayed good agreement between K
-i values for displacement of H-3-dofetilide binding (47 +/- 7 nM, 38
+/- 8 nM, 12 +/- 5 mu M, and similar to 100 mu M, respectively) and EC
(25) values for increasing ERP in papillary muscles (45.0 nM, 76.9 nM,
20.2 mu M and 63.5 mu M, respectively). Ibutilide and RP58866, which
have been reported to act via mechanisms other than I-Kr block, had K-
i values for displacement of H-3-dofetilide binding (16 +/- 7 nM and 1
7 +/- 2 nM, respectively) that were similar to 10-fold lower than EC(2
5) values for increasing ERP in papillary muscles (185.8 nM and 223.5
nM, respectively). The potent displacement of high-affinity H-3-dofeti
lide binding by ibutilide and RP58866 strongly suggest a role for inte
raction with I-Kr in their actions. The discrepant functional activiti
es of these agents, however, suggest a combination of effects beyond t
hose on I-Kr and implicate modulation of Na+ or other K+ current subty
pes.