pH-dependent blocking actions of three novel antiarrhythmic compounds on K+ and Na+ currents in rat ventricular...

Three novel chemically related compounds were studied for their pH-dependent ion channel blocking actions on the transient outward K+ current (I(to)) and the Na+ current (I(Na)) in isolated rat ventricular myocytes. The (+/-)-trans-napthylethoxycyclohexylamines, RSD1108, RSD1070 and RSD1067, showed similar potencies in reducing the inactivation time course of I(to) at pH 7.4. However, RSD1108 (pK(a) 6.8) was a more potent blocker of I(to) at pH 6.4 than the other two compounds (pK(a) values near 8.0). The reduction of inactivation times induced by the RSD compounds was consistent with open channel blockade and in consequence an open channel block model was used in order to estimate blocking and unblocking rate constants. This analysis showed no apparent correlation between pK(a) and onward blocking rate constants for the compounds. However, the unblocking rate constant for the low pK(a) compound RSD1108 at acid pH decreased markedly from that found at normal pH. Both RSD1108 and RSD1070 showed an enhanced potency to block I(Na) at acid pH relative to pH 7.4. However, RSD1108 showed significantly less inhibition of I(Na) at both pH values compared to RSD1070 and RSD1067. Differences in channel block were also evident between RSD1070 and RSD1067, which could be attributed to the difference in napthyl groups between their chemical structures. The compounds exhibited use- and frequency-dependent blockade of I(Na) with the amount of use-dependent blockade greater for RSD1108 and RSD1067 than for RSD1070 at acid pH compared to neutral pH. Greater frequency-dependent inhibition was apparent for RSD1108 as compared to RSD1070 and RSD1067 at both pH 7.4 and 6.4. These results point out the importance of the magnitude of pK(a) and chemical structure in ion channel blocking actions of a series of structurally related compounds.