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

Three novel chemically related compounds were studied for their pH-dependen t ion channel blocking actions on the transient outward K+ current (I-to) a nd the Na+ current (I-Na) in isolated rat ventricular myocytes. The (+/-)-t rans-napthylethoxycyclohexylamines., RSD1108. RSD1070 and RSD1067, showed s imilar 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 in activation times induced by the RSD compounds was consistent with open chan nel blockade and in consequence an open channel block model was used in ord er to estimate blocking and unblocking rate constants. This analysis showed no apparent correlation between pK(a) and onward blocking rate constants f or the compounds. However, the unblocking rate constant for the low pK(a) c ompound 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 inhibitio n 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 b e attributed to the difference in napthyl groups between their chemical str uctures. The compounds exhibited use- and frequency-dependent blockade of I -Na with the amount of use-dependent blockade greater for RSD1108 and RSD10 67 than for RSD1070 at acid pH compared to neutral pH. Greater frequency-de pendent inhibition was apparent for RSD1108 as compared to RSD1070 and RSD1 067 at both pH 7.4 and 6.4. These results point out the importance of the m agnitude of pK(a) and chemical structure in ion channel blocking actions of a series of structurally related compounds. (C) 2001 Elsevier Science B.V. All rights reserved.