Stereoselective block of cardiac sodium channels by RAC109 in single guinea pig ventricular myocytes.

Abstract

The effects of the optical stereoisomers of the local anesthetic RAC109 (RAC109-I and RAC109-II) on sodium current in isolated guinea pig ventricular myocytes were investigated by use of the whole-cell variation of the patch-clamp technique. RAC109-I and RAC109-1I produced similar levels of tonic block, but RAC109-I produced a significantly larger usedependent block on repetitive pulsing to potentials positive to -60 mV. Definition of the time courses of block development at -20 mV and recovery at -140 and -160 mV indicated that RAC109-I had a higher affinity for activated and inactivated channels and dissociated more slowly at hyperpolarized potentials compared with RAC109-II. Removal of fast inactivation by a>-chymotrypsln intensified tonic block but did not reduce use-dependent block by RAC109-I; this finding suggests that channel inactivation is not necessary for use-dependent block. The guarded-receptor model was used to calculate apparent rate constants of drug binding and unbinding. According to the model, RAC109-I and RAC109-II have significantly different unbinding rate constants for channels when they exist predominantly in rested, activated, or inactivated states, as well as significantly different binding rate constants when channels are activated. However, the apparent rates of drug binding to closed (rested and inactivated) channels are not significantly different for the two isomers; this finding indicates that drug binding to dosed channels is not markedly stereospecific, in contrast to unbinding. The effects of RAC109 stereoisomers on cardiac sodium channels were also qualitatively similar to those previously reported in nerve; these findings suggest that the binding sites for local anesthetics in both tissue types have a similar structural topography. (Circulation Research 1989;65: 1306-1323

Sodium Channel Inactivation: Molecular Determinants and Modulation

“…Many LA are racemates whose constituents often differ pharmacologically, in particular in binding to the receptor (182, 515) but also in unbinding leading to differences in use dependence (86,105,459). No stereoselective action on TTX-resistant channels was observed (51).…”

The effects of the stereoisomers of propafenone and diprafenone in guinea‐pig heart

“…Modulation of cardiac sodium channel function is thought to be mediated by binding of the drugs to a receptor site directly associated with the ion channel (Catterall, 1987;Sheldon et al, 1987). Stereoselectivity of this putative binding site has been demonstrated in experiments with the local anaesthetic RAC 109 (Yeh, 1980;Postma & Catterall, 1983;Clarkson, 1986) as well as the antiarrhythmic tocainide . A comparative study, however, revealed considerable stereospecific differences in the binding of type 1 antiarrhythmics to cardiac sodium channels, and disopyramide as well as flecainide were found to bind nonstereoselectively (Hill et al, 1988).…”

Stereoselective Interactions between Local Anesthetics and Ion Channels

“…R (+)bupivacaine was about 1.6 times more efficient in blocking Na + channels than the other enantiomer (Fig. (A)) …”

“…2(A)). 6,22 Different amino acid substitutions at position N434 (DI-S6) led to an increase or to a decrease in bupivacaine potency that depended on the physicochemical characteristics of the amino acid introduced. Thus, the potency of bupivacaine enantiomers was increased in N434 mutant Nav1.4 channels in which the native asparagine was substituted by amino acids containing an aromatic group (phenylalanine, tryptophan, or tyrosine), a polar group (cysteine), or a negative charge (aspartic) and decreased in a mutation containing a positive charge (lysine).…”