Abstract:
:The modulated receptor hypothesis states that sodium channels have a specific receptor for antiarrhythmic drugs. Therefore, two agents that block sodium channels by binding to this receptor are expected to compete for occupancy. Glycylxylidide (GX) is a deethylated metabolite of lidocaine that accumulates in patients on lidocaine therapy. In single, voltage-clamped cardiocytes, GX, like lidocaine, blocked cardiac sodium channels in a use-dependent manner. However, its kinetics of recovery from block were markedly different from lidocaine: at potentials between -80 and -100 mV, GX-blocked channels recovered faster and more completely than lidocaine-blocked channels but recovered more slowly at more negative potentials (-120 to -140 mV). If lidocaine and GX compete for a common receptor, then there are conditions in which addition of a "faster" drug to a "slower" drug will produce less block than the slower drug alone. At potentials between -120 and -140 mV, addition of GX (slower drug) to lidocaine always increased the level of block, but addition of lidocaine to GX decreased the block in four of nine experiments and did not increase it in three of nine experiments. Conversely, at potentials between -80 and -100 mV, addition of lidocaine (slower drug) to GX always increased block, whereas addition of GX to lidocaine reduced the level of block in five of 16 experiments and did not increase it in seven of 16 experiments. Thus, upon addition of more blocker, the sodium current increased in 36% of cases or did not decline in 76% of cases. These results can be explained by the modulated receptor hypothesis with two drugs competing for the same receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
journal_name
Circulationjournal_title
Circulationauthors
Bennett PB,Woosley RL,Hondeghem LMdoi
10.1161/01.cir.78.3.692subject
Has Abstractpub_date
1988-09-01 00:00:00pages
692-700issue
3eissn
0009-7322issn
1524-4539journal_volume
78pub_type
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