Responsiveness of cardiac Na+ channels to antiarrhythmic drugs: The role of inactivation
- 27 Downloads
Elementary Na+ currents were recorded at 9°C in inside-out patches from cultured neonatal rat heart myocytes. In characterizing the sensitivity of cooled, slowly inactivating cardiac Na+ channels to several antiarrhythmic drugs including propafenone, lidocaine and quinidine, the study aimed to define the role of Na+ inactivation for open channel blockade.
In concentrations (1–10 μmol/liter) effective to depressNP o significantly, propafenone completely failed to influence the open state of slowly inactivating Na+ channels. With 1 μmol/liter, τopen changed insignificantly to 96±7% of the control. Even a small number of ultralong openings of 6 msec or longer exceeding τopen of the whole ensemble several-fold and attaining τopen (at −45 mV) in cooled, (-)-DPI-modified, noninactivating Na+ channels proved to be drug resistant and could not be flicker-blocked by 10 μmol/liter propafenone. The same drug concentration induced in(-)-DPI-modified Na+ channels a discrete block with association and dissociation rate constants of 16.1 ± 5.3 × 106 mol−1 sec−1 and 675 ± 25 sec−1, respectively. Quinidine, known to have a considerable affinity for activated Na+ channels, in lower concentrations (5 μmol/liter) left τopen unchanged or reduced, in higher concentrations (10 μmol/liter) τopen only slightly to 81% of the predrug value whereasNP o declined to 30%, but repetitive blocking events during the conducting state could never be observed. Basically the same drug resistance of the open state was seen in cardiac Na+ channels whose open-state kinetics had been modulated by the cytoplasmic presence of F− ions. But in this case, propafenone reduced reopening and selectively abolished a long-lasting open state. This drug action is unlikely related to the inhibitory effect onNP o since hyperpolarization and the accompanying block attenuation did not restore the channel kinetics. It is concluded that cardiac Na+ channels cannot be flicker-blocked by antiarrhythmic drugs unless Na+ inactivation is removed.
Key Wordssingle cardiac Na+ channels open-state kinetics drug-induced blockade (-)-DPI
Unable to display preview. Download preview PDF.
- 4.Colquhoun, D., Sigworth, F. 1983. Fitting and statistical analysis of single channel records.In: Single Channel Recordings. B. Sakmann and E. Neher, editors. pp. 191–264, Plenum. New YorkGoogle Scholar
- 9.Hille, B. 1984. Ionic channels of excitable membranes. Sinauer, Sunderland, (MA)Google Scholar
- 15.Kohlhardt, M., Fichtner, H. 1988. Block of single cardiac Na+ channels by antiarrhythmic drugs: The effect of amiodarone, propafenone and diprafenone.J. Membrane Biol. 102:105–119Google Scholar
- 16.Kohlhardt, M., Fichtner, H., Fröbe, U. 1988. Predominance of poorly reopening single Na+ channels and lack of slow Na+ inactivation in neonatal cardioytes.J. Membrane Biol. 103:283–291Google Scholar
- 18.Kohlhardt, M., Fröbe, U., Herzig, J.W. 1986. Modification of single cardiac Na+ channels by DPI 201-106.J. Membrane Biol. 89:163–172Google Scholar
- 20.Kohlhardt, M., Seifert, C. 1983. Tonic and phasicI Na blockade by antiarrhythmics. Different properties of drug binding to fast sodium channels as judged from278-2 studies with propafenone and derivatives in mammalian ventricular myocardium.Pfluegers Arch. 396:199–209Google Scholar