Block of the cardiac pacemaker current (If) in the rabbit sino-atrial node and in canine Purkinje fibres by 9-amino-1,2,3,4-tetrahydroacridine.
We have investigated the action of 9-amino-1, 2, 3, 4-tetrahydroacridine (THA) on the pacemaker current If in rabbit sino-atrial node myocytes and in canine Purkinje fibers. THA at concentrations in the range 3-300 microM blocked If in a voltage-independent manner, as revealed by measurements on the fully activated I/V relation for If. The dose/response relationship of the If maximal slope conductance (Gf) can be fitted by assuming a cooperative binding reaction where two THA molecules are required to block one If channel. Half-maximal block occurred at 18.2 microM in the sino-atrial node and 36.6 microM in Purkinje fibers. THA also affected the If kinetic properties. This was examined in the sino-atrial node where the current activation curve was shifted in the negative direction on the voltage axis (- 21 mV at 30 microM THA). The delayed rectifier current, IK, was also reduced by THA in sino-atrial node myocytes: at - 40 mV the IK fully activated value was decreased to 37% of its control value by 30 microM THA, with only a minor modification of the position of the activation curve at the same potential. Thus, although THA blocks If at a lower concentration than other known If-channel blockers [DiFrancesco (1982) J Physiol (Lond) 329:485-507], its action on the pacemaker current is not specific.
DiFrancesco
D
D
Università di Milano, Dipartimento di Fisiologia e Biochimica Generali, Italy.
Porciatti
F
F
Janigro
D
D
Maccaferri
G
G
Mangoni
M
M
Tritella
T
T
Chang
F
F
Cohen
I S
IS
D000818:Animals; D001683:Biological Clocks / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects*; D011817:Rabbits; D012849:Sinoatrial Node / Q000187:drug effects*; D013619:Tacrine / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D013619:Tacrine