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Keywords:

  • Sinoatrial node;
  • hyperpolarization activated current;
  • If;
  • specific bradycardic agent;
  • ZD7288;
  • alinidine;
  • zatebradine;
  • patch clamp;
  • UL-FS 49
  • 1
    ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride) is a sinoatrial node (SAN) modulating agent which produces a selective slowing of the heart rate. Its effects have been studied in single, freshly dissociated guinea-pig SAN cells, by standard patch clamp procedures.
  • 2
    Whole-cell inward currents were evoked by hyperpolarizing voltage clamp steps from a holding potential of −40 mV. ZD7288 inhibited the hyperpolarization activated cationic current (If) in a concentration-dependent manner. The ‘selective bradycardic agents' alinidine and UL-FS 49 (zatebradine) both also inhibited If.
  • 3
    The activation of If was investigated by measuring tail current amplitudes at +20 mV after hyperpolarizing steps to different potentials to activate the current. The reduction in If resulted from both a shift in the If current activation curve in the negative direction on the voltage axis, and also a reduction in the activation curve amplitude.
  • 4
    ZD7288 did not affect the ion selectivity of the If channel, since the tail current reversal potential was unchanged in the presence of the drug.
  • 5
    With ZD7288 the inhibition of If was not use-dependent, whereas UL-FS 49 displayed use-dependence in the block of the If current.
  • 6
    Whereas ZD7288 had no significant effect on the delayed rectifier current (Ik) in these cells, both alinidine and UL-FS 49 significantly reduced Ik at the same concentrations which reduced If.
  • 7
    The data show that ZD7288 reduces If by affecting the activation characteristics of the If current; this inhibition may account for this agent's selective bradycardic properties.