The IK1/Kir2.1 channel agonist zacopride prevents and cures acute ischemic arrhythmias in the rat

Fig 1. The preventative and curative effects of zacopride on MI- induced ventricular arrhythmias in anesthetized rats in vivo. (A) Representative condensed ECGs (25 s/div). I, pretreatment; II, post-treatment; III, therapeutic treatment. (B) Time course of ECG traces for saline control rats (coronary occlusion + saline i.v.). Zac, zacopride, at 15 μg/kg. Lidoc, lidocaine, at 7.5 mg/kg.

Fig 2. Effects of zacopride on ischemia-induced ventricular tachyarrhythmias in the ex vivo rat hearts. Zacopride at 1 μmol/L decreased the total number of PVC episodes (A), the mean episode duration of VT (B) or VF (C), and the incidence of VT or VF (D). BaCl2 at 1 μmol/L partially reversed the effect of zacopride. Zac, zacopride. * P < 0.05, ** P < 0.01.

Fig 3. The effect of zacopride on the IK1 of hypoxic native rat ventricular myocytes. (A) A typical recording for IK1. (B) The current-voltage (I-V) curves of IK1. All traces indicated Ba2+-sensitive currents and were normalized for cell capacitance. The inset shows an enlarged outward portion of the I-V curves. (C) The outward IK1 currents (at –60 mV) decreased soon after the onset of hypoxia and were restored by zacopride. The maximal efficacy appeared at 1 μmol/L and attenuated by 1 μmol/L BaCl2. Zac, zacopride; hyp, hypoxia. * P < 0.05, ** P < 0.01.

Fig 4. Representative transmembrane potentials (TMPs) showing the effects of zacopride on the RMP (A) and AP (B) in rat ventricular myocytes under hypoxic conditions. The right panel of B shows the statistical analysis of APD changes in response to zacopride (1 μmol/L) or zacopride (1 μmol/L) plus BaCl2 (1 μmol/L). Zac, zacopride. h, hypoxia. N = 6. ** P < 0.01, vs. normoxia. # P < 0.05, ## P < 0.01, vs. Zac.

Fig 5. Zacopride did not affect hypoxia-induced and glibenclamide-sensitive currents in isolated rat ventricular myocytes. (A) The I-V curves of the measured currents. a, baseline. b, hypoxia. c, 10 μmol/L glibenclamide. (B) Time course of the membrane currents measured at 20 mV under hypoxic condition. One μmol/L zacopride and 10 μmol/L glibenclamide were applied in succession.

Fig 6. Representative transmembrane potential (TMP) traces showing hypoxia- or Iso-induced DADs in rat ventricular myocytes. a, normoxia. b, normoxia + Zac (1 μmol/L). c, hypoxia. d, hypoxia + Zac (1 μmol/L). e, Iso (1 μmol/L). f, Iso (1 μmol/L) + Zac (1 μmol/L). Zac, zacopride. Iso, isoproterenol.

Fig 7. Effects of zacopride on IKir2.x currents in hypoxic CHO cells. (A) and (B), Kir2.1. (C) Kir2.2. (D) Kir2.3. The hypoxia-induced decrease of IKir2.1 was reversed by zacopride, whereas IKir2.2 and IKir2.3 were refractory to both hypoxia and zacopride treatment. Zac, zacopride. Hyp, hypoxia. N = 6. * P < 0.05, ** P < 0.01.