Hyperpolarized cardioplegic arrest with nicorandil: Advantages over other potassium channel openers

Background: Our laboratory has demonstrated that the potassium channel openers (PCOs) aprikalim and pinacidil are effective cardioplegic agents but exhibit toxicity at high doses. In this study, the effectiveness of another PCO, nicorandil, was investigated for several reasons. The chemical structure of nicorandil is distinct from other PCOs, in part because of a nitrate moiety, which may confer additional cardioprotection. Moreover, nicorandil has been approved for human use and has not been shown to exhibit significant toxicity in clinical trials. Methods and Results: Using a blood-perfused, parabiotic, isolated rabbit heart model, 45 hearts underwent 30 minutes of global normothermic ischemia after infusion of 50 mL of cardioplegia, followed by 30 minutes of reperfusion. Cardioplegia consisted of Krebs- Henseleit solution either alone (control) or with nicorandil (100 μmol/L, 300 μmol/L, or 1 mmol/L), 20 mmol/L KCl, or nicorandil (100 μmol/L) plus glibenclamide (10 μmol/L), a potassium channel blocker. Over a wide range of volumes, left ventricular systolic function and diastolic compliance were measured at baseline and after reperfusion. The percentage of recovery of developed pressure (mean±SEM) for control; glibenclamide plus nicorandil, 100 μmol/L nicorandil, 1 mmol/L nicorandil, and 20 mmol/L KCl was 44.1±3.4%, 44.9±2.9%, 61.1±4.7%, 58.4±3.0%, and 63.2±1.5%, respectively. Postreperfusion end-diastolic pressures were significantly increased in control, 300 μmol/L nicorandil, and nicorandil plus glibenclamide groups. Conclusions: Nicorandil (100 μmol/L and 1 mmol/L) significantly improved functional recovery compared with control and was as effective as KCl cardioplegia. The protective effect of nicorandil was eliminated by glibenclamide, indicating that nicorandil is cardioprotective primarily through its capability as a PCO. In contrast to other PCOs, nicorandil produced mechanical arrest as quickly as KCl and did not show toxicity.