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 agen ts but exhibit toxicity at high doses. In this study, the effectivenes s of another PCO, nicorandil, was investigated for several reasons. Th e chemical structure of nicorandil is distinct from other PCOs, in par t because of a nitrate moiety, which may confer additional cardioprote ction. Moreover, nicorandil has been approved for human use and has no t been shown to exhibit significant toxicity in clinical trials. Metho ds and Results Using a blood-perfused, parabiotic,isolated rabbit hear t model, 45 hearts underwent 30 minutes of global normothermic ischemi a after infusion of 50 mt of cardioplegia, followed by 30 minutes of r eperfusion. Cardioplegia consisted of Krebs-Henseleit solution either alone (control) or with nicorandil (100 mu mol/L, 300 mu mol/L, or 1 m mol/L), 20 mmol/L KCl, or nicorandil (100 mu mol/L) plus glibenclamide (10 mu mol/L), a potassium channel blocker. Over a wide range of volu mes, 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 ni corandil, 100 mu mol/L nicorandil, 1 mmol/L nicorandil, and 20 mmol/L KCl was 44.1+/-3.4%, 43.9+/-2.9%, 61.1+/-4.7%, 58.4+/-3.0%, and 63.2+/ -1.5%, respectively. Postreperfusion end-diastolic pressures were sign ificantly increased in control, 300 mu mol/L nicorandil, and nicorandi l plus glibenclamide groups. Conclusions Nicorandil (100 mu mol/L and 1 mmol/L) significantly improved functional recovery compared with con trol and was as effective as KCI cardioplegia. The protective effect o f nicorandil was eliminated by glibenclamide, indicating that nicorand il is cardioprotective primarily through its capability as a PCO. In c ontrast to other PCOs, nicorandil produced mechanical arrest as quickl y as KCl and did not show toxicity.