Right atrial tissue obtained from patients regularly treated with or without
nicorandil (mean of 20 mg/d for 18.6 +/- 2.5 months) and undergoing cardiac surgery was sliced and equilibrated for 30 minutes and then subjected to 90 minutes of simulated
ischemia, followed by 120 minutes of reoxygenation. In study 1 the following groups were studied to investigate the effect of
nicorandil on the susceptibility of the myocardium to
ischemia and on the protective effect of ischemic and pharmacologic preconditioning: (1) aerobic control; (2) simulated
ischemia and reoxygenation alone; (3) ischemic preconditioning with 5 minutes of simulated
ischemia and 5 minutes of reoxygenation; and (4)
phenylephrine (0.1 micromol/L) for 5 minutes and 5 minutes' washout before simulated
ischemia and reoxygenation. In study 2 the following groups were studied to investigate the effect of
nicorandil on the responsiveness of mitochondrial
adenosine triphosphate-dependent
potassium channels: (1) aerobic control; (2) simulated
ischemia and reoxygenation; (3) ischemic preconditioning; (4)
diazoxide (100 micromol/L) for 10 minutes before simulated
ischemia and reoxygenation, and (5)
5-hydroxydecanoate (1 mmol/L) for 10 minutes before simulated
ischemia and reoxygenation. In study 3 the following groups were included to investigate the effect of the long-term administration of
nicorandil on the
kinase pathway involved in preconditioning: (1) aerobic control; (2) simulated
ischemia and reoxygenation alone; (3) ischemic preconditioning; (4)
phorbol 12-myristate 13-acetate (1 micromol/L), a
protein kinase C activator, for 10 minutes before simulated
ischemia and reoxygenation; and (5)
anisomycin (1 nmol/L), a
p38 mitogen-activated protein kinase activator, for 10 minutes before simulated
ischemia and reoxygenation. At the end of each protocol, the leakage of
creatine kinase (in units per gram wet weight) and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium
bromide into insoluble
formazan dye (in millimoles per gram wet weight) were measured.
RESULTS: In study 1 the leakage of
creatine kinase and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium
bromide induced by simulated
ischemia and reoxygenation were similar in the groups with or without
nicorandil (
creatine kinase, 3.4 +/- 0.1 and 3.5 +/- 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium
bromide, 74.6 +/- 3.9 and 67.9 +/- 7.3, respectively;
P >.2 in each instance). Ischemic preconditioning and pharmacologic preconditioning protected the myocardium from patients without
nicorandil (
creatine kinase, 2.3 +/- 0.1 and 2.4 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium
bromide, 131.4 +/- 4.9 and 128.4 +/- 5.6, respectively; P < 0.001 vs simulated
ischemia and reoxygenation alone in each instance) but not the myocardium from patients receiving
nicorandil (
creatine kinase, 3.3 +/- 0.1 and 3.3 +/- 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium
bromide, 89.7 +/- 6.5 and 86.4 +/- 5.2, respectively;
P >.2 vs simulated
ischemia and reoxygenation alone in each instance). In study 2 the administration of
diazoxide had identical protection to that of ischemic preconditioning in the myocardium of patients not receiving
nicorandil (
creatine kinase, 2.1 +/- 0.2 and 2.3 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium
bromide, 141.4 +/- 7.4 and 131.4 +/- 4.9, respectively; P < 0.001 vs simulated
ischemia and reoxygenation alone in each instance) but failed to precondition the myocardium from patients treated with
nicorandil (
creatine kinase, 3.3 +/- 0.2 and 3.4 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium
bromide, 90.1 +/- 7.2 and 86.4 +/- 5.2, respectively; P > 0.2 vs simulated
ischemia and reoxygenation alone in each instance). In study 3
phorbol 12-myristate 13-acetate or
anisomycin given for 10 minutes before simulated
ischemia and reoxygenation afforded similar protection to that of ischemic preconditioning in the myocardium from patients with (
creatine kinase, 1.5 +/- 0.3 and 1.4 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium
bromide, 147.0 +/- 4.9 and 160.0 +/- 16.1, respectively; P < 0.001 vs simulated
ischemia and reoxygenation alone in each instance) and without
nicorandil (
creatine kinase, 1.7 +/- 0.4 and 1.4 +/- 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium
bromide, 160.3 +/- 13.6 and 158.3 +/- 11.8, respectively; P <.001 vs simulated
ischemia and reoxygenation alone in each instance).
CONCLUSION: