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J Thorac Cardiovasc Surg 2002;124:750-757
© 2002 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CSP)

Long-term administration of nicorandil abolishes ischemic and pharmacologic preconditioning of the human myocardium: Role of mitochondrial adenosine triphosphate-dependent potassium channels

From the Department of Integrative Human Cardiovascular Physiology and Functional Genomics, Division of Cardiac Surgery, University of Leicester, Glenfield Hospital, Leicester, United Kingdom.

Supported in part by a grant from Mason Medical Research Foundation and a personal contribution from Professor M. Galiñanes.

Received for publication Nov 9, 2001. Revisions requested Dec 19, 2001; revisions received March 6, 2002. Accepted for publication April 16, 2002. Address for reprints: Manuel Galiñanes, MD, PhD, Department of Integrative Human Cardiovascular Physiology and Functional Genomics, Division of Cardiac Surgery, University of Leicester, Glenfield Hospital, Leicester, United Kingdom (E-mail: mg50{at}le.ac.uk).

Background: Acute administration of mitochondrial adenosine triphosphate-dependent potassium channel openers preconditions the heart, but whether their long-term administration induces a permanent state of protection is unknown. These studies investigate the effect of long-term treatment with the mitochondrial adenosine triphosphate-dependent potassium channel opener nicorandil on the response of the human myocardium to ischemia and preconditioning.
Methods: 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 µmol/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 µmol/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 µmol/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: The myocardium of patients chronically treated with nicorandil cannot be preconditioned either by ischemia or pharmacologically, and this is because of unresponsive mitochondrial adenosine triphosphate-dependent potassium channels. However, protection can be obtained by protein kinase C and p38 mitogen-activated protein kinase activation, which are downstream of mitochondrial adenosine triphosphate-dependent potassium channels in the signaling transduction pathway of preconditioning.

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