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CLINICAL STUDY: MYOCARDIAL ISCHEMIA

Failure to precondition pathological human myocardium

Sudip Ghosh, FRCS^*, Nicholas B. Standen, PhD and Manuel Galiñanes, MD, PhD^*

^* Division of Cardiac Surgery, Department of Surgery, University Hospitals Leicester, Glenfield Campus, Leicester, United Kingdom
Department of Cell Physiology and Pharmacology, University Hospitals Leicester, Glenfield Campus, Leicester, United Kingdom

Manuscript received June 6, 2000; revised manuscript received September 28, 2000, accepted November 3, 2000.

Reprint requests and correspondence: Professor Manuel Galiñanes, Division of Cardiac Surgery, Department of Surgery, University Hospitals Leicester, Glenfield Campus, Leicester LE3 9QP, United Kingdom
mg50{at}leicester.ac.uk

OBJECTIVES

We investigated the effects of ischemic preconditioning (PC) on diabetic and failing human myocardium and the role of mitochondrial K_ATP channels on the response in these diseased tissues.

BACKGROUND

There is conflicting evidence to suggest that PC is a healthy heart phenomenon.

METHODS

Right atrial appendages were obtained from seven different groups of patients: nondiabetics, diet-controlled diabetics, noninsulin-dependent diabetics (NIDD) receiving K_ATP channel blockers, insulin-dependent diabetics (IDD), and patients with left ventricular ejection fraction (LVEF) >50%, LVEF between 30% and 50% and LVEF <30%. After stabilization, the muscle slices were randomized into five experimental groups (n = 6/group): 1) aerobic control—incubated in oxygenated buffer for 210 min, 2) ischemia alone—90 min ischemia followed by 120 min reoxygenation, 3) preconditioning by 5 min ischemia/5 min reoxygenation before 90 min ischemia/120 min reoxygenation, 4) diazoxide (Mito K_ATP opener, 0.1 mm)—for 10 min before the 90 min ischemia/120 min reoxygenation and 5) glibenclamide (10 µm)—10 min exposure prior to PC (only in the diabetic patient groups). Creatine kinase leakage into the medium (CK, U/g wet wt) and MTT reduction (OD/mg wet wt), an index of cell viability, were assessed at the end of the experiment.

RESULTS

Ischemia caused similar injury in both normal and diseased tissue. Preconditioning prevented the effects of ischemia in all groups except NIDD, IDD and poor cardiac function (<30%). In the diazoxide-treated groups, protection was mimicked in all groups except the NIDD and IDD groups. Interestingly, glybenclamide abolished protection in nondiabetic and diet-controlled NIDD groups and did not affect NIDD groups receiving K_ATP channel blockers or IDD groups.

CONCLUSIONS

These results show that failure to precondition the diabetic heart is due to dysfunction of the mitochondrial K_ATP channels and that the mechanism of failure in the diabetic heart lies in elements of the signal transduction pathway different from the mitochondrial K_ATP channels.

Abbreviations and Acronyms   CK = creatine kinase   DCD = diet-controlled diabetes   IDD = insulin-dependent diabetes   KATP = ATP-dependent potassium channels   LVEF = left ventricular ejection fraction   MTT = 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide   NIDD = noninsulin-dependent diabetes   PC = preconditioning   PKC = protein kinase C

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