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J Thorac Cardiovasc Surg 2002;124:371-376
© 2002 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CSP)

Gap junction uncoupling protects the heart against ischemia

From the Division of Cardiothoracic Surgery^a and the Department of Physiology and Biophysics,^b The Institute for Molecular Cardiology, State University of New York at Stony Brook, Stony Brook, NY.

Received for publication Oct 10, 2001. Revisions requested Nov 8, 2001; revisions received Feb 8, 2002. Accepted for publication Feb 18, 2002. Address for reprints: Adam E. Saltman, MD, PhD, Division of Cardiothoracic Surgery, State University of New York at Stony Brook, Health Sciences Center T19-080, Stony Brook, NY 11794-8191 (E-mail: adam.saltman{at}sunysb.edu).

Background: Many stimuli can successfully protect the heart against ischemia. We investigated whether gap junction uncoupling before ischemia was myoprotective. We also studied the function of the adenosine triphosphate-dependent potassium channel, which has been implicated in the mechanism of pharmacologic preconditioning, with respect to gap junction physiology.
Methods: Twenty-eight rabbit hearts were placed on a Langendorff perfusion apparatus. Five were given a 5-minute infusion of 1 mmol/L heptanol (a gap junction uncoupler), 5 were given 10 µmol/L 2,3-butanedione monoxime (an electromechanical uncoupler), and 6 were given no drug. The left anterior descending coronary artery was then occluded for 1 hour and reperfused for 2 hours. Six hearts received 10 µmol/L glybenclamide before heptanol to evaluate the role of the adenosine triphosphate-dependent potassium channel. Six hearts underwent ischemic preconditioning with 2 cycles of 5 minutes of global ischemia and reperfusion. Action-potential duration of the ischemic zone, left ventricular developed pressure, and coronary flow were measured continuously. Infarct size was determined at the end of reperfusion.
Results: Heptanol significantly reduced infarct size (from 46% ± 2% to 22% ± 5%, P < .01), an effect that was not prevented by glybenclamide. Butanedione monoxime decreased developed pressure but did not significantly reduce infarct size (46% ± 5% vs 46% ± 2%, P = not significant). There were no differences among groups with regard to developed pressure or action-potential duration.
Conclusion: Directly blocking gap junctions preconditions the heart. This protection is not a direct result of a decrease in developed pressure before a prolonged ischemic period nor is it achieved through a mechanism involving the adenosine triphosphate-dependent potassium channel.

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