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J Thorac Cardiovasc Surg 1994;108:455-466
© 1994 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Pretreatment with the adenosine triphosphate–sensitive potassium channel opener nicorandil and improved myocardial protection during high-potassium cardioplegic hypoxia

Rome, Italy

Supported in part by a grant from the Ministry of Foreign Affairs of Italy and by a grant-in-aid from Chugai Pharmaceutical Co., Tokyo, Japan, to Satoru Sugimoto, on leave from the Department of Surgery, Section 2, Sapporo Medical College, Sapporo, Japan.

Received for publication April 13, 1993. Accepted for publication Feb. 4, 1994. Address for reprints: P. E. Puddu, MD, Istituto di Chirurgia del Cuore e Grossi Vasi, II Cattedra di Cardiologia, Università degli Studi di Roma "La Sapienza," Viale del Policlinico, 155, Rome 00161, Italy.

Abstract

We hypothesized that pretreatment with the potassium channel opener nicorandil might enhance myocardial protection achieved by cold (20°C) high-potassium (16 mmol/L) cardioplegia (5 ml/min) during long-duration (120 minutes) myocardial hypoxia (average oxygen content 5.4 ml/dl). We tested a 15-minute infusion of nicorandil (1 mmol/L) given only before (group A, n = 8) or before and during cardioplegia (group B, n = 8) in guinea pig papillary muscle preparations contracting isometrically while stimulated (4 mA, 2 msec) at 1600 msec cycle length. Nicorandil was significantly negative inotropic before cardioplegia and shortened significantly action potential duration. During cardioplegia, time to arrest of contraction was shortened from 145±28 seconds (mean±standard error) in the vehicle group (dimethyl sulfoxide 1:100; n = 8) to 56±10 seconds (p < 0.02) and 68±5 seconds (p < 0.05) in groups A and B, respectively. Recovery of developed tension at 60 minutes of normothermic reoxygenation (expressed as percent of prehypoxia basal value) was ameliorated from 54%±6% (vehicle group) to 92%±4% (group A, p < 0.01) and to 119%±19% (group B, p< 0.01). The specific potassium channel blocker glibenclamide (glib: 1µmol/L, n = 8) prolonged action potential duration and was without effect on time to arrest. On reoxygenation, the glib group had prolonged time to half relaxation (versus group A, p < 0.02) and the worst percent developed tension at 60 minutes (40%±4%). In the overall study, time to arrest and percent developed tension at 60 minutes were inversely correlated (r = -0.45, p < 0.01). Arrhythmias were never observed. Multivariate analysis showed that pretreatment with nicorandil (with or without drug adjunct to cardioplegic solution) was a significant factor (r ²= 0.65, p = 0.0001) to influence reoxygenation-mediated recovery of mechanical function. Neither the negative inotropic effect of nicorandil before cardioplegia nor its abbreviating action on time to arrest during cardioplegia was contributory to explain recovery of function on reoxygenation. In subgroup analysis, negative inotropism and the shortening of action potential duration were contributory factors. These data suggest that nicorandil pretreatment activates potassium channels and enhances the myocardial protection provided by cold cardioplegia an effect, which is evident after a long hypoxic period, late on reoxygenation. (J THORAC CARDIOVASC SURG 1994;108:455-66)

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