Activation of ATP-dependent K+ channels enhances myocardial protection due to cold high potassium cardioplegia: a force-frequency relationship study.
The hypothesis that nicorandil might enhance myocardial protection due to cold St Thomas' Hospital (STH) solution ([K+]o 16 mmol/l) through opening of cardiac KATP channels was assessed in isometrically contracting guinea-pig papillary muscles submitted to 120 min of cardioplegic hypoxia followed by 60 min of normothermic reoxygenation. Right ventricular papillary muscles were paced (2 ms, 4 mA) in an organ bath and superfused with oxygenated (O2 content 16 ml/l) Tyrode's solution (37 degrees C). The force-frequency relationship in the range 1600-300 ms cycle length (CL) was studied. Preparations were randomized to receive 120 min cold (20 degrees C), non-oxygenated (O2 content 5 ml/l) STH solution while continuously stimulated at 1600 ms CL, with: (1) saline (No-additive, n = 12); (2) DMSO 1% (Vehicle, n = 8); (3) nicorandil 1 mmol/l (n = 8); (4) nicorandil 1 mmol/l plus glibenclamide 1 mumol/l, the latter also given, before STH solution, in Tyrode's solution for 15 min (n = 8); (5) glibenclamide 1 mumol/l, also circulated, before STH solution, in Tyrode's solution for 15 min (n = 8); (6) nitroglycerin 100 mumol/l (n = 4); in addition, we studied: (7) STH solution with no-additive and no-pacing (n = 4); (8) cold Tyrode's in place of cold STH solution (n = 4). Inotropic state was investigated by measuring: (i) velocity of developed tension (DT), obtained by dividing DT by time to peak tension; (ii) percentage (from precardioplegia values) velocity changes of DT; (iii) log velocity of DT. Post-cardioplegic recovery of contractility (including force-frequency relationship) was assessed in all preparations: (a) 60 min after reoxygenation with Tyrode's solution; (b) after further 15 min superfusion with the positive inotropic agent dobutamine (10 mumol/l). In parallel experiments, action potential duration (APD) 50% changes induced by nicorandil or glibenclamide plus nicorandil in spontaneously beating atrial (n = 4) or electrically driven (1600 ms CL) ventricular (n = 8) tissues during 10 min of STH solution were investigated. Based on force-frequency relationship, at 60 min reoxygenation, in absence of cardioplegia, the lowest recovery of myocardial contractility was seen (stunning). In STH solution, there was moderate to severe stunning, which was unaffected by removing pacing during cardioplegia, or by vehicle or nitroglycerin. In contrast, nicorandil improved recovery of contractility (F = 3.01, P = 0.0106). After dobutamine, nicorandil preparations showed the highest positive inotropic response, which was completely offset by glibenclamide (F = 3.47, P = 0.0046).(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Cardiac Surgery, University of Rome La Sapienza, Italy.
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Sugimoto
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Puddu
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Monti
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Dawodu
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del Monte
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Schiariti
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Campa
B
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Marino
D000818:Animals; D003080:Cold Temperature; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006324:Heart Arrest, Induced; D015640:Ion Channel Gating; D009119:Muscle Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D005996:Nitroglycerin / Q000494:pharmacology; D011188:Potassium; D015221:Potassium Channels / Q000819:agonists*; D014665:Vasodilator Agents / Q000494:pharmacology*
D015221:Potassium Channels; D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D005996:Nitroglycerin; D011188:Potassium; D005905:Glyburide