Mechanisms of the effects of nicorandil in the isolated rat heart during ischemia and reperfusion: a 31P-nuclear magnetic resonance study.
Nicorandil (SG75) is a potent K+-channel activator with an additional nitro moiety. In the present study we investigated the potential mechanisms (K+-channel activation and nitric oxide [NO] release) for the effects of nicorandil on isolated perfused rat hearts during total global ischemia using 31P-nuclear magnetic resonance. After a 10-min control perfusion, hearts were subjected to treatment with nicorandil-containing (100, 300, or 1000 microM) buffer for 10 min, 15 min of total global ischemia, and 30 min of reperfusion. At high dose (10(-3) M), nicorandil reduced ATP depletion during ischemia by 26% compared with untreated hearts. Blockade of K+ channels by glibenclamide prevented this protective effect. At all doses (10(-4) to 10(-3) M), nicorandil reduced the accumulation of protons during ischemia compared with untreated hearts (pH 6.22 +/- 0.03 vs. 6.02 +/- 0.05 in untreated hearts at the end of ischemia). This effect was preserved after blockade of K+ channels by glibenclamide. Hearts treated with nitroglycerine before ischemia also showed reduced proton accumulation. Therefore, NO release accompanied by increased coronary flow before ischemia, which is caused by the nitro moiety of nicorandil and nitroglycerine treatment, results in reduced proton accumulation. During reperfusion, a pro-arrhythmic effect was observed in hearts treated with the nonpharmacologically high dose of nicorandil (1000 microM). Thus, we conclude that the effects of nicorandil are caused by the simultaneous action of both mechanisms K+-channel activation and NO release. The activation of K+ channels prevents deterioration of ATP during ischemia, whereas NO release and increased coronary flow reduce the accumulation of protons--and thus the decrease in pH--during ischemia.
Horn
M
M
Department of Medicine, University of Würzburg, Germany.
Hügel
S
S
Schroeder
M
M
Ertl
G
G
Schnackerz
K D
KD
Neubauer
S
S
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects*; D005905:Glyburide / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000503:physiopathology; D015425:Myocardial Reperfusion; D020108:Nicorandil / Q000494:pharmacology*; D010758:Phosphorus; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D020108:Nicorandil; D010758:Phosphorus; D005905:Glyburide