Effects of nicorandil and glyceryl trinitrate on infarct size, adenosine release, and neutrophil infiltration in the dog.
OBJECTIVE
The major aim of this study was to determine if nicorandil, a potassium channel opener nitrate, produces a reduction in myocardial infarct size at a non-hypotensive dose in dogs and to determine if this effect is the result of an increase in adenosine release or reduction in neutrophil infiltration into the ischaemic area. Glyceryl trinitrate was used for purposes of comparison.


METHODS
Barbitone anaesthetised dogs were subjected to 60 min of left anterior descending coronary artery occlusion followed by 3 h of reperfusion. Nicorandil (100 microgram.kg-1 bolus followed by a 10 microgram.kg-1.min-1 infusion; NC/pre group), glyceryl trinitrate (10 microgram.kg-1 bolus followed by a 1 microgram.kg-1.min-1 infusion; GTN/pre group), or an equivalent volume of saline (control group) were given intravenously 15 min before occlusion and continued to the time of reperfusion. In two other groups, nicorandil (NC/post group) or glyceryl trinitrate (GTN/post group) were given 10 min before reperfusion and continued until the end of the experiment. To measure the release of adenosine from the ischaemic region, coronary venous blood samples were collected before occlusion, during occlusion, and at various times following reperfusion. Myocardial infarct size was determined by triphenyltetrazolium chloride and transmural myocardial blood flow by radioactive microspheres. Transmural myeloperoxidase activity, an index of neutrophil infiltration, was measured in biopsies obtained from the area at risk.


RESULTS
Pretreatment with nicorandil and glyceryl trinitrate caused a marked reduction in myocardial infarct size expressed as percent of the area at risk [NC/pre group, 7.8(SEM 1.6)%; GTN/pre group, 11.9(2.3)%; control group, 31.0(5.6)%]. When nicorandil and glyceryl trinitrate were given before reperfusion, both drugs still produced a significant reduction in infarct size [NC/post group, 13.8(2.0)%; GTN/post group, 18.9(4.3)%]. Coronary venous adenosine concentrations during reperfusion were significantly lower in both nicorandil and glyceryl trinitrate pretreated groups, but not in the post-treated groups. Transmural myeloperoxidase activity was significantly lower in both nicorandil treated groups.


CONCLUSIONS
Pretreatment with a non-hypotensive dose of nicorandil or glyceryl trinitrate markedly reduces myocardial infarct size and adenosine release from the ischaemic-reperfused area. These agents were also effective, but to a lesser degree, when given just before reperfusion. The cardioprotective actions of nicorandil appear to be related not only to its potassium channel opening activity but also in part to its nitrate activity.
Mizumura
T
T
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
Nithipatikom
K
K
Gross
G J
GJ
D000241:Adenosine / Q000097:blood*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D005260:Female; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020108:Nicorandil; D005996:Nitroglycerin / Q000627:therapeutic use; D009195:Peroxidase / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents / Q000627:therapeutic use*
D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D009195:Peroxidase; D005996:Nitroglycerin; D000241:Adenosine