Cardioprotective effects of N-hydroxyguanidine PR5 in myocardial ischaemia and reperfusion in rats.
1. The potential for the N-hydroxyguanidine compound PR5 (N-(3, 4-dimethoxy-2-chlorobenzylideneamino)-N'-hydroxyguanidine) as a cardioprotective agent in heart ischaemia and reperfusion injury was investigated using rat models. 2. Administration of 1-10 mg kg-1 of PR5 5 min before 10 min of left coronary artery occlusion, followed by 20 min reperfusion, strongly inhibited reperfusion burst of arrhythmias and markedly improved the survival of the animals (e.g. ventricular fibrillation incidence 93 vs 43% (P<0.05); mortality 47 vs 0% (P<0.05), for controls and for 3 mg kg-1 of PR5, respectively). 3. Administration of 3 mg kg-1 of PR5 1 min before reperfusion to rats subjected to 10 min occlusion, 20 min reperfusion was most effective in reducing arrhythmias and decreasing mortality (43 vs 0%, P<0.05), but effects were also seen when PR5 was administered 0, 1 and 5 min after start of reperfusion. 4. Coronary occlusion/reperfusion (10 - 20 min) increased malondialdehyde (MDA) of rat hearts (0.88+/-0.13 for sham vs 1.45+/-0.12 nmol mg-1 protein for ischaemic; P<0.05). In rats where 3 mg kg-1 PR5 were administered 1 min before reperfusion the increase was attenuated (MDA being 1.04+/-0.12; P<0.05 vs ischaemic). 5. PR5 caused a substantial reduction of the infarction size in rats subjected to 180 min left coronary artery occlusion, followed by 120 min of reperfusion; the necrotic zone being 326+/-32 mg for controls vs 137+/-21 mg for animals treated with 3x3 mg kg-1 of PR5 (P<0.01). 6. PR5 reduced the elevation of the ST-segment of the ECGs, as well as caused pronounced attenuation of the rapid blood pressure drop seen at the start of reperfusion following coronary artery occlusion. 7 We conclude that the N-hydroxyguanidine PR5 provides remarkable protection against ischaemia and reperfusion induced myocardial necrosis and life-threatening arrhythmias. These effects of PR5 are discussed in relation to a recently discovered ability of N-hydroxyguanidines to function as electron acceptors at the xanthine oxidase enzyme.
Veveris
M
M
Department of Medicinal Chemistry, Latvian Institute of Organic Synthesis, Riga, Latvia.
Dambrova
M
M
Cirule
H
H
Meirena
D
D
Kalvinsh
I
I
Wikberg
J E
JE
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006143:Guanabenz / Q000031:analogs & derivatives / Q000627:therapeutic use; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D006898:Hydroxylamines; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D000959:Antihypertensive Agents; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D006898:Hydroxylamines; C402768:hydroxyguanidine pr5; D008315:Malondialdehyde; C029604:hydroxyguanidine; D014969:Xanthine Oxidase; D006143:Guanabenz; C028782:guanoxabenz