Cardioprotective effects of N-hydroxyguanidine PR5 in myocardial ischaemiaand reperfusion in rats

1 The potential for the N-hydroxyguanidine compound PR5 (N-(3,4-dimethoxy-2 -chlorobenzylideneamino)-N'-hydroxyguanidine) as a cardioprotective agent i n 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 coron ary artery occlusion, followed by 20 min reperfusion, strongly inhibited re perfusion burst of arrhythmias and markedly improved the survival of the an imals (e.g. ventricular fibrillation incidence 93 vs 43% (P < 0.05); mortal ity 47 vs 0% (P < 0.05), for controls and for 3 mg kg(-1) of PR5, respectiv ely). 3 Administration of 3 mg kg(-1) of PR5 1 min before reperfusion to rats sub jected to 10 min occlusion, 20 min reperfusion was most effective in reduci ng arrhythmias and decreasing mortality (43 vs 0%, P < 0.05), but effects w ere also seen when PR5 was administered 0, 1 and 5 min after start of reper fusion. 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) protei n 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 subject ed to 180 min left coronary artery occlusion, followed by 120 min of reperf usion; the necrotic zone being 326 +/- 32 mg for controls vs 137 +/- 21 mg for animals treated with 3 x 3 mg kg(-1) of PR5 (P < 0.01). 6 PR5 reduced the elevation of the ST-segment of the ECGs, as well as cause d 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 protectio n against ischaemia and repel fusion induced myocardial necrosis and life-t hreatening arrhythmias. These effects of PR5 are discussed in relation to a recently discovered ability of N-hydroxyguanidines to function as electron accepters at the xanthine oxidase enzyme.