Cardioprotective effects of N‐hydroxyguanidine PR5 in myocardial ischaemia and reperfusion in rats

Abstract

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 71 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 ®brillation incidence 93 vs 43% (P50.05); mortality 47 vs 0% (P50.05), for controls and for 3 mg kg 71 of PR5, respectively). 3 Administration of 3 mg kg 71 of PR5 1 min before reperfusion to rats subjected to 10 min occlusion, 20 min reperfusion was most e ective in reducing arrhythmias and decreasing mortality (43 vs 0%, P50.05), but e ects 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 71 protein for ischaemic; P50.05). In rats where 3 mg kg 71 PR5 were administered 1 min before reperfusion the increase was attenuated (MDA being 1.04+0.12; P50.05 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 363 mg kg 71 of PR5 (P50.01). 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 e ects of PR5 are discussed in relation to a recently discovered ability of N-hydroxyguanidines to function as electron acceptors at the xanthine oxidase enzyme.

The effect of cigarette smoking on functional recovery following peripheral nerve ischemia/reperfusion injury

“…In this study MDA was used as a biochemical marker of I/R injury. MDA is an indicator of lipid peroxidation induced by oxygen free radicals, and has frequently been used as a marker of I/R injury severity in studies of peripheral nerves and other tissues 37–40. In this study, as in prior ones, tissue MDA levels are seen to reach their peak at ∼1 week following injury and then to trend downward during recovery 37…”

In vivo measurements of the cerebral perfusion and cardiovascular effects of the novel guanidine ME10092 in the non-human primate, Papio ursinus

“…The current observation in the baboon may suggest an a-adrenoreceptor action for ME10092 inducing the prolonged anaesthesia observed during these studies. The pro-drug of ME10092 was reported to be devoid of any a 2 -adrenoreceptor activity (Vereris et al, 1999).…”

“…From recent studies, the cardioprotective effects in rats of PR5 (N-(3,4-dimethoxy-2-chlorobenzylideneamino)-N 1 -hydoxyguanidine) were reported against ischaemia and reperfusion induced myocardial necrosis and life-threatening arrhythmias (Vereris et al, 1999). Subsequently this protection of PR5 was found to be exerted by the metabolite of PR5, namely (N-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine, i.e.…”

N-Hydroxyguanidines oxidation by a N3S copper-complex mimicking the reactivity of Dopamine β-Hydroxylase

“…N-Hydroxyguanidines display interesting pharmacological properties with cardioprotective, antihypertensive and vasorelaxant activities [6][7][8]. Several NOHG are potent antiviral, cytotoxic and antitumor agents [9,10], and they also act as antioxidant molecules by reacting with superoxide and peroxynitrite [11,12].…”