No abstract

The reactions of [2+3] cycloaddition of pyridylnitrile oxides to vinyl-and allylgermanes proceed regioselectively and afford 5-Ge-substituted isoxazolines-2. We have synthesized 9 new pyridyl substituted 5-Si(Ge)-isoxazolines-2 and investigated their biological activity. The vasodilating, anticoagulant and cardioprotective activities of 5-Si(Ge) substituted isoxazolines-2 have been studied in vitro and in vivo. Substitution of the silicon atom for the germanium one leads to the significant increase in vasodilating, antithrombotic and cardioprotective activity. The insertion of the methylene group between Ge and the isoxazoline ring reduces the vasodilating activity. The most active isoxazoline-3-(5"-triethylgermyl-3"-isoxazolinyl)pyridine hydrochloride protects the heart from rhythm disturbances and lethality during ischaemia-reperfusion.

The study provides experimental evidence that the combination of orotic acid and mildronate possesses additive pharmacological effects and that mildronate orotate might be considered as a powerful therapeutic agent facilitating recovery from ischemia-reperfusion injury.

INTRODUCTIONCoronary heart desease (CHD) remains the leading cause of death in the industrialized countries. The primary cause of CHD is athemsclemsis, a disease characterized by the deposition of lipids in the artedal vessel wall, resulting in a narrowing of the vessel passages and ultimately hardening the vascular system. Atherosclerosis as manifested in its major clinical complication, ischaemic heart disease, is thought to begin with local injury to the arterial endothelium followed by proliferation of artedal smooth muscle cells from the medial layer to the intJmal layer along with deposition of lipid and

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.