Hemodynamic changes of hyperhomocysteinemic rats treated with oral heparin


DUCKWORTH Shannon;HffiBERT Linda;LEE Paul;


<正>Several studies have found a positive correlation between hypertension and hyperhomocysteinemia. Increasing evidence implicates oxidative stress as one of the initiating events closely linked to the homocysteine's ability to damage endothelium,subsequently causing vascular dysfunction.We previously found that heparin protects cultured endothelial cells from free radical injury and oral heparin at 1 mg/kg/48 h prevents venous thrombosis in a rat model in vivo.Our objective was to study the protective effects of oral heparin in a hyperhomocysteinemic rat model.Elevated plasma homocysteine(Hcy)levels were induced by feeding male Wistar Kyoto rats a diet containing an additional 1.7%methionine for 8 weeks.Groups included rats fed additional methionine(n=10),methionine plus oral heparin(1 mg/kg/48 h by gastric feeding tube;n=5),and age-matched controls(n=10)fed normal rat chow.At the end of 8 weeks of treatment,rats were anesthetized using 1.5% isoflurane in 100%oxygen.Hemodynamics parameters were assessed by inserting a Millar Mikro Tip pressure transducer into the left ventricular chamber and the thoracic aorta.Fasting plasma total Hcy levels were measured using a Hcy immunoassay kit with an Abbott IM_x instrument.Results were expressed as mean±SEM.Unpaired Student's two-tailed t-test was employed to assess the difference between groups with P<0.05 considered significant. Plasma Hcy was significantly elevated in the methionine(7.2±0.5μmol/L)and methionine plus heparin treated rats (7.0±0.4μmol/L)compared to control(5.5±0.4μmol/L).All measures of arterial pressure(expressed as mean arterial pressure and diastolic pressure in mmHg,respectively)were significantly elevated in rats fed the methionine diet without heparin(97.7±2.9;90.3±3.5)but not with heparin(93.8±2.7;83.4±2.4)compared to controls (88.8±2.2;79.2±2.1).Left ventricular end diastolic pressure(LVEDP)was significantly elevated with the methionine diet without heparin(14.2±2.5 mmHg)but not the methionine with heparin(8.4±1.9 mmHg)versus controls (7.1±1.1 mmHg).These results indicate that hyperhomocysteinemia correlates with the development of hypertension. Oral heparin treatment prevented a significant increase in arterial pressures and LVEDP seen in hyperhomocysteinemic rats.We conclude that hyperhomocysteinemia contributes to the development of hypertension and oral heparin can reduce the negative hemodynamic effects induced by hyperhomocysteinemia.


hyperhomocysteineniia;;endothelial damage;;heparin


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