RESUMEN
The status of nitric oxide (NO) in spontaneously hypertensive rats (SHR) is unclear and its bioavailability may be affected by imbalance with reactive oxygen species. We studied cardiovascular effects of an NO donor, pentaerythrityl tetranitrate (PETN) in SHR. We used Wistar rats, SHR and SHR treated with PETN (200 mg/kg/day). After six weeks, myocardium and aorta from each group were taken for biochemical and iliac artery for functional and morphological study. Long-term administration of PETN to SHR increased cGMP level in platelets and did not affect blood pressure. In myocardium, the therapy resulted in a decrease in cardiac hypertrophy and MDA level, and the increased antioxidant enzyme activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx). In aorta, PETN decreased the NO-synthase activity and had no affect on the enzyme activities of SOD and GPx or on MDA level. In the iliac artery, the endothelium-dependent relaxation to acetylcholine was slightly improved and the maximum vasoconstriction to noradrenaline was decreased. Wall thickness, cross-sectional area, inner diameter, and wall thickness/ inner diameter measured after perfusion fixation (120 mmHg) were not affected. The small effect of PETN on cardiovascular system suggests that NO deficiency is probably not the main cause of pathological alterations in SHR.
Asunto(s)
Aorta/efectos de los fármacos , Corazón/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Arteria Ilíaca/efectos de los fármacos , Donantes de Óxido Nítrico/uso terapéutico , Tetranitrato de Pentaeritritol/uso terapéutico , Acetilcolina/farmacología , Animales , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , GMP Cíclico/sangre , Glutatión Peroxidasa/metabolismo , Hipertensión/patología , Hipertensión/fisiopatología , Arteria Ilíaca/patología , Arteria Ilíaca/fisiopatología , Masculino , Miocardio/metabolismo , Óxido Nítrico Sintasa/metabolismo , Norepinefrina/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Superóxido Dismutasa/metabolismo , Vasoconstrictores/farmacología , Vasodilatadores/farmacologíaRESUMEN
The study was designed to characterise the influence of a novel acyl-CoA:cholesterol acyltransferase inhibitor, VULM 1457, on the severity of myocardial ischaemia-reperfusion injury in a model of diabetes mellitus and hypercholesterolaemia induced by co-administration of streptozotocin and a high fat-cholesterol diet. We used Langendorff-perfused rat hearts to measure the size of myocardial infarction after 30 min of regional ischaemia, followed by a 2-h reperfusion period, and open-chest rats were exposed to 6 min of ischaemia and 10 min of reperfusion to analyse ventricular arrhythmias. In addition to the high fat-cholesterol diet, VULM 1457 was administered to the diabetic-hypercholesterolaemic rats for 5 days. Decreased plasma and liver cholesterol levels and a significantly reduced occurrence of ventricular fibrillation (29% vs. 100%, P<0.01), determined via the mean number and duration of episodes (0.6+/-0.4 and 2.1+/-1.4 s vs. 2.8+/-0.8 and 53.5+/-14.4 s in diabetic-hypercholesterolaemic rats, both P<0.01), were observed in these animals. Lethal ventricular fibrillation was suppressed, and arrhythmia severity was also significantly decreased in these animals as compared to the non-treated animals (2.9+/-0.6 vs. 4.9+/-0.2; P<0.05). A smaller infarct size, normalised to the size of area at risk, was observed in the treated diabetic-hypercholesterolaemic group as compared to the non-treated group (16.3+/-1.9% vs. 37.3+/-3.1%; P<0.01). Aside from remarkable hypolipidaemic activity, VULM 1457 improved the overall myocardial ischaemia-reperfusion injury outcomes in the diabetic-hypercholesterolaemic rats by suppressing arrhythmogenesis as well as by reducing myocardial necrosis.