Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of pravastatin and simvastatin, HMG-CoA reductase inhibitors, on stunned myocardium in vivo. Pravastatin and simvastatin were given orally 2 mg/kg for 3 weeks. After 3 weeks of administration, pentobarbital-anesthetized dogs were subjected to 15-min left anterior descending (LAD) coronary artery occlusion followed by 2-h reperfusion. Myocardial segment function was determined by sonomicrometry. The tissue energy and carbohydrate metabolites were determined in the 2-h-reperfused hearts. Administration of pravastatin and simvastatin for 3 weeks decreased serum cholesterol level and blood pressure (BP). Simvastatin resulted in a worsening of segment shortening in the reperfused myocardium as compared with control and pravastatin groups. The level of ATP in the simvastatin group was significantly lower as compared with that in the control group. The other metabolite levels were not significantly altered by either pravastatin or simvastatin. These results suggest that simvastatin enhances stunning of the myocardium in association with ATP reduction after reperfusion subsequent to ischemia.
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PMID:Influences of pravastatin and simvastatin, HMG-CoA reductase inhibitors, on myocardial stunning in dogs. 750 4

1. Effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, pravastatin and simvastatin, on the myocardial level of coenzyme Q10, and on mitochondrial respiration were examined in dogs. 2. Either vehicle (control), pravastatin (4 mg kg-1 day-1), or simvastatin (2 mg kg-1 day-1) was administered orally for 3 weeks. First, the myocardial tissue level of coenzyme Q10 was determined in the 3 groups. Second, ischaemia was induced by ligating the left anterior descending coronary artery (LAD) in anaesthetized open chest dogs, pretreated with the inhibitors. After 30 min of ischaemia, nonischaemic and ischaemic myocardium were removed from the left circumflex and LAD regions, respectively, and immediately used for isolation of mitochondria. The mitochondrial respiration was determined by polarography, with glutamate and succinate used as substrates. 3. Simvastatin significantly decreased the myocardial level of coenzyme Q10, but pravastatin did not. 4. Ischaemia decreased the mitochondrial respiratory control index (RCI) in both groups. Significant differences in RCI between nonischaemic and ischaemic myocardium were observed in the control and simvastatin-treated groups. 5. Only in the simvastatin-treated group did ischaemia significantly decrease the ADP/O ratio, determined with succinate. 6. The present results indicate that simvastatin but not pravastatin may cause worsening of the myocardial mitochondrial respiration during ischaemia, probably because of reduction of the myocardial coenzyme Q10 level.
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PMID:Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischaemic dog hearts. 852 76

Long-term pretreatment with statins reduces myocardial injury after acute ischemia and reperfusion by increasing the expression of endothelial nitric oxide synthase (eNOS). We hypothesized that statins may act rapidly enough to protect the myocardium from ischemia/reperfusion injury when given right at the beginning of the reperfusion period and tried to delineate the role of PI 3-kinase/Akt pathway in early eNOS activation. Activated simvastatin was given intravenously 3 minutes before starting the reperfusion after temporary coronary artery occlusion (CAO) in anaesthetized rats. Simvastatin significantly increased myocardial PI 3-kinase activity, AktSer473, and eNOSSer1177 phosphorylation and reduced infarct size by 42%. Infarct size reduction as well as activation of PI 3-kinase/Akt/eNOS pathway were not observed in rats co-treated with the PI 3-kinase inhibitor wortmannin. Contribution of eNOS was further delineated using the NOS inhibitor L-NAME, which could completely block cardioprotection by the statin. In summary, simvastatin acutely reduces the extent of myocardial necrosis in normocholesterolemic rats in an NO- dependent manner by activating the PI 3-kinase/Akt pathway. This is the first study demonstrating short-term cardioprotective effects of simvastatin in an in vivo model of ischemia/reperfusion.
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PMID:Simvastatin acutely reduces myocardial reperfusion injury in vivo by activating the phosphatidylinositide 3-kinase/Akt pathway. 1547 33

Simvastatin is cholesterol lowering agent and also a modulator of cytokine in the nervous system. The functional significance and neuroprotectiove mechanism of simvastatins in ischemic brain injury is controversial. The purpose of study is to evaluate the effect of simvastatin on ischemic brain injury and to investigate the perfusion capability of brain microvessels in the ischemic injury. This study included two series of experiments. In the first series, we studied if simvastatin is neuroprotective in an embolic model of stroke. The treatments began 2 weeks before middle cerebral artery (MCA) occlusion. Infarct volume was measured at 48 h post stroke. Neurological deficits were assessed at 2 h, 24 h and 48 h post stroke. Results showed that infarct volume in rats which received saline and simvastatin was 32.5 +/- 9.3% (mean +/- SD) and 18.7 +/- 6.5%, respectively. The infarct volume in the simvastatin group was significantly smaller than in the controls (P < 0.002). Treatment with simvastatin also improved neurological deficits and reduced brain edema significantly (P < 0.05). In the second series, we studied if simvastatin can improve microvascular reperfusions after ischemia. Perfusion deficits were detected at 8 h post stroke using Evens blue dye. Neurological deficits were assessed at 2 h and 8 h post stroke. Results showed that perfusion deficit in saline and simvastatin-treated groups were 58.7 +/- 8.7% and 23.4 +/- 7.5%, respectively. The perfusion deficit in simvastatin-treated group was decreased 61% (P < 0.01). These studies thus suggest that simvastatin is a protective agent in ischemic brain injury and this protective effect may be partially due to its action in the improvement of microvascular reperfusion.
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PMID:Simvastatin reduced ischemic brain injury and perfusion deficits in an embolic model of stroke. 1582 46

Statins, the most widely used lipid lowering drugs, have been demonstrated to play a protective role in stroke. Animal studies confirmed the observations obtained in clinical trials and provided additional data on the putative mechanism/s of action underlying this beneficial effect. We have shown that simvastatin reduced the size of the infarct to a different extend, according to the animal model used. Indeed, in the rat neonatal model of hypoxia/ischemia simvastatin affords protection only when is administered before the ischemic insult. In contrast, in adult rats bearing middle cerebral artery occlusion, simvastatin exerted its beneficial effect on brain injury when injected for 3 days either before or after induction of ischemia. Studies carried out to determine the therapeutic window of simvastatin demonstrated that the protective effect is observed after a single dose and when the drug is administered within 3-6 hours after ischemia. Simvastatin-dependent activation of eNOS has been claimed to be one of the main mechanisms responsible for neuroprotection. This hypothesis is confirmed in the adult animal model where eNOS is activated by either pre- or post- simvastatin treatment but is not supported by the data obtained in the neonate where eNOS activity is not affected by drug treatment. These observations suggest that the protective effect of simvastatin on stroke may be mediated by multiple mechanisms as can be expected by its pleiotropic effects.
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PMID:Neuroprotective effect of simvastatin in stroke: a comparison between adult and neonatal rat models of cerebral ischemia. 1592 39

Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has long been thought to exert its benefits by reducing cholesterol synthesis, and has been shown to significantly reduce cardiovascular events and mortality in patients with or without coronary artery disease. However, it is still unknown whether acute administration of simvastatin beneficially affects the cardiac function prior or during ischemia-reperfusion. The aim of this study is to evaluate the cardioprotective effect of acute simvastatin treatment on isolated rat hearts or isolated ischemia-reperfusion hearts. Hearts were isolated from male Sprague-Dawley rats and attached to a Langendorff apparatus. The isolated hearts with or without ischemia (15 min) and reperfusion (60 min) were perfused with different concentrations of simvastatin. The parameters of cardiac function (such as left ventricular developed pressure [LVDP], +dp/dt max, and -dp/dt max), heart rate, and coronary flow were recorded. Simvastatin (3-30 micromol/l) significantly increased LVDP, +dp/dt max, and -dp/dt max in isolated rat hearts perfused for 60 min. Heart rate was depressed by 30 micromol/l simvastatin and the coronary flow was increased by 10 and 30 micromol/l simvastatin. At a concentration of 100 micromol/l simvastatin, worsening of heart function and subsequent cardiac arrest occurred. Administration of simvastatin (3-30 micromol/l) significantly preserved cardiac function detected by LVDP, +dp/dt max, and -dp/dt max in the isolated ischemia/reperfused (15/60 min) rat hearts. Simvastatin also significantly decreased heart rate at 30 micromol/l, and increased coronary flow at 10 and 30 micromol/l in these rat hearts. However, the protective effect of simvastatin reverted to increased damage at 100 micromol/l. Only 3 micromol/l simvastatin pretreatment before 15/60 min ischemia-reperfusion altered LVDP, +dp/dt max, and -dp/dt max. Both heart rate and coronary flow were unaltered after simvastatin pretreatment. Since simvastatin at a concentration lower than 100 micromol/l exerted beneficial effects on cardiac function in isolated perfused rat hearts, it could be applied just after myocardial ischemia and reperfusion.
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PMID:Effects of simvastatin on cardiohemodynamic responses to ischemia-reperfusion in isolated rat hearts. 1655 Mar 13

We tested the hypothesis that statins would decrease renal injury in renal artery stenosis (RAS) by restoring angiogenesis and attenuating intrarenal microvascular (IMV) remodeling. Single-kidney hemodynamics and function were quantified using electron-beam-computed tomography (CT) in normocholesterolemic pigs after 12 wk of experimental RAS, RAS supplemented with simvastatin (RAS+simvastatin), and normal controls. Renal circulation was also studied in vivo using angiography and ex vivo using a unique 3D micro-CT imaging technique. Angiogenic and remodeling pathways were subsequently explored in renal tissue. Blood pressure and the degree of stenosis were similarly increased in RAS groups. Simvastatin in RAS enhanced both intrarenal angiogenesis and peri-stenosis arteriogenesis and increased the expression of angiogenic growth factors and hypoxia-inducible factor-1alpha. Furthermore, simvastatin decreased tissue-transglutaminase expression and IMV inward remodeling, restored IMV endothelial function, decreased fibrogenic activity, and improved renal function. Chronic simvastatin supplementation promoted angiogenesis in vivo, decreased ischemia-induced IMV remodeling, and improved IMV function in the stenotic kidney, independent of lipid lowering. These novel renoprotective effects suggest a role for simvastatin in preserving the ischemic kidney in chronic RAS.
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PMID:Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia. 1679 May 24

This study examined the effects of simvastatin (10 mg/ kg) and VULM 1457 (50 mg/kg), an ACAT inhibitor, in the heart model of 6 min ischemia followed by 10 min reperfusion injury in the diabetic-hypercholesterolaemic (DM-HCH) rats. In the DM-HCH rats, the incidence of ventricular tachycardia (VT) had a tendency to be increased, while ventricular fibrillation (VF) occurred in all diseased rats (p < 0.01). Simvastatin and VULM 1457 with the shown hypolipidemic effect, significantly (p < 0.01) suppressed a formation of VF (38% and 29%; respectively).
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PMID:Protective effect of simvastatin and VULM 1457 in ischaemic-reperfused myocardium of the diabetic-hypercholesterolemic rats. 1702 Jan 64

The effect of acute pretreatment with a single dose of simvastatin (1 mg/kg, i.v.; 30 min before ischemia) on renal dysfunction caused by ischemia-reperfusion (I/R) injury in the rat was investigated. I/R injury was induced by clamping both renal vascular pedicles for 45 min, followed by 4 h of reperfusion with saline (2 ml/kg per hour). Simvastatin significantly improved both parameters of glomerular and tubular dysfunction (e.g., creatinine levels and fractional excretion of Na(+), respectively) and especially improved the histological score, compared to control I/R-injured rats treated with saline or 10% DMSO only.
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PMID:Single-dose intravenous simvastatin treatment attenuates renal injury in an experimental model of ischemia-reperfusion in the rat. 1713 Jun 71

This study investigated whether oral simvastatin and manidipine interact in protecting the perfused rat heart from ischemia-reperfusion damage. Simvastatin (0.3 to 3 mg/kg) and manidipine (1 to 10 mg/kg) were given orally singly or together to normocholesterolemic rats once a day for seven consecutive days. At the end of treatment, systolic blood pressure and heart rate were measured in conscious rats, and the lipid profile and other biochemical markers, such as thromboxane B(2), nitrite/nitrates and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)) were determined in the plasma. Hearts were then isolated, perfused with Krebs-Henseleit, and subjected to low flow ischemia-reperfusion injury. Post-ischemic recovery of left ventricular function was measured as left ventricular developed pressure and left ventricular end-diastolic pressure. Creatine kinase, lactate dehydrogenase, tumor necrosis factor-alpha and 6-keto-PGF(1alpha) were measured in the heart effluents. In conscious animals, simvastatin alone increased plasma 6-keto-PGF(1alpha) release while manidipine alone reduced systolic blood pressure with a slight sympathetic reflex increase in heart rate, and increased plasma nitrite/nitrates. The combined treatment produced the same effects, but significantly more marked, and accompanied by a significant reduction of thromboxane B(2). Combined treatment was also significantly more effective than the single drugs in protecting the hearts from ischemia-reperfusion injury, with inhibition of creatine kinase, lactate dehydrogenase and tumor necrosis factor-alpha, and enhancement of 6-keto-PGF(1alpha) during reperfusion. These data show that simvastatin and manidipine interact positively in protecting the rat heart from ischemia-reperfusion injury, possibly through increased prostaglandin and nitric oxide formation by the vascular endothelial cells.
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PMID:Combined simvastatin-manidipine protect against ischemia-reperfusion injury in isolated hearts from normocholesterolemic rats. 1844 13


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