Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischemic rat hearts

The aim of the present study was to examine the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on mitochondrial respiration in ischemic rat hearts, and to compare the effects between water-soluble pravastatin and lipid-soluble simvastatin. Either vehicle (0.5% carboxymethyl cellulose), pravastatin (2 or 4 mg/kg per day), or simvastatin (1 or 2 mg/kg per day) was orally administered for 3 weeks. Ischemia was induced by ligating the aorta for 60 min in anesthetized open chest rats under artificial respiration. The hearts were removed, mitochondria were isolated, and the respiration was determined by polarography using glutamate and succinate as substrates. When succinate was used as a substrate, the ADP-stimulated respiration (QO₃) and ATP production per unit oxygen (ADP/O ratio) were decreased by ischemia. The decreases in QO₃ and ADP/O ratio in the pravastatin-and simvastatin-treated groups appeared to be more prominent than those in the vehicle-treated group. This was especially true in the simvastatin-treated group. The ADP-limited respiration (QO₄) with succinate in the vehicle-treated heart was slightly increased by ischemia, while that in the pravastatin- or simvastatin-treated hearts was decreased. In conclusion, HMG-CoA reductase inhibitors may result in worsening of myocardial mitochondrial respiration during ischemia.     

Influence of heart rate on the effects of prenalterol on regional myocardial blood flow and function during coronary stenosis in dogs.

The effects of prenalterol, a selective beta 1-adrenoceptor agonist with potent cardiac positive inotropic properties have been investigated on regional myocardial blood flow (RMBF) (microspheres) and contractile function (ultrasonic crystals) during partial circumflex coronary artery stenosis in 8 open-chest anaesthetized dogs. Prenalterol was investigated at two intravenous doses: 5 micrograms kg-1, which increased myocardial contractility (dP/dt max: +29%) more than heart rate (+12%, up to 150 beats min-1) and 20 micrograms kg-1 which induced almost similar increases in contractility (+35%) and heart rate (+31% up to 175 beats min-1). The induced modifications of regional flow and function were then compared to those produced in another series of 6 dogs by atrial pacing at 150 and 175 beats min-1 respectively. Prenalterol significantly increased RMBF and segment length (SL)-shortening in a dose-dependent manner in the nonischaemic zone. In the ischaemic zone, RMBF was maintained and SL-shortening increased with prenalterol, 5 micrograms kg-1 whereas both RMBF and contractile function were severely decreased with prenalterol, 20 micrograms kg-1. Atrial pacing had almost no effect on RMBF and SL-shortening in the nonischaemic zone. In the ischaemic zone, atrial pacing rate-dependently decreased both RMBF and SL-shortening. Thus, a significant increase in contractility, associated with little tachycardia (prenalterol, 5 micrograms kg-1), induces beneficial effects on RMBF and function in both the nonischaemic and ischaemic myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of nipradilol on myocardial energy metabolism in the dog ischaemic heart

The effect of nipradilol, a newly developed beta-adrenoceptor blocking agent with a vasodilatory action, on myocardial energy metabolism has been examined in the dog ischaemic heart, and compared with that of propranolol. Ischaemia was induced by ligating the left anterior descending coronary artery. Either saline, nipradilol (0.3 mg kg-1), or propranolol (1 mg kg-1) was injected intravenously 5 min before coronary ligation. After 3 or 30 min of coronary ligation, the ischaemic region of the myocardium was removed, and the endocardial portion used to determine the levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), creatine phosphate (CrP) and lactate. Ischaemia decreased the levels of ATP and CrP, and increased the levels of ADP, AMP and lactate. Immediately after the injection of nipradilol, rapid falls in blood pressure and heart rate were observed. Pretreatment with nipradilol lessened the decreases in the levels of ATP and CrP and the increases in the levels of AMP and lactate, caused by 3 min of ischaemia, to the same extent as propranolol. However, after 30 min of ischaemia, nipradilol had no effect on myocardial metabolism unlike propranolol. These results indicate that nipradilol can reduce ischaemic influences on myocardial metabolism as well as propranolol, but only in the early stages of ischaemia.     

Cardioprotective actions of pentoxifylline in an animal model of acute myocardial ischaemia

The action of pentoxifylline on some of the consequences of acute myocardial ischaemia was studied in cats in vivo. Occlusion of the left anterior descending coronary artery (LAD) for 5 h resulted in a significant elevation in the ST-segment of the ECG, a reduction in free platelet count in right atrial blood and a loss of creatine phosphokinase (CK) and cathepsin D activities in homogenates of the severely ischaemic myocardium as compared to non-ischaemic myocardium. Intravenous infusions of pentoxifylline (0.30 mg kg-1 min-1 for 1 h and 0.15 mg kg-1 min-1 for the remainder of the 5 h observation period, starting 0.5 h after LAD occlusion) significantly reduced the loss of enzymes from the ischaemic myocardium, prevented any further increase in the ST-segment and restored the platelet count to its control level. There were no significant changes in plasma immunoreactive 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) and thromboxane B2 (TXB2), although a tendency for a reduction in TXB2 levels was observed. Pentoxifylline seems to affect, beneficially, the myocardium in this animal model of acute myocardial ischaemia. The reason for this cardioprotective action remains to be elucidated. It is, however, noteworthy that the overall profile of action of pentoxifylline resembles that of PGI2 administration in this model.     

Enhanced role for the opening of potassium channels in relaxant responses to acetylcholine after myocardial ischaemia and reperfusion in dog coronary arteries

1. Anaesthetized dogs were subjected to 1 h occlusion of the left circumflex coronary artery followed by 2 h of reperfusion. Relaxant responses were examined in coronary artery rings removed proximal (nonischaemic) or distal (ischaemic) to the site of occlusion. 2. Relaxant responses to acetylcholine (ACh) were similar in nonischaemic and ischaemic artery rings. In addition ACh-induced relaxation of nonischaemic and ischaemic artery rings was equally susceptible to inhibition of nitric oxide (NO) synthase using L-N(G)-nitroarginine (L-NOARG, 10(-4) M), or to inhibition of soluble guanylate cyclase using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10(-5) M). 3. In nonischaemic arteries, the relaxation to ACh was unaffected by high K+ (67 mM) but in ischaemic arteries, the maximum relaxation to ACh was significantly reduced from 113+/-6 to 60+/-2% (ANOVA, P<0.05). Tetraethylammonium (TEA, 10(-3) M), an inhibitor of large conductance calcium activated potassium (BK(Ca)) channels did not inhibit the response to ACh in nonischaemic arteries but in ischaemic arteries TEA significantly shifted the concentration response curve to ACh to the right (pEC(50); nonischaemic, 7.07+/-0.25; ischaemic, 6.54+/-0.21, P<0.01, ANOVA) without decreasing the maximum relaxation. TEA did not affect the responses to sodium nitroprusside in either nonischaemic or ischaemic arteries. 4. In conclusion, ischaemia/reperfusion did not change the sensitivity of endothelium-dependent relaxation to L-NOARG or ODQ indicating that ischaemia did not affect the contribution of NO or cyclic GMP to ACh-induced relaxation. However, in ischaemic arteries the opening of the BK(Ca) channels contributed to relaxation caused by ACh whereas TEA had no effect in nonischaemic arteries. The factor responsible for the opening of this potassium channel was a factor other than NO and may be endothelium derived hyperpolarizing factor (EDHF).     

Effect of nadolol, a beta-adrenoceptor blocking agent, on myocardial metabolism in the dog ischaemic heart

The effect of nadolol at a dose of 1 mg kg-1, i.v. on the ischaemic myocardial metabolism has been examined in the dog. Ischaemia was induced by ligating the left anterior descending coronary artery for 3 min, and nadolol was injected 5 min before ligation. Ischaemia caused myocardial metabolic changes; it decreased energy charge potential and inhibited glycolytic flux through phosphofructokinase reaction. Pretreatment with nadolol lessened the decrease in energy charge potential and the inhibition of glycolytic flux being caused by ischaemia. Nadolol may have a beneficial effect on the ischaemic myocardium.     

The effect of body temperature on myocardial protection conferred by ischaemic preconditioning or the selective adenosine A1 receptor agonist GR79236, in an anaesthetized rabbit model of myocardial ischaemia and reperfusion

1 The cardioprotective effect of N-[(1S, trans)-2-hydroxycyclopentyl]adenosine (GR79236), an adenosine A1 receptor agonist, was compared with that produced by ischaemic preconditioning in an anaesthetized rabbit model of myocardial ischaemia and reperfusion. In addition, we examined the effect of different body core temperatures on GR79236- or ischaemic preconditioning-induced cardioprotection when administered prior to ischaemia, and on cardioprotection induced by GR79236 administered 10 min prior to the onset of reperfusion. 2 When rabbits were subjected to 30 min occlusion of the left coronary artery, followed by 2 h reperfusion, GR79236 (3 x 10(-8) mol kg-1 i.v. (10.5 microg kg-1 i.v.)) or ischaemic preconditioning (5 min ischaemia followed by 5 min reperfusion), administered or applied 10 min prior to the occlusion, significantly limited the development of infarction. The cardioprotective effect of ischaemic preconditioning was significantly greater than that seen after administration of GR79236. Pre-treatment with the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 3.3 x 10(-6) mol kg-1 (1 mg kg-1 i.v.)), prevented the cardioprotective effect of GR79236, but not that of ischaemic preconditioning. 3 Maintaining body core temperature at 38.5 degrees C rather than at 37.0 degrees C did not influence infarct size in control groups of rabbits, but reduced the cardioprotective effect of GR79236 when administered 10 min prior to occlusion or 10 min prior to the onset of reperfusion. The cardioprotective effect of ischaemic preconditioning was not temperature-dependent. 4 In conclusion, myocardial protection conferred by GR79236 in anaesthetized rabbits is mediated via adenosine A1 receptors. Myocardial protection can be conferred when GR79236 is administered before the onset of ischaemia or reperfusion, and is reduced when body core temperature is maintained at 38.5 degrees C rather than at 37.0 degrees C. In contrast, myocardial protection conferred by ischaemic preconditioning is not reduced by adenosine A1 receptor blockade, or by maintaining body core temperature at 38.5 degrees C rather than at 37.0 degrees C. These findings point to distinct differences in the mechanisms of induction of myocardial protection by adenosine A1 receptor agonist and ischaemic preconditioning. They also highlight the need for careful control of body core temperature when investigating the phenomenon of cardioprotection.     

The effect of chemical sympathectomy on mitochondrial function in the ischaemic and reperfused myocardium.

1 Isolated rabbit hearts were perfused aerobically for 120 min, made ischaemic for 90 min, or made ischaemic for 90 min and then reperfused for 30 min. 2 Some rabbits were pretreated with 6-hydroxydopamine (6-OHDA), given as three separate intravenous doses of 30, 20 and 20 mg/kg, 20 to 48 h before they were killed; others (controls) received saline according to the same regime. 3 Mitochondria were harvested from left ventricular homogenates and their function assessed by measuring state 3O2 consumption (state 3 QO2), respiratory control index (RCI), phosphate: oxygen ratio (ADP:O), Ca2+ content, and ATP-producing activity. In other experiments peak left ventricular developed tension was recorded. 4 In hearts from saline-treated animals, mitochondrial state 3 QO2, RCI and ATP producing activities were reduced after global ischaemia, with or without reperfusion. There was a small gain in mitochondrial Ca2+ after ischaemia, and a large gain upon reperfusion. 5 6-OHDA pretreatment provided some protection against the effects of ischaemia and reperfusion on mitochondrial function and on peak developed tension. 6 It was concluded that chemical sympathectomy with 6-OHDA does not duplicate the effect of prolonged beta-adrenoceptor blockade in protecting mitochondrial function against the deleterious effects of ischaemia and reperfusion.     

Effect of a novel thromboxane A2 synthetase inhibitor on ischemia-induced mitochondrial dysfunction in canine hearts

This study was designed to determine the effect of sodium 6-(2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b] thiophene)carboxylate (RS-5186), a new thromboxane A2 (TXA2) synthetase inhibitor, on mitochondrial function and lysosomal integrity in ischemic myocardium. 17 anesthetized mongrel dogs were divided into 2 groups. In the control group (n = 11), the left anterior descending arteries (LAD) of the dogs were occluded for 2 h and physiological saline was infused until the end of the experiment. In the RS-5186 treated group (n = 6), 25 min prior to LAD occlusion, RS-5186, 10 mg/kg, was injected for 10 min. 2 h after occlusion, mitochondria were prepared from both ischemic and non-ischemic areas, which were confirmed by Evans' blue dye, and mitochondrial function (respiratory control index: RCI, and the rate of oxygen consumption in state III respiration: St.III O2) was measured polarographically with succinate as substrate. Fractionation of myocardial tissue from both ischemic and non-ischemic areas was also performed, and the activities of lysosomal enzymes (N-acetyl-beta-glucosaminidase: NAG, beta-glucuronidase: beta-gluc) of each fraction were measured. 2-h LAD occlusion induced a significant greater decrease in mitochondrial function from the ischemic area of the control group (RCI: 2.80 +/- 0.45, St.III O2: 133.5 +/- 35.6 natoms/mg protein/min) compared with those from the non-ischemic area (RCI: 4.49 +/- 0.46, St.III O2: 344.0 +/- 31.9).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the effects of EXP3174, an angiotensin II antagonist and enalaprilat on myocardial infarct size in anaesthetized dogs.

1. In order to determine whether the renin-angiotensin system is involved in myocardial ischaemia-reperfusion injury, we investigated and compared the effects on infarct size of two different drugs which interfere with this system, i.e., an angiotensin II (AT1) antagonist, EXP3174, and an angiotensin I-converting enzyme inhibitor (ACEI), enalaprilat in a canine model of ischaemia-reperfusion. 2. EXP3174 (0.1 mg kg-1, i.v. followed by 0.02 mg kg-1 h-1 for 5.5 h) and enalaprilate (0.3 mg kg-1, i.v. followed by 0.06 mg kg-1 h-1 for 5.5 h) were used in doses inducing a similar level of inhibition (87 +/- 4 and 91 +/- 3%, respectively) of the pressor responses to angiotensin I. Control animals received saline. 3. Infarct size and area at risk were quantified by ex vivo dual coronary perfusion with triphenyltetrazolium chloride and monastral blue dye. Regional myocardial blood flows (ischaemic and nonischaemic, endocardial, epicardial) were assessed by the radioactive microsphere technique. 4. Both EXP3174 and enalaprilat induced a decrease in mean arterial blood pressure. However, non significant changes in regional myocardial blood flows, whether ischaemic or nonischaemic, were observed after administration of either the ACEI or the AT1 antagonist. 5. The size of the area at risk was similar in the three groups. By direct comparison, there were no significant differences between infarct sizes in the three groups. Furthermore, there was a close inverse relationship between infarct size and transmural mean collateral blood flow in controls, and none of the treatments altered this correlation. Thus, neither EXP3174 nor enalaprilat limited infarct size.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of LP-805, a Newly Developed Vasodilator,on Myocardial Metabolism in Ischaemic Dog Hearts

Abstract— The effects of LP-805, a newly developed vasodilator, on changes in the myocardial energy and carbohydrate metabolism induced by ischaemia were studied in open-chest anaesthetized dogs. Ischaemia was induced by ligating the left anterior descending coronary artery for 3 min. The myocardial energy stores were depleted, and the levels of glycolytic intermediates were altered 3 min after the onset of ischaemia. Energy change potential was decreased, and ([G6P] + [F6P])/[FDP] and [lactate]/[pyruvate] ratios were increased by ischaemia. These findings indicated that the myocardial metabolism was converted from an aerobic to an anaerobic type by ischaemia. LP-805 (10, 30, or 100 μg kg^?1) was injected intravenously 5 min before the onset of ischaemia. LP-805 prevented the myocardial energy depletion and alterations of myocardial carbohydrate metabolism due to ischaemia, indicating that it appeared to convert the anaerobic metabolism back to aerobic metabolism in the ischaemic myocardium. In conclusion, LP-805 may reduce the ischaemic influence on the myocardium.     

Defibrotide reduces infarct size in a rabbit model of experimental myocardial ischaemia and reperfusion.

1. Defibrotide, a single-stranded polydeoxyribonucleotide obtained from bovine lungs, has significant anti-thrombotic, pro-fibrinolytic and prostacyclin-stimulating properties. 2. The present study was designed to evaluate the effects of defibrotide on infarct size and regional myocardial blood flow in a rabbit model of myocardial ischaemia and reperfusion. 3. Defibrotide (32 mg kg-1 bolus + 32 mg kg-1 h-1, i.v.) either with or without co-administration of indomethacin (5 mg kg-1 x 2, i.v.) was administered 5 min after occlusion of the left anterior-lateral coronary artery and continued during the 60 min occlusion and subsequent 3 h reperfusion periods. 4. Defibrotide significantly attenuated the ischaemia-induced ST-segment elevation and abolished the reperfusion-related changes (R-wave reduction and Q-wave development) in the electrocardiogram. In addition, defibrotide significantly improved myocardial blood flow in normal and in ischaemic, but not in infarcted sections of the heart. The improvement in blood flow in normal perfused myocardium, but not in the ischaemic area was prevented by indomethacin. 5. Although the area at risk was similar in all animal groups studied, defibrotide treatment resulted in a 51% reduction of infarct size. Indomethacin treatment abolished the reduction of infarct size seen with defibrotide alone. 6. The data demonstrate a considerable cardioprotective effect of defibrotide in the reperfused ischaemic rabbit myocardium. This effect may be related, at least in part, to a stimulation of endogenous prostaglandin formation. Other possible mechanisms are discussed.     

Prenylamine and the myocardial response to ischaemia and reperfusion: effects of acute and chronic treatment

The ability of prenylamine gluconate (Segontin) to influence the extent of myocardial ischaemic injury was investigated in the isolated 'working' rat heart preparation. The drug was administered either acutely alone (4 microM litre-1 in the perfusion medium) or chronically plus acutely in which case animals were pre-treated (10 mg kg-1 day-1 orally) for 10 days and the drug was then also added (4 microM litre-1) to the perfusate. Acute administration alone resulted in a small reduction in spontaneous functional performance in the aerobic isolated heart in comparison with gluconate treated controls. It also increased the percentage of hearts able to recover functional activity after a period of severe ischaemia and decreased ischaemia induced injury as assessed by enzyme leakage. In contrast to the acute results the combination of chronic and acute administration of prenylamine did not significantly alter spontaneous cardiac function. Although a small increase in the number of hearts that recovered function was apparent, there was a concomitant decrease in post-ischaemic functional performance with no reduction of ischaemia induced enzyme leakage.     

Protective effect of propranolol on mitochondrial function in the ischaemic heart

1. The present study was aimed to determine whether propranolol improves contractile function of the ischaemic/reperfused heart through protection of the mitochondrial function during ischaemia. 2. Isolated perfused rat hearts were subjected to 35-min ischaemia followed by 60-min reperfusion. Pre-treatment with propranolol at the concentrations of 10 to 100 microM for the final 3 min of pre-ischaemia resulted in the improvement of ischaemia/reperfusion-induced contractile dysfunction, release of creatine kinase (CK) into perfusate, and decrease in myocardial high-energy phosphates. Propranolol also attenuated ischaemia-induced accumulation in Na+, suggesting that cytosolic sodium overload during ischaemia was prevented by propranolol. 3. The mitochondrial oxygen consumption rate of skinned bundles from the perfused heart decreased at the end of ischaemia and it further decreased at the end of reperfusion. These decreases were cancelled by treatment with propranolol. A release of cytochrome c from the perfused heart was observed during ischaemia, and this release was suppressed by treatment with propranolol. 4. To elucidate the direct effect of propranolol on mitochondria, the mitochondria were isolated from normal hearts and their activities were determined in the presence of various concentrations of Na+ and propranolol. The addition of sodium lactate, which mimicked sodium overload in the ischaemic heart, reduced the state 3 respiration, whereas this reduction was not attenuated by the presence of propranolol. 5. These results suggest that cardioprotection of propranolol may be exerted via attenuating Na+ influx into cardiac cells followed by prevention of the mitochondrial dysfunction in the ischaemic heart, leading to improvement of energy production of the heart during reperfusion.     

Inhibitory effects of several anthracyclines on mitochondrial respiration and coenzyme Q10 protection

A set of three novel anthracyclines, active as antitumour agents, has been examined for their possible effects on rat heart mitochondrial respiration. The in vitro inhibiting effects of the compounds have been compared with that of the older doxorubicin. Aclacinomycin was generally more inhibitory than doxorubicin, 4'-epi-doxorubicin and 4'-epi-tetrahydropyranyl-adriamycin, with both succinate and NAD+-linked substrates. Attempts to prevent anthracycline from inhibiting the succinate oxidase activity by means of adding exogenous coenzyme Q10 gave encouraging results, the inhibiting effect being in fact reduced.     

Treatment of acute myocardial ischaemia with a selective antagonist of thromboxane receptors (BM 13.177).

In order to elucidate the role of endogenous thromboxane A2 in myocardial ischaemia, cats were subjected to 5 h of permanent occlusion of the left anterior descending coronary artery (LAD) and treated with the thromboxane receptor antagonist BM 13.177 (5 mg kg-1 h-1, i.v.). In comparison with vehicle-treated LAD-occluded cats, BM 13.177 significantly attenuated the loss of creatine phosphokinase-specific activity from the ischaemic myocardium and antagonized the ischaemia-induced rise in the ST-segment of the electrocardiogram. BM 13.177 at the dose used did not reduce plasma thromboxane levels or ischaemia-induced platelet aggregate formation but considerably antagonized thromboxane-dependent platelet secretion ex vivo. The study demonstrates some beneficial effects of selective blockade of thromboxane receptors on biochemical and electrophysiological parameters of acute myocardial ischaemia.     

Simvastatin induces mitochondrial dysfunction and increased atrogin-1 expression in H9c2 cardiomyocytes and mice in vivo

Simvastatin is effective and well tolerated, with adverse reactions mainly affecting skeletal muscle. Important mechanisms for skeletal muscle toxicity include mitochondrial impairment and increased expression of atrogin-1. The aim was to study the mechanisms of toxicity of simvastatin on H9c2 cells (a rodent cardiomyocyte cell line) and on the heart of male C57BL/6 mice. After, exposure to 10 μmol/L simvastatin for 24 h, H9c2 cells showed impaired oxygen consumption, a reduction in the mitochondrial membrane potential and a decreased activity of several enzyme complexes of the mitochondrial electron transport chain (ETC). The cellular ATP level was also decreased, which was associated with phosphorylation of AMPK, dephosphorylation and nuclear translocation of FoxO3a as well as increased mRNA expression of atrogin-1. Markers of apoptosis were increased in simvastatin-treated H9c2 cells. Treatment of mice with 5 mg/kg/day simvastatin for 21 days was associated with a 5 % drop in heart weight as well as impaired activity of several enzyme complexes of the ETC and increased mRNA expression of atrogin-1 and of markers of apoptosis in cardiac tissue. Cardiomyocytes exposed to simvastatin in vitro or in vivo sustain mitochondrial damage, which causes AMPK activation, dephosphorylation and nuclear transformation of FoxO3a as well as increased expression of atrogin-1. Mitochondrial damage and increased atrogin-1 expression are associated with apoptosis and increased protein breakdown, which may cause myocardial atrophy.     

The effects of simvastatin and pravastatin on objective and subjective measures of nocturnal sleep: a comparison of two structurally different HMG CoA reductase inhibitors in patients with primary moderate hypercholesterolaemia.

1. It has been suggested that HMG CoA reductase inhibitors which are administered as inactive, lipophilic lactones (e.g. simvastatin) have a greater propensity to evoke nocturnal sleep disturbances than pravastatin, an inhibitor given in the active, hydrophilic, open-acid form. 2. The effects of 4 weeks treatment with equipotent doses of simvastatin (20 mg day-1) and pravastatin (40 mg day-1) have been compared using polysomnography and subjective sleep assessments in a double-blind, placebo-controlled, two-period, incomplete block design study involving 24 male patients with primary moderate hypercholesterolaemia (mean LDL cholesterol 5.11 mmol l-1). 3. Analysis of sleep EEG measures relevant to insomnia provided no evidence of significant differences between pravastatin, simvastatin and placebo, except in terms of entries and latency to stage I sleep. The number of entries to stage I sleep was significantly greater after simvastatin treatment than after either pravastatin or placebo (P < 0.05), but by contrast the latency to stage I sleep was significantly prolonged only in the pravastatin group (P < 0.05 vs placebo). 4. Subjective ratings of sleep initiation, maintenance and quality made during and after therapy were not significantly different between the three treatment groups. 5. It appears that the inherent hydrophobicity of simvastatin does not increase the occurrence of sleep disturbances in this patient population at a dose shown to elicit a characteristic hypolipidaemic response.     

Preserved cardiac mitochondrial function and reduced ischaemia/reperfusion injury afforded by chronic continuous hypoxia: Role of opioid receptors

Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to acute ischaemia/reperfusion injury. The objective of this study was to find out whether the cardioprotective effect of CNH mediated by opioid receptors is associated with preservation of mitochondrial function. Rats were adapted to CNH (12% oxygen) for 3 weeks. Isolated perfused hearts were subjected to 45 min of global ischaemia and 30 min of reperfusion; subgroups were pretreated with non‐selective opioid receptor antagonist naloxone (300 nmol/L) for 10 min. Cardiac contractile function, creatine kinase activity in coronary effluent, mitochondrial respiration rate, and calcium retention capacity were assessed. Adaptation to CNH decreased myocardial creatine kinase release during reperfusion and improved the post‐ischaemic recovery of contractile function, mitochondrial state 3 and uncoupled respiration rates, and calcium retention capacity compared to the normoxic group. These protective effects were completely abolished by naloxone. The contractile recovery positively correlated with state 3 respiration and calcium retention capacity. The results suggest that the preserved mitochondrial function contributes to the protected cardiac phenotype afforded by adaptation to CNH and point to an important role of opioid receptor activation.     

Pretreatment with simvastatin reduces myocardial no-reflow by opening mitochondrial K(ATP) channel

BACKGROUND AND PURPOSE: Simvastatin, a cholesterol-lowering agent, can protect against endothelial dysfunction. However, the effects of simvastatin treatment on the restoration of blood flow to ischemic myocardium are not known. This study sought to assess such effects of simvastatin on an experimental model of myocardial no-reflow and to explore possible mechanisms. EXPERIMENTAL APPROACH: Coronary ligation area and area of no-reflow were determined by myocardial contrast echocardiography in vivo and by histology in mini-pigs randomized into 7 study groups: controls, pretreated with simvastatin for 2 days, treated with 5-hydroxydecanoate (5-HD, the selective mitochondrial K(ATP) channel blocker), treated with simvastatin+5-HD, treated with HMR 1883 (the selective sarcolemmal K(ATP) channel blocker), treated with simvastatin+HMR 1883 and a sham-operated group. The myocardial no-reflow model was induced with 3 h occlusion of the left anterior descending coronary artery followed by 2 h reperfusion. KEY RESULTS: Compared with the control group, simvastatin significantly increased coronary blood flow, decreased the area of no-reflow assessed echocardiographically and reduced the necrotic area, by histology. There was no significant difference in these outcomes between simvastatin and simvastatin+HMR 1883 groups. In contrast, 5-HD abolished the effect of simvastatin. CONCLUSIONS AND IMPLICATIONS: Simvastatin can reduce the area and myocardial no-reflow after ischaemia and reperfusion. This beneficial effect is due to its activation of mitochondrial K(ATP) channels.