Beneficial effect of nipradilol (K-351) on acute myocardial ischemia. Study of the relationship between regional myocardial blood flow and energy metabolism

To examine the effects of nipradilol on ischemic myocardium, experiments were performed on regional myocardial blood flow (MBF) and energy metabolism in anesthetized, open-chest dogs. Nipradilol at a dose of 0.3 mg/kg was i.v.-administered 10 min after coronary ligation. MBFs at various sites, including ischemic and non-ischemic areas, were determined by the hydrogen gas clearance method. The levels of ATP and creatine phosphate (CP) at the site of MBF determination were measured 60 min after ligation, and mitochondrial function (RCI, QO2) in the ischemic and non-ischemic areas was determined. Following nipradilol administration, aortic pressure and heart rate were significantly lowered. In ischemic areas with MBF below 40 ml/min/100 g, nipradilol had no influence on MBF. However, the tissue level of ATP in nipradilol treated hearts was significantly higher as compared with untreated hearts. In the area of mild ischemia with MBF of 40-60 ml/min/100 g, nipradilol preserved the tissue ATP and CP levels in spite of a decrease in MBF. Moreover, an inhibition of the decrease in mitochondrial respiratory function was observed in ischemic areas with MBF below 20 ml/min/100 g. Thus, nipradilol administered following ischemia preserved ATP content and mitochondrial function in the ischemic myocardium with reduction of heart rate and aortic pressure. This suggests that nipradilol exerts a cardioprotective effect in acute ischemia. It seems that the cardioprotective effect is due to a decrease in myocardial oxygen demand and preservation of mitochondrial function.     

Radical scavenging properties of novel benzopyran derivatives, TA248 and TA276, and effects of the compounds on ischemic/reperfused myocardium in dogs

Characteristics of novel benzopyran derivatives, TA248 and TA276, and their effects on myocardial contraction in ischemic/reperfused hearts in dogs were examined. TA248 and TA276 inhibited NADPH-dependent lipid peroxidation induced by Fe(3+) in the rat brain homogenate. Both compounds reduced *O(2-) produced by xanthine-xanthine oxidase system in a dose-dependent manner. TA276 scavenged.OH generated by Fenton reaction in a dose-dependent manner. TA248 also inhibited the.OH production, but the effect was neither complete nor dose dependent. Myocardial contraction was assessed as segment shortening of the left ventricular wall in pentobarbital-anesthetized open-chest dogs. The segment shortening was decreased by the left anterior descending coronary artery ligation (ischemia) and returned by release of the ligated artery (reperfusion). The segment shortening did not recover fully during reperfusion. Either TA248 or TA276 injected 10 min before ischemia improved the recovery of myocardial contraction during reperfusion. Both compounds preserved the level of ATP in the 60-min reperfused myocardium. However, the level of lipid peroxides was not changed by TA248 and TA276. TA248 and TA276 may protect myocardium against ischemic/reperfusion insult, partly because of their free radical scavenging activity, but no significant change in myocardial lipid peroxide level was observed.     

Effects of nebivolol on ischemia-induced metabolic changes in dog hearts

dl-Nebivolol has a beta(1)-adrenergic blocking property and l-nebivolol has an endothelial-dependent vasodilating property, sp that a racemic mixture, deltal-nebivolol, shows both properties. This study examined the effect of dl-nebivolol on ischemic myocardium in anesthetized open chest dogs. Ischemia was induced for 3 min by ligating the left anterior descending coronary artery 10 min after IV injection of vehicle, dl-nebivolol (0.03, 0.1, and 0.3 mg/kg), or d- or l-nebivolol (0.15 mg/kg). Ischemia significantly decreased the levels of ATP, creatine phosphate, and fructose-1,6-diphosphate and increased those of ADP, AMP, hexose monophosphates, and ratio of [lactate]/[pyruvate]. dl-Nebivolol at higher doses significantly attenuated some metabolic changes caused by ischemia. Although neither enantiomers significantly affected these ischemia-induced metabolic changes, d-nebivolol appeared to attenuate adenine nucleotide reduction due to ischemia. Pretreatment with Nw-nitro-l-arginine methyl ester did not abolish the restoration of ischemia-induced myocardial metabolic changes by dl-nebivolol. In conclusion, dl-nebivolol lessens ischemic derangement of myocardial metabolism, and the effects may be due mainly to its beta-adrenergic blocking property but not to endothelium-dependent vasorelaxing property.     

Effects of SEA0400, a novel inhibitor of the Na+/Ca2+ exchanger, on myocardial stunning in anesthetized dogs

Activation of the Na+/Ca2+ exchanger may contribute to Ca2+ overload during reperfusion after transient ischemia. We examined the effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a selective inhibitor of Na+/Ca2+ exchange, on a canine model of ischemia/reperfusion injury (myocardial stunning). Myocardial stunning was induced by a 15-min occlusion of the left anterior descending coronary artery followed by a 4-h reperfusion in anesthetized open-chest dogs. Reperfusion gradually restored myocardial percent segment shortening but remained depressed during a 4-h reperfusion period. A bolus intravenous injection of SEA0400 (0.3 or 1.0 mg/kg), given 1 min before reperfusion, improved significantly the recovery of percent segment shortening in the ischemic/reperfused myocardium. SEA0400 did not affect the hemodynamics and electrocardiogram parameters. In addition, SEA0400 did not affect reperfusion-induced change in coronary blood flow. These results suggest that the Na+/Ca2+ exchanger is involved in the stunned myocardium of dogs after reperfusion, and that SEA0400 has a protective effect against myocardial stunning in dogs.     

外源性磷酸肌酸预处理对大鼠心肌缺血-再灌注损伤的保护作用

目的研究外源性磷酸肌酸(CP)预处理对大鼠心肌缺血-再灌注(I-R)损伤的保护作用。方法健康雄性SD大鼠30只,随机均分为三组:假手术(S)组、I-R组和CP预处理组(CP组)。I-R、CP预处理组结扎冠状动脉左前降支30 min,再灌注120 min制备心肌I-R损伤模型。缺血前30 min,CP组经腹腔注射CP 10 ml/kg。于再灌注120 min时处死大鼠,测定心肌三磷酸腺苷(ATP)含量和超氧化物岐化酶(SOD)活性,光学显微镜和透射电镜下观察心肌组织结构变化及线粒体水肿情况。结果 CP组心肌组织中ATP含量、SOD活性显著高于I-R组[(2.76±0.98)μmol/mg vs.(1.65±0.84)μmol/mg、(42.47±2.16)U/mg vs.(49.56±3.28)U/mg](P<0.05)。I-R组心肌组织明显水肿、出血和坏死;CP组心肌组织结构及线粒体变化较I-R组明显减轻。结论外源性CP对大鼠心肌I-R损伤具有明显保护作用。     

Effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on ischemic myocardial energy and carbohydrate metabolism in dogs

The effect of betaxolol, a beta 1-adrenoceptor antagonist, on ischemic myocardial metabolism was studied in dog hearts subjected to an occlusion of the left anterior descending coronary artery for 10 or 30 min. Betaxolol (0.1 or 0.3 mg/kg) was injected i.v. 5 min before ischemia. Betaxolol decreased heart rate, (+)dp/dt, coronary flow and blood pressure. Coronary occlusion decreased the levels of creatine phosphate, adenosine triphosphate, total adenine nucleotides and energy charge potential in the ischemic myocardium. Ten minutes after ischemia, betaxolol significantly diminished these impairments of energy metabolism. Even 30 min after ischemia, a higher dose of betaxolol significantly inhibited the depletion of total adenine nucleotides. Myocardial ischemia produced a breakdown of glycogen, an accumulation of lactate and an inhibition of glycolytic flux through the phosphofructokinase reaction. Betaxolol also reduced these alterations of carbohydrate metabolism 10 min after ischemia. These results indicate that betaxolol delays the onset of myocardial metabolic change from aerobic to anaerobic during ischemia and hence reduces the severity of myocardial ischemic injury.     

Cardioprotective effects of YM934, an ATP-sensitive potassium channel opener, on stunned myocardium in anesthetized dogs.

The effects of YM934 [2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl) pyridine N-oxide], an adenosine triphosphate (ATP)-sensitive potassium channel opener, on stunned myocardium were examined. Forty eight anesthetized dogs were subjected to 15 min of left anterior descending (LAD) coronary artery occlusion followed by 3 hours of reperfusion. To elucidate the possible contribution of the cardioprotective property of YM934 to stunned myocardium, a nonhypotensive dose of YM934 was directly injected into the LAD coronary artery before the ischemic insults. Intracoronary artery infusion (i.c.) of YM934 (0.1 microg/kg/min) produced a marked improvement in post-ischemic regional contractile dysfunction. The effects were not associated with improvement of hemodynamics, including regional myocardial blood flow during ischemia, heart rate and mean arterial blood pressure. The anatomic areas at risk expressed as a percentage of the left ventricle and regional myocardial blood flow were not significantly different between groups. The cardioprotective effect of YM934 was completely blocked by pretreatment with an ATP-sensitive potassium channel blocker, glibenclamide (1.0 mg/kg i.v. bolus). These results suggest that YM934 exerts cardioprotective effect on stunned myocardium through opening myocardial ATP-sensitive potassium channels.     

Improvement of stunned myocardium in dogs with olmesartan, an angiotensin II type 1 receptor antagonist, is independent of type 2 receptors

Olmesartan is a selective angiotensin II type 1 receptor (AT1) antagonist. In pentobarbital-anesthetized open-chest dogs, ischemia/reperfusion was induced by ligating the left anterior descending coronary artery for 20 min and releasing it for 60 min, respectively. The myocardial contraction in the ischemic area decreased and returned towards its pre-ischemic level during reperfusion but incompletely. Olmesartan improved the recovery of myocardial contraction during reperfusion associated with restoration of myocardial ATP. Angiotensin II repelled by AT1 receptors occupied by olmesartan can reach and stimulate the angiotensin II type 2 (AT2) receptors, resulting in some beneficial effects on the ischemic myocardium. In fact, AT2 receptor mRNA was found in the adult dog myocardium. In addition, the plasma level of angiotensin II was significantly increased by olmesartan. PD123319, a selective AT2 receptor antagonist, however, did not modify the effect of olmesartan on the cardiac contraction. The hypertensive response to exogenous angiotensin II was completely inhibited by olmesartan, whereas PD123319 did not abolish the effect of olmesartan. In conclusion, olmesartan protects the ischemic/reperfused heart against ischemic injury through inhibition of AT1 receptors but not indirect activation of AT2 receptors.     

Effects of MCI-176, a new quinazolinone calcium antagonist, on myocardial energy and carbohydrate metabolism in ischemic dog hearts.

The effect of 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)- 6-isopropoxy-4(3H)-quinazolinone hydrochloride (MCI-176), a calcium antagonist, on ischemic myocardial metabolism was studied in dog hearts subjected to an occlusion of the left anterior descending coronary artery (LAD) for 3 or 30 min. MCI-176 (0.03 or 0.1 mg/kg), when injected i.v. 5 min before occlusion, increased coronary blood flow and decreased systemic aortic pressure. When the LAD was ligated, the levels of creatine phosphate, ATP, total adenine nucleotides and energy change potential decreased in the ischemic myocardium. Three minutes after ischemia, MCI-176 (0.1 mg/kg) significantly (P less than 0.05) diminished these impairments of energy metabolism. Even 30 min after ischemia, pretreatment with MCI-176 tended to lessen the depletion of ATP and total adenine nucleotides, although these effects were not statistically significant. Myocardial ischemia produced a breakdown of glycogen, an accumulation of lactate, and an inhibition of glycolytic flux through phosphofructokinase reaction. MCI-176 (0.1 mg/kg) significantly (P less than 0.05) reduced these alterations of carbohydrate metabolism after 3 min of ischemia. These results suggest that pretreatment with MCI-176 reduces the impairments of myocardial energy and carbohydrate metabolism in ischemic dog hearts, suggesting that the drug is capable of improving the imbalance between oxygen supply and oxygen demand in the ischemic myocardium.     

Lipophilic HMG-CoA reductase inhibitors increase myocardial stunning in dogs

Pretreatment of dogs with simvastatin, a lipophilic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, increases myocardial contractile dysfunction during reperfusion after ischemia (stunning), with reduction of tissue adenosine triphosphate (ATP). This was thought to be a consequence of prevention of ubiquinone biosynthesis by the lipophilic inhibitor in the myocardial cell. We examined whether other lipophilic HMG-CoA reductase inhibitors also influence myocardial stunning in dogs. Vehicle, atorvastatin (2 mg/ kg/day), fluvastatin (4 mg/kg/day), or cerivastatin (40 microg/kg/ day) was orally administered for 3 weeks. Hydrophilic pravastatin (4 mg/kg/day) also was given. After 3 weeks, pentobarbital-anesthetized dogs were subjected to 15-min left anterior descending coronary artery occlusion followed by 2-h reperfusion. Myocardial segment function was determined by sonomicrometry. Tissue levels of ATP were determined in 2-h reperfused hearts. All inhibitors significantly decreased serum cholesterol level. The three lipophilic inhibitors resulted in a worsening of segment function in the reperfused myocardium, as compared with the vehicle group. The levels of ATP in the atorvastatin, fluvastatin, and cerivastatin groups were significantly lower than that in the vehicle group. These results confirm that lipophilic HMG-CoA reductase inhibitors enhance myocardial stunning in association with ATP reduction after ischemia and reperfusion.     

Improvement of postischemic contractile dysfunction of dog heart by MCI-154, a novel cardiotonic agent

The effects of MCI-154, a cardiotonic agent which has direct effects on cardiac myofilaments, on postischemic contractile dysfunction were studied in dog heart subjected to a 30-min occlusion of the left anterior descending coronary artery followed by reperfusion, and compared with the effects of milrinone and dobutamine, that have largely cyclic AMP-dependent mechanisms of action. Regional myocardial contractility (segment shortening) and tissue ATP levels were severely depressed in reperfused myocardium. MCI-154 (0.3 and 1 microgram/kg per min) improved the regional function of postischemic myocardium and decreased left ventricular end-diastolic pressure and systemic aortic pressure when infused i.v. from 30 min after reperfusion. The improvement of regional function caused by MCI-154 (1 microgram/kg per min) was more pronounced than that caused by milrinone (1 microgram/kg per min) or dobutamine (1 microgram/kg per min), although the drugs produced an equal increase in cardiac performance (peak positive left ventricular dP/dt). These results suggest that MCI-154 produces a more pronounced improvement of regional myocardial function than milrinone and dobutamine, presumably by increasing the responses of the contractile protein system to Ca2+. In this respect, MCI-154 would be of much benefit for the treatment of postischemic left ventricular dysfunction.     

羟苯氨酮保护大鼠心脏对抗心肌缺血-再灌注损伤

目的研究强心扩血管新药羟苯氨酮(oxyphenamone)对心肌缺血-再灌注损伤的保护作用。方法对离体或在体大鼠心脏，阻断冠脉前降支10 min后行再灌注15 min(离体)或30 min(在体)，形成心肌缺血-再灌注损伤模型，从心电图、心肌酶学与心肌超微结构等方面观察药效。结果羟苯氨酮(离体心脏灌流1-10 μmol·L^-1，或静脉注射0.1-1.0 mg·kg^-1)剂量依赖性地明显减少再灌注时的心律失常，对抗损伤所致心肌CPK，LDH与MDA的变化，减轻心肌超微结构损伤。结论羟苯氨酮明显保护离体和在体大鼠心肌对抗冠脉阻断所致缺血-再灌注损伤。     

丹参酮、纳络酮对缺血再灌注心肌局部血流量的影响

目的：观察丹参酮、纳络酮对缺血再灌注心肌局部血流量的影响。方法：用结扎冠状动脉左前降支的方法复制犬心肌缺血再灌注模型，心肌局部血流量用氢气清除法测定。结果：丹参酮、纳络酮均能明显增加正常及部分再灌注心肌血流量，丹参酮主要增加缺血周围区血流量，纳络酮可增加缺血中心区及周围区血流量。结论：丹参酮、纳络酮均能缩小缺血区范围，纳络酮还能减轻缺血程度。     

Cardioprotective effects of abciximab (ReoPro) in an isolated perfused rat heart model of ischemia and reperfusion

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction as well as myocardial injury, due in large part to endothelial dysfunction, upregulation of cell adhesion molecules and subsequent neutrophil induced cardiac injury. We studied the effects of abciximab (ReoPro), an anti-IIb/IIIa antibody, which has been shown to attenuate platelet interactions, in a neutrophil-platelet mediated isolated perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min). Administration of abciximab (6.5 micrograms/kg) 10 min prior to the perfusion of the PMN + platelet perfused I/R heart improved post-reperfusion coronary flow and preserved post-reperfusion left ventricular developed pressure (LVDP) and +dP/dt max as indices of cardiac contractile function. Abciximab-treated hearts reperfused in the presence of PMNs and platelets preserved all indices of cardiac contractile function. I/R heart perfused with PMNs and platelets produced a profound injury to the hearts which was attenuated with the treatment of abciximab. In addition, abciximab significantly reduced PMN accumulation in the ischemic myocardium from 38 +/- 1 PMNs/mm2 in untreated hearts to 7 +/- 1 in rats given abciximab. Similar results were obtained with PMN perfused I/R rat hearts without platelets. These results provide evidence that abciximab is a potent and effective cardioprotective agent that inhibits leukocyte-endothelial cell interactions as well as platelet-endothelial cell interaction and preserves cardiac contractile function and coronary perfusion following myocardial ischemia and reperfusion. Therefore, IIb/IIIa may be important in attenuating both platelet and neutrophil-mediated myocardial dysfunction.     

Daltroban, a thromboxane receptor antagonist, protects the myocardium against reperfusion injury following myocardial ischemia without protecting the coronary endothelium

The effects of daltroban, a specific thromboxane receptor antagonist, were investigated in a model of myocardial ischemia consisting of 1.5 h of coronary artery occlusion followed by reperfusion for 4.5 h in anesthetized cats. Daltroban (1 mg/kg) was infused as a bolus 10 min prior to reperfusion of the left anterior descending (LAD) coronary artery. Daltroban infusion resulted in a significantly lower necrotic area expressed as a percentage of the myocardial area-at-risk compared to the MI + vehicle group. However, daltroban failed to retard increases in myeloperoxidase activity in the ischemic myocardium, indicating no reduction in neutrophil accumulation. Moreover, left anterior descending coronary artery ring preparations isolated from daltroban treated MI cats exhibited endothelial dysfunction following ischemia reperfusion. Thus, daltroban significantly protected the myocardium from reperfusion injury without protecting the coronary endothelium or retarding neutrophil accumulation.     

3,6-[二甲氨基]-二苯骈碘杂六环枸橼酸盐对大鼠心肌缺血的保护作用

目的　观察 3,6- [二甲氨基 ]-二苯骈碘杂六环枸橼酸盐 ( I- 65 )对急性心肌缺血的影响。方法　采用结扎左冠状动脉制备大鼠在体心肌缺血模型 ,于缺血 2 4 h后分别测定心肌梗死范围、血清肌酸激酶、乳酸脱氢酶活性和游离脂肪酸含量。结果　 I- 65能缩小大鼠心肌梗死范围 ,降低心肌缺血大鼠血清肌酸激酶和乳酸脱氢酶活性 ,减少血清游离脂肪酸含量。结论　I- 65对大鼠缺血心肌有保护作用     

Effects of bepridil on regional and global myocardial ischemia/reperfusion-induced injury

The effectiveness of the calcium entry blocker bepridil in protecting the myocardium from ischemic injury, was assessed in a canine model of regional ischemia and in a feline model of global ischemia. Bepridil administration (5 mg/kg or 15 mg/kg/24 h intravenously) did not reduce ultimate infarct size as assessed in anesthetized, open-chest dogs subjected to 90 min of occlusion of the left circumflex coronary artery and 24 h of reperfusion. Bepridil (5 mg/kg administered intravenously to a blood donor cat) did not provide any protection of the isolated blood-perfused cat heart from 90 min of normothermic global ischemia and 60 min of reperfusion. Treatment of the perfused cat heart with bepridil did not prevent tissue accumulation of calcium or loss of tissue potassium and ATP. Bepridil, however, significantly reduced reperfusion tachyarrhythmias in the dog model for assessing ultimate infarct size and prevented reperfusion-induced ventricular fibrillation of the cat isolated heart. These results indicate that the calcium entry blocker, bepridil, as assessed in the models employed, does not protect the myocardium from ischemic reperfusion injury. However, it does prevent reperfusion-induced tachyarrhythmias and ventricular fibrillation.     

The effect of Allium sativum on ischemic preconditioning and ischemia reperfusion induced cardiac injury

In the present study, the effect of garlic (Allium sativum) extract on ischemic preconditioning and ischemia-reperfusion induced cardiac injury has been studied. Hearts from adult albino rats of Wistar strain were isolated and immediately mounted on Langendorff's apparatus for retrograde perfusion. After 15 minutes of stabilization, the hearts were subjected to four episodes of 5 min ischemia, interspersed with 5 min reperfusion (to complete the protocol of ischemic preconditioning), 30 min global ischemia, followed by 120 min of reperfusion. In the control and treated groups, respective interventions were given instead of ischemic preconditioning. The magnitude of cardiac injury was quantified by measuring Lactate Dehydrogenase and creatine kinase concentration in the coronary effluent and myocardial infarct size by macroscopic volume method. Our study demonstrates that garlic extract exaggerates the cardio protection offered by ischemic preconditioning and per se treatment with garlic extract also protects the myocardium against ischemia reperfusion induced cardiac injury.     

Effects of bunazosin, a selective alpha 1-adrenergic blocking agent, on myocardial energy metabolism in ischemic dog heart

Effects of a selective alpha 1-adrenergic blocking agent, bunazosin, on myocardial energy metabolism in the ischemic heart were studied. Ischemia was induced by ligating the left anterior descending coronary artery of the dog heart. Bunazosin was injected intravenously either 5 or 20 min before coronary artery ligation. Hearts were removed 3 min after coronary ligation and used for determination of the levels of cardiac tissue metabolites. Ischemia decreased the levels of ATP, creatine phosphate, glycogen and glucose, and increased the levels of ADP, AMP, hexose monophosphates and lactate. The energy charge potential (ECP) calculated was decreased by ischemia. Pretreatment with bunazosin inhibited the decrease in ATP and the increase in AMP caused by ischemia, resulting in the high value of ECP in the ischemic myocardium. Bunazosin also prevented the changes in carbohydrate metabolism caused by ischemia. It is concluded that bunazosin may reduce the influence of ischemia on the myocardium.