山莨菪碱对外源性自由基发生系统加重离体大鼠心脏缺血再灌注损伤的保护作用

缺血前10min灌流FeSO_4(0.1μmol·L~(-1)抗坏血酸(1μmol·L~(-1))自由基发生系统.可加重大鼠离体心脏缺血再灌注损伤.缺血前10min给予山莨菪碱能显著减少FeSO_4/抗坏血酸自由基发生系统所致再灌注室颤发生率.同时使心肌超氧化物歧化酶和谷胱甘肽过氧化物酶活力升高.丙二醛含量降低,冠脉流出液中乳酸脱氨酶含量减少.效果与还原型谷胱甘肽近似。     

Cardioprotective effects of recombinant human extracellular-superoxide dismutase type C in rat isolated heart subjected to ischemia and reperfusion.

The cardioprotective effect of recombinant human extracellular-superoxide dismutase type C (rh-EC-SOD C) was studied in isolated perfused rat heart subjected to left coronary artery ligation for 30 or 60 min followed by 30-min reperfusion. A comparison was made with the effects of bovine CuZn-SOD. Reperfusion after 30-min coronary artery ligation was associated with a release of creatine kinase (CK) into the coronary effluent (71 +/- 5.2 IU/30 min), which was markedly reduced (39 +/- 5.5 IU/30 min) in hearts perfused with rh-EC-SOD C (28 mg/L). CuZn-SOD (4 or 20 mg/l) or a lower concentration of rh-EC-SOD C (5.6 mg/l) did not significantly attenuate CK outflow during reperfusion, however. In both vehicle- and SOD-treated hearts, the left ventricular developed pressure (LVDP) and the coronary flow recovered to 80-90% of baseline at the end of the reperfusion period. Increasing the ischemic period from 30 to 60 min caused a much more pronounced cardiac injury measured after 30-min reperfusion. In the hearts that received vehicle, recovery of LVDP (in percentage of baseline values) at the end of reperfusion was 58 +/- 2%, which was increased to 84 +/- 3 and 83 +/- 5% after treatment with rh-EC-SOD C (28 mg/L) and CuZn-SOD (20 mg/L), respectively. The corresponding values for recovery in coronary flow were 54 +/- 3% (vehicle), 69 +/- 4% (rh-EC-SOD C), and 74 +/- 3% (CuZn-SOD).(ABSTRACT TRUNCATED AT 250 WORDS)     

巯基化合物对离体大鼠心脏缺血再灌所致心律失常的保护作用

本文研究了半胱氨酸(Cys)及其结构类似物半胱胺(MEA),N-乙酰半胱氨酸(NAC)、胱胺(CSSC),γ-氨丙基甲基异硫脲(APMT),对离体大鼠Langendortff心脏缺血再灌所致心律失常的保护作用.给药(0.1,0.6,3,6μmol/min)10min,结扎LAD 10 min再灌5 min。结果表明含游离巯基的Cys,NAC,MEA在0.6和3.6 μmol/min时,与生理盐水对照组相比可显著降低室颤发生率(P<0.01～0.001),缩短室颤时程(P<0.01～0.001).CSSC和APMT未见明显保护作用。此外,Cys,NAC和MEA还可明显增加冠脉流量(P<0.01),CSSC和APMT则反而使冠脉流量降低。     

Reperfusion-induced arrhythmias and free radicals: studies in the rat heart with DMPO

We have shown that the free radical spin trap DMPO (5,5-dimethyl-1-pyrroline-N-oxide) reduces reperfusion-induced arrhythmias in a dose-dependent manner in the isolated perfused rat heart subjected to 10 min regional ischemia and 3 min reperfusion. At its optimal concentration (1,000 mumol/L) DMPO, added to the perfusate 5 min prior to ischemia, reduced (p less than 0.05) the incidence of reperfusion-induced irreversible ventricular fibrillation from 83 (10 of 12) to 33% (4 of 12). When hearts were subjected to ischemia (10 min) and reperfusion, with DMPO (1,000 mumol/L) added to the perfusion fluid only 2 min before reperfusion, comparable protection was observed. To ascertain whether or not DMPO achieved an absolute reduction in vulnerability to arrhythmias irrespective of the duration of ischemia, hearts (12 for each group) were also subjected to 5, 10, 20, 30, or 40 min of ischemia; DMPO (1,000 mumol/L) was added to the perfusate either 5 min before ischemia or 2 min before reperfusion. In each instance a bell-shaped time-response profile was obtained. In the DMPO-free controls this gave a maximal vulnerability to arrhythmias after 10 min of ischemia. In the DMPO-treated hearts this curve was shifted to the right, with a peak vulnerability at 20 min. These results indicate that the primary action of DMPO is to exert a delaying effect which extends the duration of ischemia that can be tolerated before the heart becomes vulnerable to reperfusion-induced arrhythmias. However, this effect is achieved during the reperfusion period and not during the preceding period of ischemia. The precise mechanism by which this free radical spin trapping agent achieves this unusual effect remains to be resolved, but in studies with light-inactivated DMPO, this protective effect was lost, indicating that its ability to be oxidized, possibly by superoxide or hydroxyl radicals, may be critical to its mechanism of action.     

Effect of a cardioselective alpha-tocopherol analogue on reperfusion injury in rats induced by myocardial ischaemia

Free radicals may cause some of the irreversible injury which occurs during myocardial ischaemia and reperfusion. In the present study the effects of a cardioselective, free radical scavenger, MDL 74270, which is an analogue of alpha-tocopherol, on myocardial infarct size in an anaesthetised rat model of coronary artery ligation (60 min) and reperfusion (30 min) has been evaluated. Infusion of MDL 74270 (0.3-3.0 mg/kg per h) commencing 10 min before occlusion until the end of reperfusion significantly reduced infarct size. The highest dose also caused a significant reduction in serum creatine phosphokinase levels. Similar findings have been obtained with the bromide salt of MDL 74270. Tissue distribution studies with 14C-labelled MDL 74270 and its tertiary amine analogue (MDL 74366) showed heart/blood ratios of total radioactivity, 1-6 h after i.v. administration, greater than 20 after MDL 74270 and around 1 after MDL 74366. The importance of accumulation of total radioactivity in the heart after MDL 74270 is supported by the fact that MDL 74366 was 30 times less potent as a myocardial protector in the ligation/reperfusion studies. It is concluded that MDL 74270 has potential for cardioprotective use in conditions of acute reperfusion.     

Metoprolol reduces reperfusion-induced fibrillation in the isolated rat heart: protection is secondary to bradycardia

We studied the effect of metoprolol on the incidence of reperfusion-induced ventricular fibrillation in the isolated rat heart with transient coronary artery occlusion and reperfusion. When administered prior to ischemia, metoprolol produced a dose-dependent reduction in reperfusion-induced ventricular fibrillation. Thus, with 1, 10, 30, 50, 100, and 200 mumol/L metoprolol, total ventricular fibrillation (reversible plus irreversible) was reduced from its control incidence of 100% to 91%, 83%, 58% (p less than 0.05), 25% (p less than 0.001), 25% (p less than 0.001), and 0% (p less than 0.001), respectively. Heart rate was also reduced in a dose-dependent manner from its control value of 268 +/- 6 beats/min to less than 75% at the highest concentration of metoprolol. Coronary flow was unaffected by metoprolol. Doses of metoprolol (1 and 10 mumol/L) that had no significant effect on heart rate had no antiarrhythmic effect. In additional experiments with a higher dose of metoprolol (50 mumol/L), hearts were paced to the rate of the drug-free control group and the antiarrhythmic effect of metoprolol was lost. When drug-free control hearts had their heart rate reduced to that of the metoprolol-treated hearts, a similar antiarrhythmic effect was observed. When metoprolol was administered just prior to reperfusion, no antiarrhythmic effects were observed. In further studies, we investigated the effect of the early administration of metoprolol (50 mumol/L) on the relationship between the vulnerability to reperfusion-induced arrhythmias and the duration of preceding ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chrysanthemum morifolium attenuated the reduction of contraction of isolated rat heart and cardiomyocytes induced by ischemia/reperfusion

The present study was aimed to investigate the effect of Chrysanthemum morifolium Ramat. (CM) on isolated rat heart and ventricular myocytes during ischemia/anoxia and reperfusion/reoxygenation. The ischemia/reperfusion injury was induced by ligation the left artery descending coronary of isolated rat heart for 30 min followed by 30 min reperfusion with Langendorff equipment. Cell contraction in enzymatically isolated ventricular myocytes was determined by a video tracking system. The results showed CM (0.25 g/L to 1.0 g/L) increased left ventricular developed pressure (LVDP), +/- dp/dt(max), LVDP x HR and coronary flow (CF) and decreased heart rate (HR) in dose dependent manner. CM (0.5 g/L) attenuated the reduction of LVDP, +/- dp/dt(max) and CF caused by ischemia/reperfusion. CM (0.25 g/L to 1.0 g/L) increased peak velocity of cell shortening/relengthening (+/- dL/dt(max)) and contraction amplitude (dL) of isolated ventricular myocytes in a dose-dependent way under control condition, but without significant effect on end-diastolic cell length (L0). Under anoxia 5 min followed by 10 min reoxygenation, CM attenuated the reduction in contractile parameters. The results suggest that CM processes cardioprotective effect during ischemia/anoxia and reperfusion/reoxygenation in the isolated rat heart and the ventricular myocytes.     

Antiarrhythmic properties of a prior oral loading of amiodarone in in vivo canine coronary ligation/reperfusion-induced arrhythmia model: comparison with other class III antiarrhythmic drugs

Amiodarone, which is generally classified as class III antiarrhythmic drug in the Vaughan Williams classification, is widely used for the treatments of refractory arrhythmias. However, we previously reported that intravenous infusion of amiodarone (6.67 mg/kg per hour) did not suppress arrhythmias induced by coronary ligation/reperfusion in dogs. In this study, we examined effects of a prior oral loading of amiodarone on arrhythmias induced by coronary ligation/reperfusion. Sixteen female beagle dogs (8.5 - 12.5 kg) were divided into two groups; one group was given amiodarone (40 mg/kg, orally, n = 8), and the other was given empty gelatin capsules (n = 8) 2 h before the operation. Dogs were anesthetized with pentobarbital and artificially ventilated. The left chest was opened, and the left anterior descending coronary artery was ligated for 30 min and then reperfused. The mean plasma concentration of amiodarone was over 1.3 mug/ml. Although the prior oral loading of amiodarone did not change the QT interval, amiodarone suppressed the number of ectopic beats during coronary ligation and the incidence of ventricular fibrillation during coronary ligation and reperfusion periods (P<0.05 vs control group). In conclusion, a prior oral loading of amiodarone suppressed arrhythmias induced by coronary ligation/reperfusion with a dose that did not prolong the QT interval. This antiarrhythmic property of amiodarone is different from those of the other class III drugs in that antiarrhythmic effects were accompanied by QT prolongation in our all previous studies.     

Cardiovascular effects of acebutolol following coronary artery occlusion and reperfusion in anaesthetized dog.

1 The effects of 5 mg/kg acebutolol given intravenously were investigated in anaesthetized dogs after (a) ligation of the left anterior descending coronary artery and (b) coronary reperfusion following 60 min of ligation of the anterior descending coronary artery. 2 Coronary artery ligation produced, after 4 to 6 h, persistent multiple ventricular ectopic beats and abnormalities of R and T waves and of the S-T segment. Administration of acebutolol, after the development of persistent ventricular arrhythmias, restored normal sinus rhythm within 5 min of injection. Electrocardiographic abnormalities were also reduced. 3 Coronary artery reperfusion (following 60 min of ligation) resulted in multiple ventricular ectopic beats, ventricular tachycardia and/or ventricular fibrillation. Pretreatment with acebutolol, 15 min before starting reperfusion, markedly reduced the arrhythmias. 4 Acebutolol did not affect peak inspiratory airway pressure. 5 Acebutolol produced significant bradycardia and slight, transient, hypotension. It was without effect on left ventricular systolic pressure, left ventricular end-diastolic pressure, cardiac output or pulmonary arterial pressure. 6 These results suggest beneficial effects of acebutolol in myocardial ischaemia and coronary reperfusion, without any significant risk of cardiodepression or bronchospasm.     

Comparison of the effect of antidepressant drugs on arrhythmias in the isolated rat heart subjected to myocardial ischaemia and reperfusion

Rat isolated hearts were perfused according to the Langendorff's method. The hearts were prelabelled with 3H-noradrenaline (3H-NA) and the left coronary artery was occluded during 10 min. The liberation of 3H-NA and the development of ventricular arrhythmias were investigated during ischaemia and the following reperfusion period. In control preparations, reperfusion was followed by ventricular fibrillation and a sudden release of radioactivity in the coronary effluent. Antidepressants such as imipramine, metapramine, mianserin and nomifensine prevented reperfusion arrhythmias in a concentration-dependent manner and caused bradycardia. Amineptine, however, was ineffective in preventing reperfusion arrhythmias even in a high concentration, this agent did not decrease heart rate. Nevertheless none of the antidepressants changed the rate of liberation of 3H-NA during the ligation and reperfusion periods. A quinidine like action seems the most appropriate explanation for the cardiac effects of these antidepressant drugs.     

Antiarrhythmic and metabolic effects of indoramin during acute regional ischemia and reperfusion in isolated rat heart.

The antiarrhythmic effect of alpha 1-adrenoceptor antagonists during myocardial ischemia and reperfusion remains controversial. The potential antiarrhythmic properties of indoramin, an alpha 1-antagonist, were assessed in the isolated perfused rat heart during regional ischemia and during sustained reperfusion. Coronary artery ligation (CAL) decreased the ventricular fibrillation threshold (VFT) of control hearts from 9.1 +/- 1.3 (pre-CAL, mean +/- SEM) to 2.1 +/- 0.5 mA 15 min post-CAL (p less than 0.0001). Perfusion with indoramin 10(-8) M (alpha 1-receptor antagonistic concentration) started 5 min prior to CAL did not prevent the fall in VFT after CAL. Indoramin 10(-6) M prevented the fall in VFT after CAL relative to the control group. Indoramin 10(-5) M markedly increased the VFT before CAL from 9.9 +/- 1.0 to 28.6 +/- 2.9 mA (p less than 0.0001) and prevented the fall in VFT after CAL. During reperfusion, indoramin 10(-5) M decreased the incidence of spontaneous ventricular fibrillation (VF) to 1 of 6 vs. 6 of 6 in the control group (p less than 0.02). Indoramin 10(-5) M preserved adenosine triphosphate in the reperfused myocardium: 2.82 +/- 0.06 vs. 2.16 +/- 0.21 mumol/g in the control group (p less than 0.05). Specific alpha 1-antagonist properties of indoramin did not appear to be involved in the antiarrhythmic effects.     

Selective mitochondrial K(ATP) channel activation results in antiarrhythmic effect during experimental myocardial ischemia/reperfusion in anesthetized rabbits

We investigated the effects of administration of non-hypotensive doses of ATP-sensitive K+ channel (K(ATP)) openers (nicorandil and aprikalim), and a specific mitochondrial K(ATP) channel blocker (5-hydroxydecanoate) prior to and during coronary occlusion as well as prior to and during post-ischemic reperfusion on survival rate, ischemia/reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. Arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery with a releaseable silk ligature. Early intervention by intravenous infusion of nicorandil (100 microg/kg bolus+10 microg/kg/min) or aprikalim (10 microg/kg bolus+0.1 microg/kg/min) just before and during ischemia increased survival rate (86% and 75% vs. 55% in the control group), significantly decreased the incidence and severity of life-threatening arrhythmias and myocardial infarct size. The antiarrhythmic and cardioprotective effects of both nicorandil and aprikalim were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus). In conclusion, intervention by intravenous administration of nicorandil and aprikalim (through the selective activation of mitochondrial K(ATP) channels) increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to and during coronary occlusion.     

立西普利和卡托普利对离体缺血再灌大鼠心脏的保护作用

本文研究了血管紧张素转移酶抑制剂立西普利(Lis)和卡托普利(Cap)对离体大鼠心脏缺血再灌引起损伤的保护作用。实验证明Lis 100nmol/L和Cap 200μmol/L能明显降低心肌组织中丙二醛(MDA)的含量,保护超氧化物歧化酶(SOD)的活性。此外,这两种转移酶抑制剂均能升高心肌组织中前列环素(PGI_2)和谷胱甘肽(GSH)的含量。表明它们对心肌缺血再灌损伤均具明显的保护作用。     

Metabolic and functional effects of carbachol and ischaemic preconditioning in rat isolated heart

1. Metabolic and functional effects of ischaemic preconditioning (IP), pretreatment with carbachol (Ch) and combined interventions were studied in rat isolated working hearts subjected to 20 min global ischaemia (37 degrees C) and 40 min reperfusion. Prior to the ischaemic period, hearts were either perfused according to Langendorff (control group), ischaemically preconditioned by 5 min global ischaemia and 5 min reperfusion (IP group), perfused with 0.1 mumol/L Ch for 5 min and then with Ch-free Krebs'-Henseleit buffer for 5 min (Ch group) or perfused with 0.1 mumol/L Ch for 5 min and then subjected to IP (Ch + IP group). 2. Although Ch exerted slight negative chronotropic and inotropic effects during pre-ischaemic Langendorff perfusion, it did not affect myocardial contents of ATP and phosphocreatine (PCr) prior to sustained ischaemia. At the end of final reperfusion, the IP and Ch groups showed similar recovery of aortic output (67.5 +/- 5.0 and 56.8 +/- 5.4%, respectively), cardiac output (65.4 +/- 5.4 and 63.5 +/- 5.7%, respectively) and stroke volume (73.4 +/- 7.5 and 67.0 +/- 6.7%, respectively) expressed as a percentage of steady state values. These indices were higher than those in the control group (42.8 +/- 4.7, 53.8 +/- 4.3 and 56.1 +/- 5.6%, respectively; P < 0.05). The Ch + IP group exhibited complete recovery of all indices of pump function, including cardiac work, expressed as the cardiac output-mean aortic pressure (CO-MAP) product. 3. There were no differences in ATP recovery between the groups after reperfusion: the ATP content was, on average, 73.1 +/- 3.5% of the initial ATP content. However, all treated groups had enhanced PCr recovery and better preservation of total creatine (sigma Cr = PCr + Cr), an index of cell membrane integrity, than control. Metabolic efficacy of the pre-ischaemic interventions can be ranked as follows: IP < or = Ch < Ch + IP. In all groups, myocardial content of sigma Cr was positively correlated with percentage recovery of the CO-MAP product at the end of reperfusion (r = 0.79, P < 0.05). 4. The results demonstrate that Ch treatment combined with IP provides significantly greater postischaemic myocardial salvage. The similarity of the metabolic and functional effects of Ch treatment and IP strongly suggests muscarinic M2 acetylcholine receptor involvement in acute adaptation of rat heart to ischaemia/reperfusion stress.     

Effects of administration of nicorandil or bimakalim prior to and during ischemia or reperfusion on survival rate, ischemia/reperfusion-induced arrhythmias and infarct size in anesthetized rabbits

We investigated the effects of administration of non-hypotensive doses of ATP-sensitive K+ channel (KATP) openers (nicorandil and bimakalim), and a specific mitochondrial KATP channel blocker (5-hydroxydecanoate) prior to and during coronary occlusion as well as prior to and during post-ischemic reperfusion on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left fourth intercostal space and after pericardiotomy the heart was exposed. In Part I, occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30 min. In Part II, arrhythmias were induced by reperfusion following a 20-min ligation of the left main coronary artery. In Part I, early intravenous infusion of nicorandil (100 microg/kg bolus + 10 microg/kg per min) or bimakalim (3 microg/kg bolus + 0.1 microg/kg per min) just prior to and during ischemia increased survival rate (75% and 67% vs. 60% in the control group), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. In Part II also, early intervention by intravenous infusion of nicorandil (100 microg/kg bolus + 10 microg/kg per min) or bimakalim (3 microg/kg bolus + 0.1 microg/kg per min) just before and during ischemia increased survival rate (86% and 75% vs. 55% in the control group), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or bimakalim at the onset and during reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and bimakalim were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus), a selective mitochondrial KATP channel blocker. In conclusion, intervention by intravenous administration of nicorandil and bimakalim (through the activation of mitochondrial KATP channels), increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to and during coronary occlusion.     

Cardioprotective and endothelial protective effects of [Ala-IL8]77 in a rabbit model of myocardial ischaemia and reperfusion.

1 We studied the effects of a form of interleukin-8 (i.e., [Ala-IL8]77) on endothelial dysfunction and myocardial injury in rabbits. Pentobarbitone-anaesthetized rabbits were subjected to 1.5 h occlusion of the marginal coronary artery and 3.5 h reperfusion. [Ala-IL8]77 (50 micrograms or its vehicle) was given i.v. as a bolus 10 min prior to reperfusion. [Ala-IL8]77 was also studied in isolated perfused hearts of rabbits. 2 Myocardial ischaemia plus reperfusion in untreated rabbits produced severe endothelial dysfunction and myocardial injury, including marked myocardial necrosis, elevated cardiac myeloperoxidase (MPO) activity in ischaemic cardiac tissue, and loss of response of marginal coronary rings to the endothelium-dependent vasodilators, acetylcholine (ACh) and A23187. 3 Administration of [Ala-IL8]77 10 min prior to reperfusion resulted in significant protective effects in post-ischaemic reperfusion. Compared with untreated rabbits, [Ala-IL8]77 caused a reduced necrotic zone (P less than 0.01), lower MPO activity in the necrotic zone (P less than 0.05), and significantly preserved vasorelaxant responses of marginal coronary artery rings to endothelium-dependent vasodilators, ACh (P less than 0.001) and A23187 (P less than 0.001). 4 These results indicate that myocardial ischaemia and reperfusion result in a severe endothelial dysfunction and myocardial injury which involved the interaction of neutrophils and endothelial cells. However, [Ala-IL8]77 did not appear to exert a direct endothelial protective effect in the absence of neutrophils in rabbit isolated perfused hearts. 5 Inhibition of neutrophil accumulation in the myocardium, perhaps by prevention of endothelial dysfunction resulting from [Ala-IL8]77, leads to significant protective effects in ischaemia and reperfusion in rabbits.     

Lidocaine reduces canine infarct size and decreases release of a lipid peroxidation product

Whether and how lidocaine reduced infarct size in a canine model of ischemia and reperfusion was investigated. Twenty dogs underwent a 90-min left anterior descending artery ligation and 300 min of reperfusion. Infarct size was measured by triphenyl tetrazolium chloride and the region at risk by 99Tc-labeled albumin microspheres injected during ischemia. In 10 dogs, lidocaine (70 micrograms/kg/min i.v.) was infused 90 min prior to and during ischemia and reperfusion, while 10 dogs were untreated. The ratio of infarct to risk area was 35.2 +/- 3.4% (SEM) in lidocaine dogs vs. 48.5 +/- 5.3% in untreated dogs (p less than 0.05). Lidocaine did not reduce neutrophil accumulation in ischemic and reperfused myocardium at 5 h of reperfusion, inhibit stimulated neutrophil superoxide production, or scavenge superoxide in vitro. However, during early reperfusion, lidocaine reduced coronary sinus levels of a lipid peroxidation product (conjugated dienes). Thus, clinically relevant lidocaine infusion rates reduced myocardial infarct size when given prior to and during ischemia and reperfusion. This protective effect may be due to lidocaine's membrane stabilizing effects, which could have protected the myocardial cell membrane from lipid peroxidation.     

Effect of diltiazem on extent of ultimate myocardial injury resulting from temporary coronary artery occlusion in dogs

The calcium antagonist, diltiazem, was evaluated for its ability to reduce the extent of myocardial injury resulting from 90 min of left circumflex (LCX) coronary artery occlusion in anesthetized dogs. Administration of diltiazem (0.75 mg/kg over 10 min, followed by 600 microgram/kg/h for 4 h) was initiated 30 min prior to LCX occlusion. Regional myocardial blood flow (RMBF) was measured with radioactive microspheres 30 min after LCX occlusion, and at 45 min and 24 h after reperfusion. At 24 h, after obtaining hemodynamic and RMBF measurements, excised hearts were processed by perfusion staining to determine the percent of left ventricle (LV) perfused by LCX (area at risk) and infarct size, with triphenyltetrazolium chloride. Infarct size, expressed as a percentage of the area at risk, was significantly lower in the diltiazem-treated group compared to the control group (27 +/- 4 vs. 42 +/- 5%, respectively). The area at risk, expressed as a percentage of left ventricular mass, was similar in both groups [41 +/- 2 and 44 +/- 3% (area at risk-LV)]. In addition, the marked elevation of tissue Ca2+ content in noninfarcted and infarcted myocardium within the area at risk (18 +/- 2 and 42 +/- 8 mumol Ca2+/g) in control animals was attenuated by diltiazem (6 +/- 3 and 18 +/- 8 mumol Ca2+/g). Diltiazem did not increase blood flow to ischemic myocardium during LCX occlusion. However, reflow to the inner layers of formerly ischemic myocardium during reperfusion was significantly greater in diltiazem-treated dogs. Both arterial blood pressure and heart rate were significantly lower in the diltiazem -treated group. In addition, mortality (1 vs. 4) and occurrence of ventricular arrhythmias during reperfusion were lower in diltiazem-treated dogs. The data suggest that diltiazem reduces myocardial ischemic injury by lowering myocardial oxygen demands indirectly via favorable hemodynamic alterations, and directly by limiting transmembrane Ca2+ fluxes during ischemia and reperfusion.