The effect of diltiazem on ST-segment elevation and myocardial blood flow distribution during pacing-induced ischemia

The purpose of this study was to determine if diltiazem can reduce the severity of pacing-induced ischemia independently of increases in overall and microregional ischemic blood flow. Sixteen anesthetized dogs were subjected to atrial pacing and had their left anterior descending coronary arteries (LAD) occluded until significant ST-elevation occurred. Cessation of pacing resulted in abolition of ST-segment elevation. ST-elevation as well as hemodynamics were measured during 5 min periods of pacing + LAD stenosis before, and 10, 40 and 70 min after treatment with intracoronary (i.c., just distal to the stenosis) diltiazem (1.8 micrograms/kg), i.v. diltiazem (180 micrograms/kg) or saline. Myocardial blood flow was measured using radioactive microspheres under baseline conditions, pacing, pacing + stenosis, and pacing + stenosis + drug (70 min post-drug). Both i.c. and i.v. diltiazem significantly and similarly reduced pacing-induced ST-elevation at 40 and 70 min post-drug with the highest measured reductions occurring for both at 70 min (50-60% reduction). Overall ischemic regional myocardial blood flow was unaffected by i.c. and i.v. diltiazem. Diltiazem given i.v. resulted in reduced flow in the lightly ischemic region and increased flows in the subepicardial half of the severely ischemic region. Diltiazem given i.c. resulted in a reduced subepicardial flow in the lightly ischemic region with no other changes occurring in the other regions. Thus, both i.c. and i.v. diltiazem can reduce the severity of pacing-induced ischemia and, in the doses given, in an equivalent fashion. Diltiazem also seems to be able to reduce severity of ischemia in a manner independent of increases in ischemic region flow and in fact can reduce flow in marginally ischemic tissue.     

Antianginal effects of hydroxyfasudil, a Rho-kinase inhibitor, in a canine model of effort angina.

1. The effects of Rho-kinase inhibitor, fasudil, and of a more specific Rho-kinase inhibitor, hydroxyfasudil, on pacing-induced myocardial ischaemia were determined in anaesthetized open-chest dogs. 2. The dogs were subjected to left anterior descending coronary artery (LAD) stenosis producing a sufficient ischaemia as measured by ST-segment depression on electrocardiograms only when the hearts were paced 60 beats min(-1) above the baseline. After a recovery (nonpacing) period, drugs or saline were infused intravenously over 30 min. The animals were again subjected to 5 min of pacing 25 min after the initiation of the treatment. 3. Hydroxyfasudil (0.1 and 0.3 mg kg(-1)) and fasudil (0.3 mg kg(-1)) suppressed the ST-segment depression. Hydroxyfasudil and fasudil also increased the regional blood flow of the LAD perfused endomyocardium region in the canine model of effort angina. 4. To determine the flow profile for hydroxyfasudil in dogs, blood flow in three vascular beds was measured. Hydroxyfasudil (0.3 mg kg(-1) for 30 min) significantly increased coronary blood flow and vertebral blood flow, without significantly changing the femoral blood flow. 5. Hydroxyfasudil had no inotropic or chronotropic effect on the isolated hearts of guinea-pigs. Hydroxyfasudil (2 mg kg(-1) for 20 min) did not affect the PR or QTc interval in anaesthetized dogs. 6. Inhibition of Rho-kinase appears to protect myocardium subjected to pacing-induced ischaemia through the increase in the regional myocardial blood flow. Hydroxyfasudil may be categorized as a novel type of anti-anginal drug, without any inotropic or chronotropic effects.     

The anti-ischemic effects of CP-060S during pacing-induced ischemia in anesthetized dogs

CP-060 S, (-)-( S)-2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-[3-[N-methyl-N-[2-(3 ,4-methylenedioxyphenoxy)ethyl]-amino]propyl]-1,3-thiazolidin++ +-4-one hydrogen fumarate, is a novel cardioprotective drug which prevents Na+-, Ca2+-overload and has Ca2+ channel blocking activity. We compared the anti-ischemic effects of CP-060S with those of diltiazem, a Ca2+ channel blocker, and R56865, N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]-N-methyl-2-benzothiazo lamine, a Na+-, Ca2+-overload inhibitor, in a canine pacing-induced ischemia model. CP-060S 100 microg kg(-1) significantly suppressed the pacing-induced ischemic epicardial ST-segment elevation by maximally 75%, while diltiazem 100 microg kg(-1) suppressed it by maximally 35%. R56865 100 microg kg(-1) significantly suppressed the ST-segment elevation by maximally 30%. In addition, diltiazem 100 microg kg(-1) caused synergistic suppression of ST-segment elevation by 70% when administered simultaneously with R56865 100 microg kg(-1). These results suggest that a Na+-, Ca2+-overload preventive action and a Ca2+ channel blocking action independently contribute to the suppression of the ST-segment elevation. Therefore, CP-060S may suppress pacing-induced ST-segment elevation by a dual action by preventing Na+-, Ca2+-overload and the Ca2+ channel blockade.     

Haemodynamic factors influencing myocardial ischaemia in a canine model of coronary artery stenosis: the effects of nitroglycerine.

At a critical degree of coronary stenosis (allowing a just adequate blood supply to the poststenotic area only at the expense of maximal hypoxic coronary vasodilatation), an additional loading of the heart induced marked local myocardial ischaemia, as indicated by appropriate biochemical, electrophysiological and haemodynamic changes. In this model myocardial oxygen demand was increased in three different ways: (i) increasing heart rate by atrial pacing; (ii) increasing afterload by aortic occlusion and (iii) increasing preload by blood infusion. These procedures were compared in their ability to produce local myocardial ischaemia and characterized by ST-segment elevation recorded from the endocardium and epicardium. Increasing afterload evoked the mildest degree of ischaemia since the resulting increase in coronary perfusion pressure and coronary flow almost met the augmented myocardial oxygen demand evoked by the elevated peripheral resistance and by the simultaneously increased preload. A rather more pronounced ischaemia was produced by increasing the preload. The most serious ischaemia of all was induced by atrial pacing. This reduced coronary flow and perfusion pressure and increased left ventricular end diastolic pressure (LVEDP). Nitroglycerine transiently reduced blood pressure and coronary blood flow and increased epicardial and endocardial ST-segment elevation; the changes had disappeared 10 min after terminating the infusion. However, at this time a prolonged protective action against pacing-induced ST-segment elevation was observed. This protection was also seen after intracoronary injections of nitroglycerine. This indicated that part of the beneficial effect of nitroglycerine in ischaemia is due to direct coronary and/or myocardial actions.     

Anti-ischemic activity of the novel benzazepine calcium antagonist SQ 31,486.

We tested the benzazepine, SQ 31,486 for its ability to selectively block the voltage-dependent calcium channel and to protect the ischemic myocardium. SQ 31,486 was found to be a selective calcium antagonist in vascular tissue with an IC50 value of 1.5 microM in KCl-contracted rabbit aorta. SQ 31,486 decreased contractile function and increased coronary flow in nonischemic isolated rat hearts in a concentration-dependent manner. SQ 31,486 also significantly reduced postischemic lactate dehydrogenase (LDH) release and end-diastolic pressure (EDP) compared to vehicle. Reperfusion double product [heart rate (HR) x left ventricular developed pressure (LVDP)] was also significantly improved by SQ 31,486. Diltiazem was a less potent anti-ischemic agent and was significantly more cardiodepressant relative to its anti-ischemic efficacy than was SQ 31,486. Thus, SQ 31,486 should have a larger therapeutic index. In a model of pacing-induced myocardial ischemia in anesthetized, open chest dogs, SQ 31,486 reduced pacing-induced ST-segment elevation approximately 50% at 10, 40, and 70 min after drug administration. This protective effect occurred despite a lack of effect of SQ 31,486 on ischemic regional blood flow and peripheral hemodynamic status.     

Effect of 2-phenylaminoadenosine (CV-1808) on ischemic ST-segment elevation in anesthetized dogs

The effect of 2-phenylaminoadenosine (CV-1808) against myocardial ischemia was studied in anesthetized dogs. During intravenous infusion of CV-1808 (0.25 and 0.5 microgram/kg/min for 10 min) the ST-segment elevation in the epicardial ECG induced by a 5-min occlusion of a coronary arterial branch was occasionally enhanced in association with cardiac acceleration. In a dose of 0.5 microgram/kg/min, the agent inhibited the ST elevation 30 and 60 min after administration. The same dose did not change myocardial blood flow in the ischemic area despite significant systemic hypotension. In hearts with continuous coronary occlusion, CV-1808 (0.3 and 1.0 microgram/kg, i.v. bolus) increased the retrograde blood flow from the ischemic area immediately after administration, suggesting a collateral vasodilating action. Nifedipine (0.5 and 2.5 microgram/kg/min, i.v. for 10 min) and nitroglycerin (0.5 and 5.0 microgram/kg/min, i.v. for 10 min) had no influence on the ischemic ST-segment elevation, while a significant inhibition was seen with propranolol (0.5 mg/kg, i.v.). A moderate hypotension was induced by CV-1808, nifedipine, and nitroglycerin, while a significant reduction in cardiac function was seen after dosing with propranolol.     

Effect of diltiazem on coronary blood flow distribution in dog heart under ischemia

Effect of intracoronary infusion of diltiazem (1 microgram/min) on regional myocardial blood flow (RMBF) was studied using 15-microns radioactive microspheres in 11 excised cross-circulated canine left ventricles. With total coronary blood flow (CBF) and heart rate (HR) held constant, regional ischemia was induced by ligating the left anterior descending coronary artery (LAD). Diltiazem at the dose used had no effects on ventricular Emax before and after LAD ligation. RMBF expressed by the counts divided by the counts averaged in all segments in each layer significantly (p less than 0.05) increased under diltiazem only in the low-flow region that had less than 50% RMBF before diltiazem; from 21% (+/- 12%) to 35% (+/- 18%) in the epicardial, from 22% (+/- 12%) to 32% (+/- 18%) in the midwall, and from 24% (+/- 10%) to 31% (+/- 12%) in the endocardial layers. We conclude that the beneficial effect of diltiazem on the ischemic heart involves a direct action on the coronary vascular system and does not necessarily depend on the concomitant changes in hemodynamics.     

Effect of nifedipine on regional O2 consumption in ischemic myocardial tissue

The effect of intravenous (i.v.) nifedipine (5 micrograms/kg/min) on regional O2 supply/consumption variables was determined in 14 anesthetized open-chest dogs subjected to left anterior descending coronary artery (LAD) stenosis sufficient to reduce blood flow 50%. Myocardial blood flow was measured using radioactive microspheres, and regional arterial and venous O2 saturations were determined using microspectrophotometry. During LAD occlusion, blood flow and O2 consumption were decreased in the ischemic region while O2 extraction was increased. With nifedipine treatment, LAD flow (flow probe) was increased 44% as compared with the initial occluded value, with most of this increase going to the subepicardium (microspheres). Flow to the ischemic subendocardium was not changed with nifedipine treatment. Ischemic subepicardial O2 consumption increased slightly in nifedipine-treated animals as compared with saline values, whereas O2 extraction decreased slightly. In the subendocardial region, nifedipine resulted in a significant decrease in O2 extraction, with a slight decrease in O2 consumption as compared with saline controls. The O2 supply/demand ratio was significantly improved with nifedipine only in the subendocardium of the ischemic region. This suggested that nifedipine could increase O2 consumption in the ischemic subepicardium through proportional increase in O2 supply while it decreased O2 consumption in the subendocardium relative to O2 supply.     

Importance of myocardial blood flow changes in the protective action of diltiazem in a new model of myocardial ischaemia.

The effect of diltiazem was studied in a new model of myocardial ischaemia in which in addition to a critical constriction of the left circumflex branch (LCX), the left anterior descending coronary artery (LAD) was suddenly occluded. This model is probably more relevant to the clinical situation in which multivessel coronary artery disease is common. In this model diltiazem exerted a beneficial effect, manifested by an increase in myocardial blood flow (MBF) within the stenosed area of the LCX; by a marked reduction of the enhanced preload (LVEDP); by a diminution of the inhomogeneity of electrical activation and by a decrease in ST-segment elevation. Diltiazem also caused a significant reduction both in the number of extrasystoles and in the incidence of ventricular fibrillation. Increased MBF within the stenosed area was associated with enhanced blood flow to the ischaemic myocardium, i.e. diltiazem directed flow to the ischaemic zone by improvement of the collateral circulation. The beneficial electrophysiological changes caused by diltiazem are probably at least partly due to the drug-induced improvement of myocardial blood supply to the ischaemic area.     

Adrenergic influences on ischemic and reperfusion arrhythmias in a canine model with diminished collateral blood flow

To examine the role of adrenergic influences on genesis of ischemic and reperfusion arrhythmias, the left anterior descending coronary artery (LAD) was cannulated and perfused by a shunt from the left carotid artery in 38 open-chest pentobarbital-anesthetized dogs. Ischemia was produced by shunt occlusion and retrograde diversion of collateral flow from the LAD. The diverted blood was collected and returned to the animal by intravenous (i.v.) injection. The shunt was opened and the ischemic myocardium reperfused after 30 min of ischemia. Microsphere injections in six dogs during shunt occlusion and retrograde bleeding showed that blood flow to the ischemic zone was less than 1.5% of normal zone flow. The remaining 32 dogs were randomized into four treatment groups. Dogs (n = 8) were treated before shunt occlusion with either saline, nadolol (1 mg/kg), prazosin (0.2 mg/kg), or bilateral stellate transection. As compared with saline treatment, nadolol and stellate transection significantly reduced heart rate (HR), and prazosin significantly reduced mean arterial blood pressure (MAP) (p less than 0.05). However, none of the antiadrenergic interventions significantly reduced the number or frequency of ectopic beats during either the 1a or 1b phases of ischemia. None of the 32 dogs developed ventricular fibrillation (VF) during ischemia, but all dogs fibrillated within 30 s of reperfusion. The size of the ischemic zone ranged from 21 to 38% of the left ventricle, and there were no differences among the four treatment groups. The results suggest that when ischemia is severe, the adrenergic nervous system does not play a significant role in genesis of ischemic-induced ectopy or reperfusion-induced VF.     

Anti-ischemic effects of fasudil, a specific Rho-kinase inhibitor, in patients with stable effort angina

Epicardial coronary stenosis causes myocardial ischemia; however, the role of coronary microvessels is poorly understood in the pathogenesis of effort angina. We have previously demonstrated that Rho-kinase pathway is substantially involved in coronary arterial hyperconstriction in patients with vasospastic angina and those with microvascular angina. In the present study, we tested our hypothesis that Rho-kinase is involved in coronary microvascular constriction in patients with effort angina. Intracoronary administration of fasudil (300 microg/min for 15 min), a specific Rho-kinase inhibitor, significantly increased oxygen saturation in coronary sinus vein from 37 +/- 3% to 41 +/- 3% (P < 0.05) but not in six age-matched controls (from 42 +/- 3% to 43 +/- 3%, P = NS). Furthermore, the fasudil treatment significantly ameliorated pacing-induced myocardial ischemia in patients with effort angina (magnitudes of symptom: 1.5 +/- 0.6 to 0.6 +/- 0.4, P < 0.01; ischemic ST-segment depression, 1.8 +/- 0.3 to 1.0 +/- 0.2 mm, P < 0.01; percent lactate production, 50 +/- 17% to 0.4 +/- 7%, P < 0.01) without significant hemodynamic changes. These results provide the first evidence that Rho-kinase is substantially involved in coronary microvascular dysfunction associated with myocardial ischemia in patients with effort angina, suggesting that Rho-kinase can be a novel therapeutic target in ischemic heart disease.     

Collateral blood flow following acute coronary artery occlusion: comparison of a new intracellular calcium antagonist (KT-362) and diltiazem

The effects of a new intracellular calcium antagonist, KT-362 (150 and 300 micrograms/kg per min), on hemodynamics and collateral function (retrograde pressure and flow, radioactive microspheres) distal to an acute coronary artery occlusion were studied in anesthetized dogs and compared with the effects of the structurally related classical calcium channel blocker, diltiazem (15 and 30 micrograms/kg per min), and a saline-treated control group. In the saline series, there were no changes in systemic hemodynamics or coronary collateral blood flow over the 90-min ischemic period. KT-362 reduced mean aortic pressure, heart rate, and dP/dt whereas diltiazem only decreased aortic blood pressure. When blood pressure was controlled by a distal aortic cuff, heart rate was significantly reduced in both groups and dP/dt was reduced in the KT-362 series and increased in diltiazem-treated dogs. In both drug-treated groups, retrograde pressure and flow were significantly increased only when aortic pressure was controlled. Regional myocardial tissue blood flow in the nonischemic or ischemic region did not change significantly after KT-362 treatment despite its hypotensive actions, and in the presence of a constant aortic pressure, transmural collateral blood flow and the ischemic/nonischemic blood flow ratio tended to increase. In contrast, diltiazem treatment resulted in a significant decrease in the ischemic/nonischemic blood flow ratio in the absence of blood pressure control. In the presence of constant aortic pressure, blood flow to the nonischemic area was markedly increased by diltiazem whereas subendocardial blood flow was significantly increased in the ischemic area.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of diltiazem on myocardial recovery after regional ischemia in dogs

The effect of diltiazem on post-ischemic metabolic and functional recovery was investigated in regionally ischemic dog hearts. The duration of ischemia was 60 min, followed by 60 min of reperfusion. Diltiazem (bolus injection of 0.1 mg X kg-1 body weight prior to ischemia, followed by a continuous infusion of 0.1 mg X kg-1 X h-1) had no effect on residual coronary flow in the centre of the ischemic area, but blunted the reactive hyperemia response after restoration of flow. The drug partially prevented the depletion of ATP and glycogen in the severely underperfused subendocardial layers, i.e. when residual flow was below 0.1 ml X min-1 X g-1. Reduction of the content of these substances in the subepicardial layers was moderate and not influenced by diltiazem. Segment shortening in the subepicardial layers disappeared whereas segment lengthening was observed in the subendocardial layers during the ischemic period. Diltiazem did not prevent the loss of contractile function. Despite an initial restoration of contractile function within 10 min after reperfusion, no significant beneficial effect of diltiazem treatment on mechanical function of the reperfused area was present thereafter.     

Effects of R 56,865, a preventer of cellular calcium overload, on left ventricular diastolic properties during pacing-induced ischemia in dogs.

The effects of R 56,865, a compound with unusual calcium antagonistic properties, on altered left ventricular (LV) diastolic properties were studied during pacing-induced ischemia in dogs with coronary stenosis. Severe coronary artery stenosis was produced on both the left anterior descending (LAD) and circumflex (Cx) coronary arteries in anesthetized beta-blocked dogs. The right atrium was paced at 200 beats/min for 3 min. In the post-pacing period and before drug intervention, the most characteristic observation was a significant increase in LV end-diastolic pressure (LVEDP) and in the time constant of (tau) LV pressure decrease; after return of LV hemodynamics to baseline values (15 min), R 56,865 (0.16 mg.kg-1) or solvent (control) was injected and four subsequent pacing runs were performed at 30-min intervals. In the postpacing period of these four subsequent runs, there was a steep increase in LVEDP and tau-values while HR returned more slowly to baseline values. After R 56,865 infusion, the increase in LVEDP and tau-values was significantly lower than in the pretreatment run and all LVEDP values were significantly lower than in the control group. We conclude that R 56,865 effectively attenuates ischemia-induced changes in LV diastolic stiffness.     

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.     

Metabolic coronary-flow regulation and exogenous nitric oxide in human coronary artery disease: assessment by intravenous administration of nitroglycerin

We sought to evaluate the effect of intravenous administration of the nitric oxide--donor substance nitroglycerin (NTG) on metabolic coronary-flow regulation in patients with coronary artery disease (CAD). In 12 patients with stable CAD, we measured coronary sinus blood flow and myocardial oxygen supply and consumption (MVO2) at sinus rhythm and during atrial pacing (30 beats/min above sinus rate), both at control and during infusion of NTG, 1 microg/kg/min, and NTG, 2 microg/kg/min. To study metabolic coronary vasodilation, changes in myocardial oxygen supply were related to pacing-induced changes in MVO2, by using standard regression analysis. The myocardial oxygen supply/consumption ratio (i.e., the slope of the regression line at control, characterizing physiological metabolic coronary flow regulation) was compared with the ratios obtained during infusion of NTG. Compared with control measurements, NTG, 1 microg/kg/min, and NTG, 2 microg/kg/min, attenuated pacing-induced increases in MVO2 by 29 and 60%, respectively, whereas coronary blood flow during pacing remained unchanged. At control, normal metabolic coronary-flow regulation resulted in a myocardial oxygen supply/demand ratio of 1.39 (95% CI, 1.29-1.49). This ratio did not change during NTG, 1 microg/kg/min: 1.44 (95% CI, 1.33-1.56). However, during NTG, 2 microg/kg/min, this ratio significantly increased to 1.84 (95% CI, 1.63-2.05; p<0.01). Intravenous administration of high-dose NTG, a donor of exogenous NO, blunts pacing-induced increases in MVO2 and may increase metabolic coronary vasodilation in patients with CAD.     

Attenuation by isosorbide dinitrate of coronary occlusion-induced acidosis in the dog myocardium.

In dogs anaesthetized with pentobarbitone, the thorax was opened and myocardial pH measured continuously by the use of a glass pH electrode inserted in the left ventricular wall. The left anterior descending coronary artery (LAD) was partially occluded so that the LAD flow could be reduced to a half or one-third of the original flow (partial occlusion). LAD partial occlusion was continued for 90 min, drug or saline being infused for the last 60 min of this period. LAD occlusion decreased myocardial pH significantly by 0.41 to 0.67 pH units, and increased ST segment of the surface electrocardiogram from 11.7 to 12.1 mV. In dogs with non-ischaemic normal hearts, isosorbide dinitrate (ISDN; 1 mg kg-1) did not change markedly either the LAD flow, myocardial pH or heart rate, whereas it decreased myocardial contractile force (determined by a strain gauge arch) slightly and both the systolic and diastolic blood pressure markedly. In dogs with partial LAD occlusion, ISDN (1 mg kg-1) increased myocardial pH significantly and decreased blood pressure, but did not change ST segment elevation in an epicardial lead. These results indicate that ISDN attenuates ischaemia-induced acidosis without attenuating ischaemia-induced ST elevation in the dog myocardium.     

Ventricular fibrillation in a conscious canine model--its prevention by UM-272

The antifibrillatory properties of UM-272 (dimethylpropranolol; Pranolium) were evaluated in a conscious canine model of sudden coronary death. The initial preparation of the animal model was carried out under surgical anesthesia and involved the intraluminal implantation of a Teflon-coated silver wire into the circumflex coronary artery so that 3 mm of the bared electrode was in contact with the endothelial surface. The left anterior descending coronary artery then was occluded for a period of 90 min and reperfused in the presence of a critical stenosis. Three days after myocardial infarction, they were randomized into two groups. One group (n = 10) served as controls and received saline. The second group (n = 10) received UM-272 in a dose of 5 mg/kg every 6 h. On day 4, a 150 microA current was applied to the intimal surface of the left circumflex coronary artery, resulting in transient or permanent alterations in circumflex coronary blood flow accompanied by electrocardiographic evidence of regional myocardial ischemia. The time to onset of ST-segment changes in the saline control group was 99 +/- 34 min and was followed by the appearance of premature ventricular complexes (111 +/- 34 min) and subsequent ventricular tachycardia (131 +/- 37 min) which terminated in ventricular fibrillation in each of the 10 dogs. Animals treated with UM-272 likewise developed ST-segment changes (156 +/- 28 min) and premature ventricular complexes (168 +/- 29 min), but 4 of 10 animals failed to develop ventricular fibrillation (P less than 0.05 vs. saline). These results demonstrate that UM-272, the dimethyl quaternary analog of propranolol, is effective in reducing the incidence of ventricular fibrillation in a conscious canine model in which the superimposition of a transient ischemic event upon an already jeopardized heart leads to the development of sudden death.     

Effects of oral carbocromene pretreatment on infarct size following experimental coronary artery occlusion

This study examines the acute effects of the antianginal drug carbocromene (chromonar) in dogs (20 mg/kg p.o., twice daily for 8 weeks) on mortality, hemodynamics, coronary collateral blood flow, and myocardial infarct size. Following the chronic pretreatment and during acute phase of the experiments, the animals received an intravenous bolus of 4 mg/kg of carbocromene 15 min prior to left anterior descending coronary artery occlusion, and 40 micrograms/kg/min as an infusion during occlusion and reperfusion. Total mortality 2 days postocclusion was 50% in saline control experiments but 20% in carbocromene-treated animals (p less than 0.05). Hemodynamics were not significantly changed during drug administration except for a significant ST-segment elevation during vessel occlusion. Coronary collateral blood flow increased after carbocromene treatment by 30% (p less than 0.05) in the ischemic endocardial region and by 60% (p less than 0.02) in the border zone of the area at risk of infarction. Flow in nonischemic myocardium did not change so that "coronary steal" was not observed. At reperfusion, a flow increase occurred in the ischemic and border zones. Myocardial infarct size was 24% smaller after carbocromene than in control animals (p less than 0.02) when compared to the AR, and 46% smaller (p less than 0.01) in relation to the total left ventricle. We conclude that carbocromene administered orally before acute coronary artery occlusion and intravenously during occlusion and subsequent reperfusion can reduce infarct size by salvage of lateral and subepicardial border zones.     

急性冠脉综合征体表心电图与冠状动脉造影相关分析

目的通过对ACS患者选择性冠状动脉造影（CAG）结果及体表心电图表现的分析,进一步加深对ACS患者冠状动脉病变程度的认识,为临床医生及早预测病情凶险,采取干预措施提供一定的参考。方法87例行冠状动脉造影的临床诊断ACS患者为研究对象。男62例,女25例,平均年龄（59．86±11．21）岁。根据冠状动脉造影结果,血管的狭窄程度判定如下：〈50％为无明显狭窄,≥50％为有意义,50％-75％为轻度狭窄,75％～90％为中度狭窄,90％-99％为重度狭窄,100％为完全闭塞。病变部位分为左主干（LM）、左前降支（LAD）、左回旋支（LCX）、右冠脉（RCA）。根据受累血管的支数分单支、双支和多支病变。结果前壁、前间壁、广泛前壁及侧壁缺血的罪犯血管为LAD;侧壁缺血的罪犯血管除LAD外,还有LCX;下壁缺血者,其罪犯血管主要为RCA,少部分为LCX,极少部分为LAD。下壁及右室同时缺血者,高度提示RCA病变。NSTMI组中以双支以上重度病变为主。LM病变存在于广泛ST段下移的UA组中。UA的ST段改变呈多样性,以ST下移和ST无变化为主;ST无变化者,以双支或多支中重度病变为多。结论ECG对ACS单支冠脉病变定位准确率较高。LM病变存在于广泛ST段下移的UA组中。NSTMI多提示多支严重病变。UA心电图ST-T改变呈多样性,以ST段下移和ST段无变化为多见。心电图正常的UA患者中,除少部分为轻度冠脉狭窄外,多为双支或多支较重病变。