Acute Coronary Occlusion In Dogs Research Articles

Decreased regional lactate production and output due to intracoronary continuous infusion of esmolol during acute coronary occlusion in dogs

This study was designed to test the hypothesis that intracoronary administration of esmolol can confer metabolic protection during coronary constriction or occlusion, without affecting hemodynamic parameters, in a canine model. Seventeen anesthetized open-chest dogs underwent direct cannulation of the left anterior descending coronary artery (LADa), its companion vein (LADv), and the distal circumflex vein (CFXv). LADa flow was measured with an electromagnetic flowmeter. Using a micrometer-driven snare around the LADa, flow was reduced by 50%, 75%, and 100% for 15 minutes, with 1 hour of normal flow before each constriction. In 7 dogs (group 1) chosen randomly, esmolol, 15 to 20 μg/kg/min, was infused continuously into the LADa; the rate was adjusted to maintain baseline hemodynamic values. The second group (10 dogs) was not treated with esmolol. Heart rate (HR), electrocardiogram (ECG), LADa flow, LV dP/dt, and aorta (Ao), pulmonary artery (PA), LADa, and left ventricular (LV) pressures were recorded continuously. Cardiac output (CO) (thermodilution) was measured and blood was sampled from all catheters before and after constrictions for analysis of glucose, lactate, sodium, potassium, and blood gases. Flow and pressure in the LADa in both groups decreased similarly during each corresponding constriction. Systolic LV pressure, LV dP/dt, and LV stroke work index were affected in both groups only during 100% constriction. HR, Ao, and PA pressures, and total and peripheral pulmonary resistances were affected similarly in both groups during each constriction. Myocardial lactate extraction and consumption were less negative (negative = net production and output) in the LAD perfusion bed during corresponding constrictions with esmolol than without it. Electrolyte and glucose concentrations and extraction and arteriovenous oxygen content differences in the ischemic and nonischemic areas during constriction were affected similarly in both groups. The ratio of oxygen delivery to oxygen consumption in the ischemic zone was higher with esmolol than without it before constriction (75% and 100%) and during constriction (50%). This study indicates that the intracoronary use of esmolol during moderate-to-severe coronary hypoperfusion can protect ischemic myocardium.

Effects of the Partial β1-Adrenergic Agonist, Xamoterol, on Hemodynamics and Regional Myocardial Function During Acute Coronary Occlusion in Dogs

Xamoterol is a partial beta 1-adrenergic agonist that has combined beta 1-stimulating and beta 1-blocking actions. We studied the effects of xamoterol on hemodynamics and regional left ventricular (LV) function after circumflex coronary artery occlusion in eight anesthetized dogs. Left ventricular systolic wall thickening (%WT: sonomicrometry) was measured in nonischemic, marginal, and ischemic zones. Xamoterol (350 micrograms/kg i.v.) increased the maximum LV pressure (dP/dt) by 62% and aortic flow (AOF) by 52% and decreased LV end-diastolic pressure (EDP) but did not change heart rate (HR) and peak LV pressure (LVP). Xamoterol increased %WT in nonischemic (23.6 +/- 2.3 to 35.1 +/- 2.6%, p less than 0.05) and marginal (5.0 +/- 0.6 to 12.0 +/- 1.5%, p less than 0.05), but not in the ischemic region [-5.7 +/- 0.7 to -2.7 +/- 0.3%, not significant (NS)]. The beta 1-blocking action of xamoterol was evaluated. Xamoterol significantly attenuated the increase in HR and maximum dP/dt caused by isoproterenol (0.1 microgram/kg/min). %WT in each region was maintained at the level caused by xamoterol after isoproterenol. Thus, xamoterol improved cardiac function, yet prevented excessive stimulation by catecholamine in the presence of acute myocardial ischemia.

Reperfusion after acute coronary occlusion in dogs impairs endothelium-dependent relaxation to acetylcholine and augments contractile reactivity in vitro.

Endothelial injury may contribute to the augmented coronary vascular tone seen in myocardial ischemia by impairing endothelial production or release of vasodilators. In vitro reactivity of arterial rings was studied after 60 min of coronary occlusion and 60 min of reperfusion in anesthetized dogs. Ischemia without reperfusion blunted contractile reactivity to potassium chloride (KCl), whereas ischemia plus reperfusion augmented contractile responses to both KCl and ergonovine. The response to acetylcholine, an endothelium-dependent vasodilator, was abolished in reperfused arteries, whereas the response to nitroprusside, an endothelium-independent vasodilator, was intact. Verapamil pretreatment restored KCl contractile responses to normal in reperfused coronary rings and partially restored endothelium-dependent relaxation. Electron microscopy revealed a nondenuding epicardial coronary endothelial injury in reperfused arteries. These data support the hypothesis that reperfusion of ischemic myocardium augments reactivity to vasoconstrictor agents by causing endothelial cell damage, excessive calcium influx, and loss of modulating vasodilator function.

Evaluation of effects of nitroglycerin therapy by echocardiography.

Echocardiography (Echo) is a convenient method in diagnosing and in quantification of cardiac abnormalities, although dependent on registration quality. M-mode and two-dimensional Echo give adequate information regarding heart dimensions and cavity volume but only indirect information of pressures. M-mode Echo gives an ideal opportunity to study left ventricular wall motion as an expression of systolic and diastolic function. Both inter and intra patient comparisons will be possible to perform. Improved wall function after intake of nitroglycerin and other nitrate preparations, has been reported in Echo studies both in resting state and in induced acute myocardial ischemia during exercise in man or in acute coronary occlusion in dogs.

Salutary effects of moderate hypothermia on the circulatory and myocardial consequences of acute coronary occlusion in dogs

The efficacy of moderate hypothermia with rewarming in attenuating the myocardial and circulatory consequences of acute coronary ligation was studied in open-chest, anesthetized dogs. Thirty minutes after ligation of the proximal left anterior descending coronary artery, 14 dogs were surface-cooled to 27 °C, maintained at this temperature for 2 hr, rewarmed to normothermic levels, and monitored for an additional hour. Fifteen dogs were maintained for a corresponding time period after coronary ligation at normothermic levels. Dogs maintained normothermic demonstrated significant depression (from preligation values) of dP dt , cardiac output (CO), stroke volume (SV), and left ventricular stroke work and power (LVSW, LVSP) at elevated levels of left ventricular end-diastolic pressure (LVEDP). Dogs subjected to the hypothermic procedure demonstrated decreased inotropic status during hypothermia, but with rewarming, exhibited significantly greater values of left ventricular pressure, dP dt , CO, SV, LVSW, and LVSP at lower values of LVEDP than observed in dogs maintained normothermic. Increased dysrhythmic activity was not observed during hypothermia. Hearts from dogs subjected to the hypothermic protocol demonstrated qualitatively greater dehydrogenase activity both at the periphery and in the center of the nonperfused region. The results suggest that moderate hypothermia during evolving myocardial infarction may preserve left ventricular cardio- and hemodynamics and thus may be useful in delaying morphological and functional deterioration until definitive treatment can be instituted.

Potentiating effects of a ventricular premature beat on the alternation of the ST-T complex of epicardial electrograms and the incidence of ventricular arrhythmias during acute coronary occlusion in dogs

A relation between ST-T alternans (STTA) and incidence of ventricular arrhythmias (VA) was examined, and the effects of a premature beat on these were tested during acute coronary occlusion in dogs. Epicardial unipolar electrograms, epicardial and endocardial bipolar electrograms and monophasic action potentials were recorded during coronary occlusion. During the period of STTA, a remarkably late conduction and its alternation were also observed in ischemic areas. The more serious delay appeared during the negative deflection of the ST-T complex. VA followed mainly the negative deflection of the ST-T complex. The first premature activation appeared in either ischemic areas or the border areas. A ventricular premature beat (VPB) which occurred spontaneously or was produced by an electrical stimulation potentiated STTA, and additional VA frequently followed the negative deflection of the ST-T complex of the second sinus beat after the VPB. A VPB pronounced the conduction delay during the second sinus beat. The discordant STTA became concordant after the VPB. The duration of a monophasic action potential of the second sinus beat after the VPB in mildly ischemic areas decreased. These changes and enhanced STTA may contribute to the occurrence of the additional VA.

Effects of the ventricular premature beat on the alternation of the repolarization phase in ischemic myocardium during acute coronary occlusion in dogs

Effects of ventricular premature beats (VPB) on the alternans of the ST segment (ST alternans, STA) in the epicardial ECG and of the monophasic action potential (MAP) were examined during acute coronary occlusion in dogs. When STA was recorded simultaneously from four different points it was discordant in most cases. The discordant STA was accompanied by discordant alternation of the repolarization phase of MAP. A VPB transformed the discordant alternans into a concordant one and potentiated the degree of alternans. Transient prolongation or shortening of the cycle length showed effects similar to those of the VPB. The concordant alternans which was transformed from a discordant one by a VPB was not remarkably potentiated by a VPB, or by prolongation or shortening of the cycle length. It is possible that the transformation of the discordant alternans into a concordant one may contribute to the potentiation of STA by a VPB, and that the effects of VPB are due to the effects of the compensatory pause as well as the short cycle length associated with the VPB.

Effects of calcium antagonists on the electrical alternans of the ST segment and on associated mechanical alternans during acute coronary occlusion in dogs.

Effects of calcium antagonists on the ST alternans and associated mechanical alternans during acute coronary occlusion were examined in anesthetized dogs. The heart rate was fixed by atrial pacing. The intravenous administration of 0.2 mg/kg verapamil attenuated the ST alternans as did 0.5 mg/kg diltiazem. Although these drugs significantly attenuated TQ depression during occlusion, the attenuation was observed after a longer period of occlusion and when the degree of TQ depression was comparable to that during the control occlusion. Nifedipine, 0.03 mg/kg, slightly attenuated the ST alternans, but 0.5 mg/kg dipyridamole had no effect. These results support the idea that slow inward currents are involved in the ST alternans. On the other hand, the mechanical alternans was attenuated in six of 11 dogs. It is probable that factors other than the electrical alternans may also contribute to the mechanical alternans.

Diastolic synchronized retroperfusion versus reperfusion: Effects on regional left ventricular function and myocardial blood flow during acute coronary occlusion in dogs

The effects of 170 minutes of diastolic synchronized retroperfusion of the coronary sinus with arterial blood during 180 minutes of coronary artery occlusion on regional myocardial contractility (ultrasonic crystals) and blood flow (microspheres) were investigated in open-chest dogs. These effects were compared with those of 180 minutes of coronary occlusion and those of 170 minutes of anterograde reperfusion after 10 minutes of coronary occlusion in separate groups of dogs. Retroperfusion was able to almost restore transmural blood flow in the moderately ischemic zones and to increase it back to 47% of its preocclusion value in the severely ischemic zones with, in both zones, a favorable redistribution of flow toward the endocardium. Simultaneously, retroperfusion significantly improved segment length shortening in the moderately ischemic zones and significantly reduced the extent of paradoxical bulging in the severely ischemic zones. These partial recoveries in regional contractility and blood flow during retroperfusion were intermediate between those induced by 170 minutes of anterograde reperfusion and those of 180 minutes of coronary artery occlusion. Thus, in the presence of coronary artery occlusion, retroperfusion appears to exert a beneficial effect by improving both regional perfusion and function in the ischemic zones and may be proposed as a medical circulatory support to the jeopardized myocardium.

Effects of antiarrhythmic drugs on the ST-T alternans during acute coronary occlusion in dogs.

The relation between the alternation of the ST-T complex (ST-T alternans, STTA) and the incidence of ventricular arrhythmias (VA) was examined, and the effects of anti-arrhythmic agents on these were tested during acute coronary occlusion in dogs. From 2 to 10 points of epicardial and end-cardial surface of ischemic areas, bipolar electrocardiograms and unipolar electrocardiograms (EPeg) were recorded. At 2 to 4 min after the start of the occlusion, STTA apeared, and as the degree of STTA increased, VA occurred. VA usually followed the deep negative deflection of the ST-T complex in EPeg. VA in some cases was preceded by the delayed conduction of the ischemic areas, but in other cases, the first premature activation appeared in the border of the ischemic and normal areas. Phenytoin,10 mg/kg i.v., attenuated STTA and the incidence of VA. Quinidine, 10 mg/kg, slightly attenuated STTA and the incidence of VA. Procaineamide, 15 mg/kg, showed almost no effect on STTA. The incidence of VA correlated to the degree of STTA rather than to conduction delay. The present results suggest that there is a close relationship between STTA and the incidence of VA and that antiarrhythmic drugs did not always attenuate STTA.

Electrophysiologic effects of encainide following acute coronary occlusion in dogs.

Encainide, a benzanilide derivative, is a local anesthetic antiarrhythmic drug. To determine its effects on infarcted and normal tissue in situ, we infused encainide (1.0 mg/kg) for 15 min intravenously followed by 0.01 mg/kg/min for an additional 105 min in 8 adult open-chest, pentobarbital-anesthetized, atrially paced dogs after left anterior descending coronary occlusion. We monitored plasma concentration, blood pressure, and surface electrocardiogram (ECG). We determined conduction intervals from the onset of the QRS in the limb lead ECG to the major deflection of bipolar electrograms recorded in the infarcted and normal zones. We found that the blood pressure did not change significantly. Encainide did significantly prolong the atrial stimulus artifact-to-QRS interval and the QRS duration, as previously reported, and also prolonged intraventricular conduction intervals. In the infarcted zone, the drug prolonged conduction in both subendocardium and subepicardium, and prolongation was of somewhat greater magnitude in this zone than in the normal zone. Encainide prolonged the effective refractory period only in the infarcted zone (19 +/- 5 msec at peak; p less than 0.01). The above electrophysiologic effects may explain in part the previously demonstrated antiarrhythmic properties of this drug.

Neural, hormonal and intrinsic mechanisms of cardiac control during acute coronary occlusion in the intact dog

Three basic mechanisms may be involved in the control of cardiac function during acute coronary occlusion: (1) neural; (2) hormonal (circulating catecholamine); and (3) intrinsic (e.g. Frank-Starling law). The response of intact, sedated (Innovar-Vet, 0.08 cc/kg), chronically instrumented dogs to a 5 min left circumflex coronary occlusion was tested to delineate the relative roles of each of the above mechanisms. First, 6 innervated and 6 cardiac denervated dogs were examined. The major difference between groups was that the occlusion-induced tachycardia was significantly smaller in the denervated dogs than in the normally innervated animals (+10 ± 7 vs +27 ± 4/min, respectively, (mean ± S.D.)). Changes in the first time derivative of left ventricular pressure (d(LVP)/dt) were similar (−898 ± 556 vs −796 ± 274 mm Hg/sec denervated vs innervated). Decreases in stroke volume and mean arterial pressure were also similar in the two groups. The occlusion-induced tachycardia was compared in a second group of denervated dogs (n = 5) before and after administration of propranolol to examine the role of circulating catecholamines, and, by exclusion, to observe the response of the heart per se, independently of extrinsic control factors. The heart rate response was similar in both cases (+8 ± 4 vs +6 ± 4/min, unblocked vs blocked). Finally, blood pressure was prevented from fallingv during coronary occlusion in 3 normally innervated dogs by coupling the femoral artery to a reservoir of saline suspended above the animals. Blunting the input to the baroreceptors in this manner did not significantly change the size of the occlusion-induced tachycardia. We conclude that during acute coronary occlusion in dog: (1) the major role of the cardiac nerves involves modulating changes in the chronotropic state of the heart; (2) changes in d(LVP)/dt result principally from intrinsic phenomena linked to ischemia-induced alterations in myocardial performance; (3) changes in circulating catecholamines play only a minor role in controlling the heart during acute coronary occlusion in denervated dog; and (4) receptors located within the heart figure significantly in the etiology of the occlusion-induced tachycardia.

Effect of calcium antagonists on the electrical alternans of the ST segment during acute coronary occlusion in dogs.

Effects of antagonists on the ST alternans during acute coronary occlusion were examined in dogs. The intravenous administration of verapamil at doses of 0.1 mg/Kg and 0.2 mg/Kg prominently attenuated the degree of alternans. Diltiazem at dose of 0.2 mg/Kg also attenuated the degree of alternans. Dipyridamole at dose of 0.5 mg/Kg did not significantly attenuate the degree of alternans. Verapamil significantly inhibited the ST-segment elevation. After verapamil, ST alternans did not occur even after a longer period of occlusion when changes in QRS complex and the ST-segment elevation were remarkable. It is possible that verapamil inhibits ST alternans by both the protecting effect against ischemic injury and a direct effect on the electrical activity of the myocardial cell membrane.

The effect of hemodilution on experimental myocardial infarct size.

Hemodilution is used frequently for patients undergoing elective coronary bypass surgery but relatively little is known about the effects of hemodilution on acute myocardial infarction. Left ventricular infarctions were planimetered after acute coronary occlusion in dogs treated with and without hemodilution. The control group was maintained at a normal hematocrit (40-45) while the intervention group was hemodiluted with 6% dextran in saline 30 min after left anterior descending coronary artery occlusion to a hematocrit less than 50% of control (20). Systemic arterial and left atrial pressure were maintained at control levels as were arterial pO2 and pH. Mean infarct size in the control group was 20.72 +/- 1.38% (SEM) of the left ventricle while the hemodiluted group had a mean infarct size of 18.80 +/- 2.11% of the left ventricle. Reduction of red cell mass to less than 50% of normal does not increase the size of myocardial infarction after acute coronary artery occlusion suggesting that oxygen supply to ischemic areas is maintained if systemic hypoxia is prevented.

Aspirin-induced increase in collateral flow after acute coronary occlusion in dogs.

Aspirin (acetylsalicylic acid) has inhibitory effects on platelet function and prostaglandin synthesis. Since alterations in either platelet function or prostaglandin-mediated vascular responses could influence blood flow to ischemic myocardium, we tested the effects of aspirin on coronary collateral flow after acute occlusion of the left anterior descending coronary artery in dogs. Aspirin dose (600 mg i.v.) consistently inhibited in vitro ADP-induced platelet aggregation. In 13 open-chest dogs, regional myocardial blood flows (radioactive microsphere technique) were determined at 5 minutes and 4 hours after occlusion). In seven of these dogs, aspirin (600 mg i.v.) was administered 1 hour before occlusion. In the aspirin-treated dogs, collateral flow increased significantly (p less than 0.05), from 0.09 +/- 0.02 ml/min/g at 5 minutes to 0.15 and 0.02 ml/min/g 4 hours after occlusion. Collateral flow was not significantly altered over 4 hours in control dogs. The aspirin-induced increase in collateral flow was confined to epicardium (12 +/- 4% of normal zone flow at 5 minutes to 23 +/- 4% at 4 hours after occlusion).

157 - Effects of extrasystoles on the electrical and mechanical alternans during acute coronary occlusion in dogs

157 - Effects of extrasystoles on the electrical and mechanical alternans during acute coronary occlusion in dogs

Distribution of coronary blood flow during acute coronary occlusion in dogs. Effect of nicotinic acid and sodium salicylate

The effects of the antilipolytic agents nicotinic acid (NA) and sodium salicylate (SS) on the distribution of coronary blood flow during acute myocardial ischaemia were studied in open chest dogs. Fifteen min following experimental coronary artery occlusion, blood flow in the ischaemic myocardium was on average 28% of flow in the non-ischaemic myocardium. The reduction in blood flow in the ischaemic mycardium was more pronounced in the endocardial than in epicardial halves of the myocardium. No significant change in blood flow was observed after administration of NA or SS in either the ischemic or nonischemic part of the myocardium. Both drugs reduced the extent of myocardial ischaemic injury as shown by reduced epicardial ST-segment elevations. Arterial concentrations of fatty acids were lowered by NA or SS, whereas the mechanical activity of the heart remained unchanged. It is concluded that the reduction of acute myocardial ischaemic injury effected by NA or SS is not due to changes in myocardial blood flow, but more likely to lower myocardial oxygen demand related to reduced fatty acid utilization.

Irreversible myocardial damage resembling catecholamine necrosis secondary to acute coronary occlusion in dogs: Its prevention by propranolol

Coagulative myocytolysis resembling catecholamine myocardial necrosis is demonstrated in ischemic and normal cardiac muscle in dogs dying of ventricular fibrillation following acute ligation of the circumflex branch of the left coronary artery. The frequency of this lesion, possibly due to secondary sympathetic overstimulation, is significantly reduced by pre-treatment with propranolol.

Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs

The effects of various drugs on delayed activation of the ischemic myocardium and the incidence of ventricular arrhythmias were studied in 34 open-chest anesthetized dogs. The left anterior descending coronary artery was occluded for 6 minutes before and 42 minutes after administration of aprindine (2.85 mg/kg body weight), quinidine (8 mg/kg) and verapamil (0.2 mg/kg) and during infusion of isoproterenol (0.2 microng/min). The time intervals from the onset of the QRS complex to the major deflection of the bipolar electrograms recorded within the normal and ischemic zones were measured at cycle lengths of 500, 400 and 300 msec and were correlated with the development of ventricular arrhythmias. At a cycle length of 500 msec, aprindine increased by 19.5 msec the delay in activation time produced by coronary ligation alone (P less than 0.05), whereas verapamil reduced by 10 msec the extent of ischemia-induced conduction delay (P less than 0.05). The delay in activation time in the ischemic zone was not significantly altered by quinidine or isoproterenol. The incidence of ventricular arrhythmias was increased by aprindine (from 1 in 11 to 8 in 11 dogs), decresed by verapamil (from 3 in 7 to 0 in 7 dogs) and was not changes by quinidine or isoproterenol. Thus, delayed activation of the ischemic myocardium appears to play an important role in the genesis of early arrhythmias due to myocardial ischemia, and drugs that significantly depress conduction in the ischemic myocardium may predispose to the development of ventricular arrhythmia whereas those that improve conduction may be protective. Contrary to their effects on slow channel-dependent conduction, verapamil improved and isoproterenol worsened conduction during ischaemia.

Distribution of coronary blood flow during acute coronary occlusion in dogs. Effect of nicotinic acid and sodium salicylate

The effects of the antilipolytic agents nicotinic acid (NA) and sodium salicylate (SS) on the distribution of coronary blood flow during acute myocardial ischaemia were studied in open chest dogs. Fifteen min following experimental coronary artery occlusion, blood flow in the ischaemic myocardium was on average 28% of flow in the non-ischaemic myocardium. The reduction in blood flow in the ischaemic mycardium was more pronounced in the endocardial than in epicardial halves of the myocardium. No significant change in blood flow was observed after administration of NA or SS in either the ischemic or nonischemic part of the myocardium. Both drugs reduced the extent of myocardial ischaemic injury as shown by reduced epicardial ST-segment elevations. Arterial concentrations of fatty acids were lowered by NA or SS, whereas the mechanical activity of the heart remained unchanged. It is concluded that the reduction of acute myocardial ischaemic injury effected by NA or SS is not due to changes in myocardial blood flow, but more likely to lower myocardial oxygen demand related to reduced fatty acid utilization.