Effects of amlodipine on myocardial ischemia-reperfusion injury in dogs

The effects of the dihydropyridine calcium channel blocker amlodipine on subendocardial segment shortening (%SS), regional myocardial blood flow, myocardial high-energy phosphate levels and tissue water content were compared with those of a saline-treated group of barbital-anesthetized dogs subjected to a 45-minute coronary artery occlusion followed by 60 minutes of reperfusion. Saline or amlodipine (200 micrograms/kg administered intravenously) was given 15 minutes before coronary occlusion. There were no significant differences between groups in ischemic bed size or hemodynamics although dP/dt was higher after amlodipine administration. Subepicardial collateral blood flow was higher in the amlodipine group during coronary occlusion. After occlusion, %SS in the ischemic region was markedly decreased in both series and passive systolic lengthening resulted. Despite similar decreases in %SS during occlusion, the amlodipine-treated dogs showed a marked improvement in myocardial segment function of the ischemic reperfused region throughout 60 minutes of reperfusion compared with saline-treated dogs. In addition, amlodipine prevented the rebound increase in phosphocreatine and attenuated the loss of adenine nucleotides and increase in tissue water in the ischemic reperfused area at 60 minutes of reperfusion. These results suggest that amlodipine has a favorable effect on the functional and metabolic recovery of the ischemic reperfused myocardium and may have potential as a therapeutic agent for the treatment of coronary artery disease. The mechanism of action of amlodipine in this model is unknown but may be partially related to a drug-induced increase in coronary collateral blood flow or a decrease in afterload.     

Beneficial actions of amlodipine in the multiple-stunned canine myocardium

Summary The effects of the long-acting dihydropyridine calcium-entry blocker, amlodipine, on subendocardial segment shortening (%SS), regional myocardial blood flow (radioactive microspheres), and tissue high-energy phosphate levels were compared with those of a saline-treated group of barbital-anesthetized dogs subjected to nine 5-minute coronary artery occlusions interspersed with 15 minutes of reperfusion and finally by 1 hour of reperfusion (multiple stunned myocardium). Saline or amlodipine (200 μg/kg, IV) were administered 15 minutes prior to the first coronary occlusion. There were no major differences between groups in ischemic bed size or hemoydnamics throughout the experiment. Subendocardial collateral blood flow was significantly increased in the amlodipine-treated group during coronary occlusion 1; however, tissue blood flow in the ischemic region was not significantly different between groups during occlusion 9. Following each occlusion, %SS in the ischemic region was equally reduced in both groups and passive systolic lengthening resulted. In spite of similar decreases in %SS during occlusion, the amlodipine-treated dogs showed a marked improvement in myocardial segment function (%SS) of the ischemic-reperfused region at 15 minutes following each occlusion (1–9) and at 15, 30, and 60 minutes of reperfusion following occlusion 9, as compared to saline-treated animals. In addition, amlodipine attenuated the loss of adenine nucleotides in the ischemic-reperfused area at 1 hour of reperfusion. These results suggest that amlodipine has a favorable effect on the functional and metabolic recovery of the multiple-stunned myocardium and may have potential as a cardioprotective agent for the treatment of myocardial reperfusion injury.     

Regional differences in postischemic recovery in the stunned canine myocardium

To determine if differences exist in the degree of ischemic damage and in postischemic recovery when different coronary arteries are occluded and reperfused, 40 barbital-anesthetized dogs were subjected to brief 15-minute periods of coronary artery occlusion followed by 3 hours of reperfusion ("stunned" myocardium) of the left anterior descending (LAD) or the left circumflex (LCX) coronary arteries. Myocardial segment shortening (%SS) in the subendocardium of nonischemic and ischemic reperfused areas was measured by sonomicrometry, and regional myocardial blood flow was measured by radioactive microspheres. Transmural tissue biopsies were taken at the end of reperfusion for the measurement of adenine nucleotides and total tissue water content. Arterial and local coronary venous blood samples were collected during preocclusion, during occlusion, and at 30 and 180 minutes of reperfusion for determination of blood oxygen content and oxygen consumption in the ischemic area. During occlusion, subendocardial blood flow (LAD flow = 0.11 +/- 0.02; LCX flow = 0.15 +/- 0.04 ml/min/gm), myocardial oxygen consumption (LAD = 2.4 +/- 0.7; LCX = 2.7 +/- 0.7 ml/min/100 gm), and areas of the left ventricle at risk (LAD = 27.4 +/- 2.3%; LCX = 32.4 +/- 2.4) were similar in both groups, thus indicating equivalent degrees of ischemia. There were no differences between groups in hemodynamics throughout the experiment or in the loss of myocardial high-energy phosphates or increase in total tissue water in the ischemic reperfused area at 3 hours of reperfusion. There was a significantly greater loss (p less than 0.05) of systolic wall function during LAD versus LCX occlusion and a greater recovery of segment function from 5 minutes throughout 1 hour of reperfusion after LCX occlusion (p less than 0.05), with no difference in %SS at 2 and 3 hours following reperfusion. Thus, although similar changes occurred in blood flow, metabolite parameters, tissue edema, wall function, and overall hemodynamics when either the LAD or LCX perfusion territories were occluded and reperfused, the loss of systolic wall function and recovery of segment shortening were more variable after regional stunning of the LCX perfusion bed. These data suggest that evaluation of pharmacologic or surgical interventions to improve postischemic functional recovery may be more reliably performed when the LAD coronary artery is the vessel occluded.     

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.     

Beneficial effects of iloprost in the stunned canine myocardium

The effect of the prostacyclin-mimetic, iloprost, on the reversibly damaged ("stunned") myocardium was studied in barbital-anesthetized, open-chest dogs subjected to 15 minutes of coronary artery occlusion and 3 hours of reperfusion. Regional myocardial segment shortening (%SS) was measured in the subendocardium of nonischemic and ischemic-reperfused areas by sonomicrometry. Iloprost was infused for 30 minutes beginning 15 minutes prior to occlusion (0.05 microgram/kg/min, ILO-LOW, or 0.1 microgram/kg/min, ILO-HIGH) or immediately prior to reperfusion (0.1 microgram/kg/min, ILO-REP). %SS in the ischemic-reperfused region recovered to 3% of pretreatment values in the control (saline-treated) group by 3 hours of reperfusion. In contrast, %SS in the iloprost-treated groups was significantly enhanced versus the control group at all times of reperfusion. At 3 hours of reperfusion, %SS recovered to 43% (ILO-LOW), 58% (ILO-HIGH), and 35% (ILO-REP) of pretreatment values. The beneficial effect on functional recovery was significantly greater when iloprost was administered before occlusion versus immediately prior to reperfusion. Thus, part of the salutory effects of iloprost appear to occur prior to and/or during ischemia. Iloprost did not improve collateral blood flow to the ischemic region or myocardial high energy phosphate content at 3 hours of reperfusion. While iloprost significantly decreased mean arterial pressure during ischemia and early reperfusion, the hypotensive action did not appear to play a role in the amelioration of postischemic dysfunction, as preocclusion treatment with an equihypotensive dose of sodium nitroprusside produced no significant effect on postischemic recovery beyond 5 minutes of reperfusion. Results of in vitro experiments indicated that iloprost had no effect on the xanthine oxidase free-radical generating system including lipid peroxidation. However, iloprost decreased the neutrophil-derived superoxide burst after chemotactic stimulation. This beneficial action may, in part, explain the efficacy of iloprost in enhancing postischemic function of the stunned myocardium.     

Prostaglandin E1 attenuates postischemic contractile dysfunction after brief coronary occlusion and reperfusion

We have previously demonstrated that administration of the prostacyclin analogue iloprost improved postischemic functional recovery in reversibly injured ischemic-reperfused myocardium. The present study investigated the effects of administering an endogenous vasodilator prostanoid, prostaglandin E1 (PGE1), in the stunned myocardium (15 minutes of coronary artery occlusion and 3 hours of reperfusion) of anesthetized dogs. The percentage of regional myocardial segment shortening (%SS) after administration of PGE1 by two routes, intravenously (1 microgram/kg/min) or intraatrially (0.1 microgram/kg/min), to avoid pulmonary metabolism, 15 minutes before and throughout the period of occlusion, was compared to %SS in a control group treated with saline solution. Nearly equivalent reductions in mean arterial pressure during occlusion compared to pretreatment control (PTC) values were produced by intravenous (33%) or intraatrial (25%) PGE1. There was no difference in transmural myocardial blood flow (radioactive microsphere technique) in the ischemic region between the PGE1-treated and control groups at any time. Although there were no differences in %SS in the nonischemic region between groups throughout the experiment, postischemic recovery of segment function in the ischemic-reperfused area was significantly improved (p less than 0.05) at all times during reperfusion by intravenous PGE1 (%SS of PTC: 30 minutes = 65 +/- 8; 3 hours = 58 +/- 7) or intraatrial PGE1 (%SS of PTC: 30 minutes = 57 +/- 12; 3 hours = 50 +/- 4) compared to the control group (%SS of PTC: 30 minutes = 25 +/- 13; 3 hours = 10 +/- 13). Thus treatment with PGE1 attenuates postischemic contractile dysfunction in the stunned myocardium.2+ both.     

Coronary steal-induced increase in myocardial infarct size after pharmacologic coronary vasodilation

This study was performed to determine if maximal coronary arterial vasodilation of nonischemlc areas would produce an increase in myocardial infarct size through a “steal” of collateral flow from an ischemic region. Myocardial infarction was produced by a 2 hour occlusion and reperfusion of the distal left anterior descending coronary artery in anesthetized dogs. Five minutes after occlusion, 7 dogs were given saline solution, and in 12 dogs the coronary vasodilator chromonar (8 mg/kg, intravenously) was administered. Chromonar produced a significant Increase (p < 0.05) in blood flow to nonischemic regions and a concomitant decrease in flow to ischemic areas. Associated with these changes in flow was an elevation in total release and peak plasma creatine kinase compared with values in saline-treated control dogs. Myocardial infarct size determined with nitroblue tetrazolium staining was significantly increased (p < 0.05). These data demonstrate that maximal coronary vasodilation of nonischemic areas can result in an extension of myocardial infarction by a steal of collateral flow away from the ischemic region.     

Evidence for a role of iron-catalyzed oxidants in functional and metabolic stunning in the canine heart

Brief (15-minute) coronary occlusion and subsequent reperfusion lead to prolonged functional and metabolic abnormalities (stunned myocardium). Previous work suggests that one factor responsible for this phenomenon is oxygen-derived free radicals. The formation of the highly reactive hydroxyl radical requires the presence of metal ions, most importantly iron. In the present study, the effect of the iron-chelator deferoxamine on the recovery of segment shortening (%SS) in the stunned myocardium was compared with a control group in barbital anesthetized dogs. Deferoxamine (500 mg intra-atrially) was administered 15 minutes prior to and throughout 15 minutes of coronary occlusion. %SS, regional myocardial blood flow, hemodynamics, and myocardial high-energy phosphates were measured. Areas at risk, collateral blood flow, and all hemodynamic parameters were similar between control and deferoxamine-treated animals. While deferoxamine did not prevent the loss of systolic wall function that occurred during ischemia, deferoxamine significantly improved the recovery of %SS at all times throughout reperfusion (3-hour %SS of pretreatment: control, 12 +/- 11; deferoxamine, 65 +/- 12), normalized endocardial ATP (percent of nonischemic area: control, 79 +/- 3%, deferoxamine, 93 +/- 6%), attenuated the reperfusion-induced rebound increase in phosphocreatine and prevented the increase in tissue edema at 3 hours after reperfusion. Thus, deferoxamine exhibited a cardioprotective action both metabolically and functionally in the stunned myocardium presumably by decreasing the redox cycling, and hence, the availability of catalytic iron for use in hydroxyl radical formation and for the initiation of lipid peroxidation. These data suggest a possible role for the hydroxyl radical as a mediator of postischemic abnormalities in reversibly injured tissue.     

Alteration of endothelium-dependent distribution of myocardial blood flow after coronary occlusion and reperfusion

We have previously demonstrated that intracoronary infusion of the endothelium-dependent vasodilators acetylcholine, ATP, or arachidonic acid produces a preferential increase in subendocardial blood flow in anesthetized dogs. This study was performed to assess the effects of coronary artery occlusion and reperfusion on the distribution of myocardial blood flow produced by endothelium-dependent and endothelium-independent vasodilators. The endothelium was damaged by occlusion of the left anterior descending coronary artery for 45 minutes followed by 60 minutes of reperfusion in pentobarbital-anesthetized dogs. Intracoronary infusions of the endothelium-dependent vasodilators acetylcholine, bradykinin and thiazolylethylamine or the endothelium-independent vasodilator sodium nitroprusside were performed, and regional myocardial blood flow (by radioactive microspheres) was measured before and after occlusion and reperfusion. There were no changes in systemic hemodynamics during intracoronary infusion of vasodilators before or after coronary occlusion and reperfusion. All vasodilators produced similar increases in transmural blood flow before occlusion; however, only the endothelium-dependent vasodilators produced a significant increase in the subendocardial-to-subepicardial blood flow ratio. Increases in transmural flow as well as the preferential increase in subendocardial blood flow produced by acetylcholine, bradykinin, and thiazolylethylamine were attenuated after coronary occlusion and reperfusion. In contrast, increases in transmural blood flow produced by sodium nitroprusside were unchanged. These results suggest that the preferential increase in subendocardial perfusion produced by acetylcholine, bradykinin, and thiazolylethylamine is endothelium-dependent and may be selectively modified by ischemic insult.     

The experimental study of the coronary reperfusion in the acute myocardial ischemia: the feasibility of the myocardial salvage

In order to know the feasibility of coronary reperfusion by thrombolysis or aorto-coronary bypass graft in the early stages of the acute myocardial infarction, we studied the effect of the coronary artery reperfusion to acutely ischemic myocardium induced by the coronary artery occlusion in ninety-five anesthetized open-chest dogs. The major factors determining the extent of the myocardial salvage by the reperfusion were the duration of the occlusion time and the degree of the reperfusion injury. These two determinants were analysed by coronary circulation, the regional myocardial function, the mitochondrial metabolism, mitochondrial Ca and Mg contents, and morphological findings of the myocardium by electron-microscopy. The regional myocardial contractility (% systolic shortening) and the mitochondrial metabolism (oxidative phosphorylation) were significantly damaged by the reperfusion more in 60 minute occlusion than in 30 minute occlusion, although the coronary circulation (coronary blood flow, regional myocardial blood flow and coronary vascular resistance) and myocardial gas contents (PO2, PCO2 and pH) in the ischemic myocardium induced by less than 60 minute occlusion were almost recovered to the pre-occluded level by 60 minutes after reperfusion. By 120 minute reperfusion, the ischemic damage calculated from mitochondrial Ca and Mg contents (MC index: 1-[Mg/Ca] ischemia/[Mg/Ca] non-ischemia) was not changed in 30 minute occlusion but was significantly deteriorated in 60 minute occlusion. Therefore, coronary reperfusion must be started within 60 minutes or less after occlusion. A supplementary way to protect the myocardium from ischemia is needed as soon as possible before reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of nifedipine on the myocardial and vascular response to myocardial ischemia

Summary Nifedipine reduces reactive hyperemia following brief coronary artery occlusions. To determine whether this is related to improvement in collateral blood flow to ischemic myocardium or alterations in myocardial oxygen consumption, ten chloralose anesthetized dogs were instrumented with coronary sinus catheters, circumflex artery flowmeters, and ultrasonic microcrystals for measurement of myocardial segment shortening. Myocardial oxygen consumption and circumflex coronary artery flow were determined at rest and during incremental infusions of isoproterenol. Myocardial blood flow measured with microspheres and segmental function were assessed during and following 30- and 60-second coronary artery occlusions. Thirty minutes after the intravenous administration of nifedipine, 10 g/kg iv, all measurements were repeated. Nifedipine did not alter myocardial oxygen consumption or the relationship between oxygen consumption and circumflex coronary artery flow either at rest or during isoproterenol infusion. Following 60-second coronary occlusions, nifedipine reduced peak circumflex coronary artery flow (176±99 vs. 128±68 cc/min) and reactive hyperemia debt repayment (221±84 vs. 158±66%; p<0.01). Nifedipine did not alter flow to ischemic segments during coronary artery occlusions (0.16±0.10 vs. 0.19±0.13 ml/min/g mean transmural flow). Furthermore, nifedipine did not affect the severity of ischemic segment dysfunction, nor the rate of recovery of ischemic segment function following release of coronary artery occlusion. We conclude that the reduction in reactive hyperemia induced by nifedipine was not related to alterations in the severity of hypoperfusion in ischemic areas, or alterations in myocardial oxygen consumption. Reductions in reactive hyperemia produced by nifedipine did not impair recovery of mechanical function in postischemic myocardium.This study was supported in part by grants HL01162 and HL20598 from the National Heart, Lung and Blood Institute of the National Institutes of Health, Bethesda, Maryland; and by a grant-in-aid from the American Heart Association, Minnesota Affiliate, Inc. Dr. Homans was a fellow of the American Heart Association, Minnesota Affiliate, and recipient of National Research Service Award (HL06575) from the National Heart, Lung and Blood Institute of the National Institute of Health at the time that this work was performed.     

Effect of Poloxamer 188 on Collateral Blood Flow, Myocardial Infarct Size, and Left Ventricular Function in a Canine Model of Prolonged (3-Hour) Coronary Occlusion and Reperfusion

Poloxamer 188 is a surfactant with hemorheological, antithrombotic, and neutrophil-inhibitory properties. This agent has been demonstrated to reduce infarct size and to improve left ventricular function in animal models of myocardial infarction and reperfusion, and recently in a randomized trial of patients receiving thrombolytic therapy for acute myocardial infarction. In addition to reducing reperfusion injury, poloxamer 188 might be beneficial by increasing collateral blood flow. The purpose of this study was to determine the effect of poloxamer 188 on collateral blood flow, myocardial infarct size, and left ventricular function in a canine model of prolonged (3 hours) coronary occlusion and reperfusion. Closed-chest dogs (n = 21) underwent a 3-hour coronary occlusion and 3 hours of reperfusion. At 1 hour of occlusion, dogs received poloxamer 188, 75 mg/kg IV bolus, followed by 150 mg/kg/h IV for the final 2 hours of coronary occlusion and throughout reperfusion, or a saline placebo. Regional myocardial blood flow was measured using colored microspheres. Myocardial infarct size and area at risk were determined by postmortem histochemical staining. Compared with controls, poloxamer 188–treated dogs showed no significant increase in collateral blood flow during the final 2 hours of a 3-hour coronary artery occlusion. In addition, poloxamer 188 treatment had no beneficial effect on infarct size or left ventricular function in this model. Increased collateral blood flow is unlikely to be a beneficial mechanism of poloxamer 188 in myocardial infarction. These data also question the benefit of this agent to reduce reperfusion injury in the setting of more prolonged (3-hour) coronary occlusion.     

Effects of short-term, diet-induced hypercholesterolemia on systemic hemodynamics, myocardial blood flow, and infarct size in awake dogs with acute myocardial infarction

BACKGROUND. Short-term cholesterol feeding has been shown to affect vasomotor tone and increase infarct size in anesthetized rabbits. The purpose of the study was to determine whether acute hypercholesterolemia reduced collateral flow to ischemic myocardium and increased infarct size in the awake dog. METHODS AND RESULTS. Acute myocardial infarction was produced in awake dogs by a 4-hour left anterior descending coronary artery occlusion followed by 6-hour reperfusion after either a cholesterol-supplemented diet (n = 14) or a control diet of dog chow (n = 15) for 10 days. Infarct size was determined using nitroblue tetrazolium staining. In two subgroups, a 15-minute transient occlusion of the left anterior descending coronary artery was produced before the diet treatments and was compared with occlusion after diet treatments, so that the effects of hypercholesterolemia of collateral flow could be determined by paired comparisons. Cholesterol feeding increased plasma cholesterol to 288 +/- 52 mg/dl, which was twofold to threefold that in the control group (127 +/- 35 mg/dl), but had no effects on baseline systemic hemodynamics and myocardial blood flow. Coronary artery occlusion produced similar increases in heart rate, mean aortic pressure, left atrial pressure, and plasma norepinephrine in both groups of animals. However, cholesterol feeding reduced collateral flow to ischemic myocardium and increased infarct size, compared with the control group. The infarct size correlated with ischemic myocardial blood flow in both groups, but the slopes of regression lines relating the two variables did not differ between the two groups. CONCLUSIONS. Short-term, diet-induced hypercholesterolemia increased infarct size in awake dogs. This change results, at least in part, from a decrease in collateral blood flow to ischemic myocardium during coronary artery occlusion.     

The Effect of Verapamil on Experimental Myocardial Ischaemia with a Particular Reference to Regional Myocardial Blood Flow and Metabolism*

Summary: The effects of verapamil on epicardial ST segment elevation, regional myocardial metabolism and collateral blood flow were studied in open-chest anesthetized dogs following left anterior descending coronary artery occlusion. Collateral blood flow was measured by radioactive microspheres (15 ± 5 μ diameter) and regional metabolism was studied by measuring lactate concentration in venous blood draining the infarcting myocardium. Verapamil (0–2 mg/kg intravenously) produced a significant reduction (50–60%) in the epicardial ST elevation when it was given before coronary occlusion; when administered 15 minutes after coronary occlusion and infusion continued for two hours, it minimized (30–40%) ST segment elevation, and prevented the fall in cardiac index and rise in systemic resistance found in the untreated animals in which the ST segment remained persistently elevated. Changes in epicardial ST segment occurred without alterations in the QRS duration. Verapamil had no effect on either the total collateral blood flow or the relative distribution of flow to the endocardial and epicardial halves of the ischemic ventricular myocardium. No significant differences were found between the levels of lactate in blood sampled from small epicardial veins at the center of the infarct when the control animals were compared with those treated with verapamil.     

Protection of regional mechanics and mitochondrial oxidative phosphorylation by amlodipine in transiently ischemic myocardium

The effects of amlodipine (0.3 mg/kg administered intravenously, n = 5) and placebo (n = 5) on recovery of myocardial function and respiration of isolated mitochondria were examined in "stunned" myocardium of normotensive pentobarbital-anesthetized dogs. Measures of myocardial wall motion, using sonomicrometers, and tissue blood flow, by radioactive microspheres, were obtained at baseline, 15 minutes after administration of amlodipine or placebo, after 10 minutes of left circumflex artery ligation and at 60 minutes of reperfusion. Mean aortic pressure decreased from 115 +/- 6 to 101 +/- 5 mm Hg after administration of amlodipine and remained decreased throughout the experiment. Heart rate was not significantly affected at any time. Both groups showed similar degrees of ischemia: elevation of ST segment to 4.7 +/- 1.4 vs 6.2 +/- 1.9 mV; reduction of ischemic zone shortening fraction to 0.6 +/- 1.9 vs -3.4 +/- 2.7%; and reduction of epicardial and endocardial blood flows (epicardial = 40 +/- 13 vs 43 +/- 13 ml/100 g/min; endocardial = 7 +/- 4 vs 13 +/- 6 ml/100 g/min [values for amlodipine vs placebo]). Mitochondrial state 3 rate of respiration and respiratory control index indicative of rate of adenosine triphosphate synthesis and membrane integrity in myocardial samples taken after 10 minutes of ischemia were significantly reduced in the placebo but not in the amlodipine group. Myocardial function showed significantly greater improvement in amlodipine vs placebo at 60 minutes of reperfusion as indicated by shortening fraction (17.7 +/- -1.4 vs 5.8 +/- -3.5%, amlodipine vs placebo), which may have been related to increased myocardial blood flow and decreased blood pressure during reperfusion. Thus, amlodipine pretreatment prevented mitochondrial dysfunction during ischemia and accelerated recovery of both myocardial mechanical function and blood flow when compared with placebo.     

Preconditioning does not attenuate myocardial stunning.

BACKGROUND. Despite numerous reports that one or more episodes of brief coronary artery occlusion preconditions the myocardium and dramatically reduces myocardial infarct size produced by a subsequent prolonged ischemia, we recently demonstrated that preconditioning does not attenuate contractile dysfunction in the peri-infarct tissue. However, the specific effects of preconditioning on myocardium in which wall motion has not been compromised by the preconditioning regimen per se and is further submitted to a short ischemic insult (that is, not confounded by necrosis) remain unknown. METHODS AND RESULTS. We addressed these issues in the canine model of myocardial stunning. Eighteen anesthetized dogs underwent 15 minutes of coronary occlusion followed by 3 hours of reperfusion. Before the 15-minute coronary occlusion, each dog received one of three treatments: no intervention (control group, n = 6), one episode of 5-minute coronary occlusion/5-minute reperfusion (PC5 group, n = 6), or one episode of 2.5-minute coronary occlusion/5-minute reperfusion (PC2.5 group, n = 6). Segment shortening (SS) in the ischemic/reperfused midmyocardium was monitored by sonomicrometry, and myocardial blood flow was assessed by injection of radiolabeled microspheres. All three groups were equally ischemic during the 15-minute coronary occlusion: Midmyocardial blood flow averaged 0.05 +/- 0.02, 0.07 +/- 0.04, and 0.08 +/- 0.03 ml/min/g in control, PC2.5, and PC5 groups, respectively. Before the 15-minute coronary occlusion, PC5 dogs exhibited significant stunning (SS = 55% baseline; p less than 0.01 versus control), whereas PC2.5 dogs did not (SS = 91% baseline; p = NS versus control). However, segment shortening during the subsequent 15-minute coronary occlusion was equally depressed at -25% to -42% of baseline values among the three groups. Furthermore, all three groups demonstrated a similar degree of stunning after reperfusion: SS at 3 hours after reflow averaged 24 +/- 12%, 34 +/- 16%, and 48 +/- 12% of baseline in control, PC2.5, and PC5 groups, respectively (p = NS). The degree of recovery of function after reperfusion correlated with the amount of midmyocardial blood flow during coronary artery occlusion. However, this relation was not different among the three groups: Specifically, for any given collateral flow during ischemia, preconditioning did not reduce the degree of stunning. CONCLUSIONS. Preconditioning neither preserves contractile function during a reversible ischemic insult nor prevents myocardial stunning during the initial hours of reflow.     

Vascular and cardiac contractile reserve in the dog heart with chronic multiple coronary occlusions.

Nineteen mongrel dogs survived chronic occlusion of the left circumflex and of the right coronary artery without infarction due to the timely development of a collateral circulation. Only 38 per cent of the conductance of the arteries before occlusion was restored by collateral vessels. In these animals and in 15 control dogs with normal coronary arteries myocardial contractility, contractility reserve, and myocardial blood flow were studied. The same was done in dogs with chronic coronary artery occlusion after aortocoronary bypass. Myocardial blood flow was determined woth the tracer microsphere technique. Contractility reserve was tested and defined as isovolumetric left ventricular pressure and dp/dt max with norepinephrine infusion and cross-clamping of the aorta. Contractile reserve was not significantly different between normal dogs and dogs with chronic coronary artery occlusion before and after aortocoronary bypass. Myocardial blood flow during control conditions was homogenously distributed in all three groups studied. The ratio of blood flow to the endocardium and the epicardium was not significantly different from inity. Coronary reserve was determined at peak reactive hyperemia following a 20 second period of coronary artery occlusion, with ongoing norepinephrine infusion. Under these conditions subendocardial fow in normal dogs rose by a factor of 7.9 while subepicardial flow increased 7.4 times. In dogs with chronic occlusion of two coronary arteries the increase of myocardial flow was nonnomogenous; subendocardial flow to areas supplied by a normal coronary artery rose by a factor of 7.0 while subepicardial flow increased 5.7 times control. Subendocardial collateral flow rose by a factor of 2.4 and subepicardial collateral flow increased 3.5 times control. In normal dogs norepinephrine alone did not result in maximal coronary flow but only 57 per cent thereof. Dogs with chronic coronary occlusion, however, required the entire coronary reserve in areas that were supplied by a normal coronary artery, whereas areas supplied by collaterals became ischemic. Opening of an aortocoronary bypass restored normal flow to previously ischemic areas, and reduced the flow to areas supplied by a normal artery. With the bypass open no differences existed between normal dogs and those with two occluded coronary arteries. We conclude that the norepinephrine-stimulated contractile reserve of hearts with chronic coronary occlusion was comparable to that of normal hearts; however, norepinephrine forced these hearts to spend the entire flow reserve of the remaining normal artery while producing ischemia in collateral-dependent areas. The same dose of norepinephrine did not require the entire flow reserve of normal dogs.     

Superoxide dismutase plus catalase improve contractile function in the canine model of the "stunned myocardium"

Fifteen minutes of coronary occlusion followed by reperfusion does not result in myocardial necrosis; however, the contractile function and high energy phosphate content of the previously ischemic myocardium remains depressed or "stunned" for several hours to days after reperfusion. Oxygen-derived free radicals have been implicated in ischemia and reperfusion-induced injury in a variety of tissues. We wished to determine whether administration of free radical scavengers superoxide dismutase plus catalase before and during occlusion, and throughout reperfusion, could attenuate the "stunning" produced by 15 minutes of left anterior descending coronary artery occlusion in anesthetized, open-chest dogs. Segment shortening in the previously ischemic zone recovered to within only +/- 10% of preinfusion values in the control group during 3 hours of reperfusion, while, in the treated dogs, segment shortening returned to a maximum of 56 +/- 16% of preinfusion at 1 1/2 hours post-reperfusion (P less than 0.0003 compared to controls). Similarly, superoxide dismutase + catalase-treated dogs exhibited improved wall thickening during reperfusion (+30% to +70% of preinfusion values), compared to controls (0% to +10%). However, this improvement in contractile function in the treated group was not accompanied by increased adenosine triphosphate stores in the previously ischemic zone (31.8 +/- 0.8 vs. 28.2 +/- 2.2 nmol/mg protein for control vs. treated groups). Infusion of superoxide dismutase + catalase did not influence blood flow during occlusion or reperfusion. However, the treated group did exhibit a significant decrease in blood pressure during reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Salutary action of nicorandil, a new antianginal drug, on myocardial metabolism during ischemia and on postischemic function in a canine preparation of brief, repetitive coronary artery occlusions: comparison with isosorbide dinitrate

The effects of two antianginal drugs, nicorandil and isosorbide dinitrate (ISDN), on metabolism and function of the ischemic myocardium were studied in a preparation of multiple coronary occlusions in barbital-anesthetized dogs. The preparation consisted of three 5 min occlusions of the left anterior descending coronary artery interspersed by 30 min of reperfusion. An equihypotensive dose of nicorandil (7.5 micrograms/kg/min) or ISDN (12.5 micrograms/kg/min) was infused 15 min before and during the second occlusion period. Hemodynamics, myocardial segment shortening (%SS), tissue blood flow, and myocardial oxygen consumption were determined throughout. Uptake of free fatty acids (FFA), glucose, and lactate were determined during control and ischemic periods. At the end of the final 30 min reperfusion period, biopsy samples of transmural tissue were taken for analysis of phosphocreatine, adenine nucleotides, and total tissue water content. No major hemodynamic changes were produced by either drug except for a 5 to 10 mm Hg decrease in mean aortic pressure. Compared with untreated and ISDN-treated hearts, hearts of dogs treated with nicorandil exhibited reversal of a significant increase in FFA uptake during recurrent ischemia. This was accompanied by an attenuation of the increase in oxygen extraction and CO2 production in the ischemic zone by nicorandil, but not by ISDN. Nicorandil, but not ISDN, improved %SS during reperfusion. Endocardial ATP and total adenine nucleotides were preserved in both nicorandil- and ISDN-treated hearts. Tissue edema was also attenuated by both compounds. Thus, nicorandil improved both function and metabolism during recurrent myocardial ischemia independent of a hemodynamic effect, whereas ISDN only attenuated the loss of adenine nucleotides and increase in tissue water.     

Ventricular fibrillation resulting from ischemia at a site remote from previous myocardial infarction: A conscious canine model of sudden coronary death

In anesthetized dogs, a 30 gauge silver wire was inserted into the lumen of the left circumflex (LC) coronary artery and myocardial ischemic injury was produced by subsequent occlusion of the left anterior descending (LAD) coronary artery for 90 minutes followed by reperfusion through a critical stenosis. Four days after acute myocardial infarction, with the dog ambulatory, the intimai surface of the LC coronary artery was injured by applying a 150 μA anodal current. Coronary artery thrombosis and subsequent reduction in coronary artery blood flow were accompanied by S-T segment changes at 132 ± 65 minutes (mean ± standard deviation [SD]) with ventricular fibrillation (VF) occurring in 29 of 30 dogs (97% ) at 141 ± 60 minutes. Infarct mass in the LAD distribution was 15 ± 8% of total left ventricular mass with no histochemical evidence of irreversible ischemic injury in the LC coronary artery distribution. VF was preceded by the development of delayed electrical activity within the LC coronary artery distribution, and the development of ventricular arrhythmias accompanied by continuous local electrical activity within the subepicardial region of the distribution of the LC coronary artery. In 10 dogs with placement of a critical stenosis around the LAD coronary artery without earlier occlusion and reperfusion, LC intimal injury and subsequent thrombus formation resulted in only 2 deaths (20% ) from VF. Thus, acute myocardial ischemia at a site distant to a previous myocardial infarction enhances the likelihood of primary VF in the conscious dog. This model of sudden coronary death may simulate the clinical state in man and might serve as an appropriate model for the study of electrophysiologic mechanisms associated with the development of VF and for the evaluation of potential antifibrillatory drugs.