The effect of superoxide dismutase in the myocardium during reperfusion in the dog.

The aim of the study was to investigate the pathological role of free radicals during myocardial reperfusion. Low (0.5 mg/kg body weight) and high doses (5 mg/kg) of superoxide dismutase (SOD) were infused into the left atrium of mongrel dogs for 4 min starting 29 min after ligation and 1 min before reperfusion of the left anterior descending coronary artery (LAD). Arterial blood pressure, heart rate, electrocardiogram, and the regional contractile force of the left ventricle were monitored throughout the ligation (30 min) and reperfusion periods (20 min). Concentrations of creatine kinase (CK) and malondialdehyde (MDA) in the coronary sinus blood were determined before (0 min) and during ligation (15 and 25 min) and during reperfusion of the LAD (2, 7, and 20 min). In other groups of dogs, the effect of the two doses of SOD on epicardial blood flow was investigated during ligation and reperfusion by the measurement of epicardial temperature using a thermocardiograph. Experimental subjects were mongrel dogs of either sex (n = 25), weight 10-35 kg. Compared to controls (mean +/- SEM, 43.1 +/- 1.2; n = 7), the number of ventricular extrasystoles during the first 5 min of reperfusion was significantly (p < .001) decreased in dogs treated with the high dose (15.01 +/- 2.14; n = 5), but not in those receiving the low dose of the drug (34.6 +/- 5.66; n = 5). The concentrations of CK increased gradually until the end of reperfusion without differences among the different groups. Plasma MDA was the highest in control dogs 7 min after reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Drug effects on myocardial ischemia- and reperfusion-induced arrhythmias in anesthetized rats

The effects of drugs on ischemia and reperfusion-induced arrhythmias were studied in vivo in anesthetized rats. The chest was opened under artificial respiration and the heart was exposed. The left anterior descending coronary artery was occluded, followed by reperfusion for 10 min each. The drugs (mannitol 10-50 mg/kg, aspirin 0.25-5 mg/kg, verapamil 5-50 micrograms/kg and propranolol 1 mg/kg iv) were tested in the vagotomized animals. The test agent was dissolved in saline and 0.5 ml infused 15 min before the coronary occlusion. The results indicated that mannitol and aspirin reduced the incidence and duration of arrhythmias (ventricular premature contraction, ventricular tachycardia and ventricular fibrillation) during ischemia and reperfusion, while verapamil and propranolol reduced the incidence of arrhythmias during ischemia.     

Anti-arrhythmic action of adenosine and the cyclic nucleotide content of the myocardium of rats with ischemia

In anesthetized rats a 30-min intravenous infusion of adenosine (2.5 mg/kg/min) performed after the coronary artery ligation significantly decreased the incidence and severity of early ischemic arrhythmias. After the infusion of adenosine, there was an increase in cGMP level in the left ventricular myocardium, cAMP content remained unchanged.     

Hemodynamic effects of procainamide and quinidine and the influence of beta-blockade before and after experimental myocardial infarction.

The use of antiarrhythmie drugs in combination has been limited because of possible side effects secondary to myocardial depression in the acute myocardial infarction patient. Therefore, we investigated in intact dogs (group I) the hemodynamic interaction of propranolol plus procainamide (subgroup A) or quinidine (subgroup B) and in dogs after experimental myocardial infarction produced by coronary artery ligation (group II). Infusion of procainamide (30 mg/kg over 5 min) in animals of group IA produced a significant (P less than 0.05) decrease of 30% in mean aortic pressure, a decrease of 40% in left ventricular dp/dt and 29% in cardiac output. When procainamide was reinfuse after propranolol (1 mg/kg), its hemodynamic effects were not significantly different from those observed before propranolol in both groups IA and IIA. Infusion of quinidine (10 mg/kg over 5 min) in animals of group IB (intact dogs) also produced significant decreases of 24% in mean aortic pressure and 38% in dp/dt while cardiac output was unchanged. However, these hemodynamic changes were seen only after beta-blockade and were significantly different from those obtained before propranolol, where heart rate increased by 14%, dp/dt by 30%, and cardiac output by 35%. These changes occurred despite a similar reduction in mean aortic pressure. This drug combination produced similar response in animals after coronary artery ligation (group IIB). In conclusion, we feel that the administration of propranolol does not prevent the depressive circulatory effects of procainamide. The combined use of quinidine and propranolol also has a negative circulatory effect although not as marked as the effects observed after procainamide with propranolol.     

Inhibition of ischemia/reperfusion-induced damage by dexamethasone in isolated working rat hearts: the role of cytochrome c release

We investigated the contribution of dexamethasone treatment on the recovery of postischemic cardiac function and the development of reperfusion-induced arrhythmias in ischemic/reperfused isolated rat hearts. Rats were treated with 2 mg/kg of intraperitoneal injection of dexamethasone, and 24 hours later, hearts were isolated according to the 'working' mode, perfused, and subjected to 30 min global ischemia followed by 120 min reperfusion. Cardiac function including heart rate, coronary flow, aortic flow, and left ventricular developed pressure were recorded. After 60 min and 120 min reperfusion, 2 mg/kg of dexamethasone significantly improved the postischemic recovery of aortic flow and left ventricular developed pressure from their control values of 10.7 +/- 0.3 ml/min and 10.5 +/- 0.3 kPa to 22.2 +/- 0.3 ml/min (p < 0.05) and 14.3 +/- 0.5 kPa (p < 0.05), 19.3 +/- 0.3 ml/min (p < 0.05) and 12.3 +/- 0.5 kPa (p < 0.05), respectively. Heart rate and coronary flow did not show a significant change in postischemic recovery after 60 or 120 min reperfusion. In rats treated with 0.5 mg/kg of actinomycin D injected i.v., one hour before the dexamethasone injection, suppressed the dexamethasone-induced cardiac protection. Electrocardiograms were monitored to determine the incidence of reperfusion-induced ventricular fibrillation. Dexamethasone pretreatment significantly reduces the occurrence of ventricular fibrillation. Cytochrome c release was also observed in the cytoplasm. The results suggest that the inhibition of cytochrome c release is involved in the dexamethasone-induced cardiac protection.     

The early consequences of myocardial ischaemia and their modification

This paper attempts to review our studies on the early haemodynamic, metabolic and electrophysiological consequences of acute coronary artery ligation in an experimental model which allows the simultaneous assessment of blood flow and sampling of blood from both normal and acutely ischaemic zones of myocardium. 1. Using local coronary venous sampling, it has been observed that the major metabolic changes which occur in the ischaemic zone during the first 30 min after coronary artery ligation are increases in PCO2, decreases in pH and oxygen content, a shift in lactate handling from extraction to production and an efflux of K+. These changes were not observed in coronary sinus blood draining essentially nonischaemic zones of myocardium. 2. The major haemodynamic change produced by coronary artery ligation was cardiac depression (decreased stroke volume and cardiac work), unchanged LV dP/dt with an elevated filling pressure. 3. Acute ligation of the anterior descending branch of the left coronary artery, l.a.d., resulted in bursts of ventricular ectopic activity which was especially marked 10-20 min after ligation and which frequently resulted in ventricular fibrillation. The incidence of arrhythmias could be modified by the species of dog used, the anaesthetic employed, the arterial oxygen tension and the administration of several antiarrhythmic drugs. The possible relevance observed in the ischaemic myocardium, to the genesis of these arrhythmias is discussed. 4. The changes in the ST-segment of epicardial leads produced by short (3 min) occlusions of the l.a.d. were studied in mongrel dogs. Evidence is presented which suggests that the evolution of ST-segment elevation is linked to the efflux of K+ from ischaemic myocardial cells.     

Effects of the thromboxane receptor antagonist SK&F 88046 in the canine, monkey and human coronary vasculature

U-46619, a stable "functional" thromboxane/endoperoxide receptor agonist, produced potent contractile responses in isolated canine, rhesus monkey and human left circumflex coronary arteries (EC50 = 9.11 x 10(-9)M, 1.98 x 10(-8)M and 3.50 x 10(-9)M, respectively). Canine intrapulmonary veins were also contracted potently by U-46619 (EC50 = 1.22 x 10(-9)M). SK&F 88046, a thromboxane A2 (TxA2) end-organ receptor antagonist, blocked the vasoconstrictor effects of U-46619 in the canine circumflex artery (KB = 1.33 x 10(-8)M), canine intrapulmonary vein (KB = 1.46 x 10(-9)M), monkey circumflex artery (KB = 8.47 x 10(-8)M), and human circumflex artery (KB = 8.49 x 10(-7)M). SK&F 88046 was 10-60 times more potent in the canine and rhesus monkey coronary vasculature than in the human coronary preparations. Intracoronary administration of U-46619 to anesthetized, open chest dogs produced a dose-related decrease in left circumflex coronary artery blood flow which resulted in decreases in left ventricular developed pressure, left ventricular positive and negative dP/dt, ascending aortic blood flow, and an increase in left ventricular end-diastolic pressure. The decrease in coronary blood flow and the hemodynamic changes were either attenuated or completely inhibited by i.v. administration of SK&F 88046 (2.5 mg/kg + 0.05 mg/kg/min or 5.0 mg/kg + 0.1 mg/kg/min). SK&F 88046 was compared to two other TxA2 receptor antagonists in canine isolated intrapulmonary veins. SQ 29,548 was approximately 2-times more potent than SK&F 88046 as an antagonist of U-44619 mediated contractions (KB = 7.0 x 10(-10)M). In contrast, BM 13.177 was 150-fold less potent (KB = 2.19 x 10(-7)M) than SK&F 88046. Thus, the present study demonstrates species variability in response to TxA2 agonists and antagonists and reconfirms the relative importance of species selection in studying these agents.     

A3 adenosine receptor agonist IB-MECA reduces myocardial ischemia-reperfusion injury in dogs

We examined the effect of the A3 adenosine receptor (AR) agonist IB-MECA on infarct size in an open-chest anesthetized dog model of myocardial ischemia-reperfusion injury. Dogs were subjected to 60 min of left anterior descending (LAD) coronary artery occlusion and 3 h of reperfusion. Infarct size and regional myocardial blood flow were assessed by macrohistochemical staining with triphenyltetrazolium chloride and radioactive microspheres, respectively. Four experimental groups were studied: vehicle control (50% DMSO in normal saline), IB-MECA (100 microg/kg iv bolus) given 10 min before the coronary occlusion, IB-MECA (100 microg/kg iv bolus) given 5 min before initiation of reperfusion, and IB-MECA (100 microg/kg iv bolus) given 10 min before coronary occlusion in dogs pretreated 15 min earlier with the ATP-dependent potassium channel antagonist glibenclamide (0.3 mg/kg iv bolus). Administration of IB-MECA had no effect on any hemodynamic parameter measured including heart rate, first derivative of left ventricular pressure, aortic pressure, LAD coronary blood flow, or coronary collateral blood flow. Nevertheless, pretreatment with IB-MECA before coronary occlusion produced a marked reduction in infarct size ( approximately 40% reduction) compared with the control group (13.0 +/- 3.2% vs. 25.2 +/- 3.7% of the area at risk, respectively). This effect of IB-MECA was blocked completely in dogs pretreated with glibenclamide. An equivalent reduction in infarct size was observed when IB-MECA was administered immediately before reperfusion (13.1 +/- 3.9%). These results are the first to demonstrate efficacy of an A3AR agonist in a large animal model of myocardial infarction by mechanisms that are unrelated to changes in hemodynamic parameters and coronary blood flow. These data also demonstrate in an in vivo model that IB-MECA is effective as a cardioprotective agent when administered at the time of reperfusion.     

A novel minimal invasive closed chest myocardial ischaemia reperfusion model in rhesus monkeys (Macaca mulatta): improved stability of cardiorespiratory parameters

The aim of this study was to report the cardiorespiratory events observed during coronary artery occlusion and reperfusion in a minimally invasive closed chest myocardial occlusion-reperfusion model in rhesus monkeys. We hypothesized that a minimally invasive technique may lead to fewer cardiac arrhythmias and complications. Eight male rhesus macaques 10-15 kg and 10-15 years old were sedated with ketamine (2 mg/kg), midazolam (1.3 mg/kg), atropine (0.01 mg/kg) and buprenorphine 0.02 mg/kg intramuscularly. Etomidate 1-2 mg/kg was injected intravenously to allow tracheal intubation. Anaesthesia was maintained with isoflurane. Pulse oximetry, electrocardiogram (ECG), heart rate, mean arterial blood pressure (MAP), inspired isoflurane fractions (F(I)ISO) and core temperature were recorded every 10 min. The coronary artery occlusion was induced by a balloon-tipped catheter advanced via the femoral artery into the left anterior descending artery and inflated to completely occlude the vessel for 20-50 min (IT) before reperfusion. Sequences of elevated ST segment, QRS complex prolongation, ventricular premature complexes and ventricular fibrillation were observed with a lower incidence than previously described in the literature. IT was (min: 17; max: 50) min long. F(I)ISO was lower than the minimal alveolar concentration in these species. Hypotension (MAP < 70 mmHg) and hypothermia (T°C < 36°C) were observed in all macaques. This minimally invasive closed chest model was successful in providing better cardiorespiratory physiological parameters than reported in previous models. The benefit (achieving ischaemia) versus risk (lethal arrhythmia) of the duration of the coronary occlusion should be considered.     

Coronary endothelial dysfunction from ischemia and reperfusion: effect of reactive oxygen metabolite scavengers

Using anesthetized mongrel dogs exposed to 60 min of ligation of the left anterior descending coronary artery followed by 60 min of reperfusion, we examined the effect of superoxide dismutase (SOD) and dimethylthiourea (DMTU) on evidence of endothelial injury in coronary rings studied in vitro. In 13 dogs treated with saline rings from the normal left circumflex coronary artery (LCF) relaxed by 98 +/- 4% when exposed to 10(-5) M acetylcholine whereas rings from the left anterior descending coronary artery (LAD) relaxed by 79 +/- 7% (p less than 0.05). In the same rings maximum relaxation with the ionophore A23187 was 107 +/- 5% versus 87 +/- 8% (p less than 0.05) for the LCF and the LAD, respectively. Comparisons of concentration-response curves through a range of doses of both acetylcholine and A23187 revealed significant differences for both vasodilators between the LCF and the LAD (p less than 0.01 for each). Nine dogs were treated with bovine SOD infused in the left atrium the last 20 min of ligation and throughout reperfusion (140 units/kg/min) and six other dogs were treated with DMTU 500 mg/kg i.v. given the last 30 min of the ligation period. Neither SOD nor DMTU prevented endothelial injury in the LAD. Despite pretreatment with these agents, there were significant reductions in maximum relaxation and in total concentration-response curves in the LAD as compared with the results in rings from the LCF with both acetylcholine and A23187. There were normal responses to nitroprusside in both the LCF and LAD in all three experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of thromboxane A2 in reperfusion injury

Thromboxane A2 (TXA2) receptor antagonists can limit infarct size in models of coronary occlusion and reperfusion, but it was unknown if these compounds can mitigate reperfusion injury. Anesthetized open chest dogs were subjected to left circumflex coronary (LCX) occlusion for 90 min. Two minutes before reperfusion, the dogs were given iv saline (0.9% NaCl) or the TXA2 antagonist SQ 29,548 (0.2 mg/kg + 0.2 mg/kg/hr). Reperfusion was instituted for 5 hr at which time infarct size was determined. Regional myocardial blood flow was determined before, during, and after occlusion. SQ 29,548 treatment resulted in a significant reduction in infarct size (57 +/- 7 and 34 +/- 8% of the left ventricular area at risk infarcted in the saline and SQ 29,548 groups, respectively). No differences in collateral flow during occlusion were observed between groups, but SQ 29,548 treatment resulted in a significantly higher subendocardial reperfusion flow (54 +/- 10 and 93 +/- 14 ml/min/100g for the saline and SQ 29,548 groups, respectively). Thus, TXA2 seems to play a role in exacerbating reperfusion injury and TXA2 receptor blockade may have potential as a mode of therapy for ischemia-reperfusion damage.     

Pentobarbital versus medetomidine-ketamine-fentanyl anaesthesia: effects on haemodynamics and the incidence of ischaemia-induced ventricular fibrillation in swine

The present study was performed to compare haemodynamic variables at baseline and the incidence of ventricular fibrillation during the early phase of ischaemia in swine during pentobarbital or medetomidine-ketamine-fentanyl anaesthesia. Twenty-two swine (mean +/- SD: 29+/- 3 kg) were anaesthetized with sodium pentobarbital (induction with 36 mg/kg intraperitoneally, and maintenance with 5-20 mg/kg/h intravenously [i.v.]) and 6 swine (27+/- 3 kg) were anaesthetized with ketamine and fentanyl (premedicated with medetomidine 0.1 mg/kg and ketamine 10 mg/kg intramuscularly, induction with ketamine 20 mg/kg and fentanyl 0.025 mg/kg i.v., and maintenance with ketamine 20 mg/kg/h and fentanyl 0.025 mg/kg/h i.v.). After a stabilization period of 30 min, the left anterior descending coronary artery (LAD) was occluded for 10 min. Haemodynamic data and occurrence of ventricular fibrillation were recorded. The ischaemic area was measured by fluorescing microspheres. Swine anaesthetized with medetomidine-ketamine-fentanyl had significantly lower heart rate, myocardial contractility, peak left ventricular pressure, arterial blood pressure, aortic blood flow, myocardial blood flow and cardiac index at baseline, than swine anaesthetized with pentobarbital. Whereas none of the swine anaesthetized with pentobarbital fibrillated during the LAD occlusion, ventricular fibrillation occurred in 83% of the animals anaesthetized with medetomidine-ketamine-fentanyl (P< 0.001). No significant difference was found in size of ischaemic area between the two groups. Thus, we show a depression in haemodynamic variables at baseline and a higher incidence of ventricular fibrillation during the early phase of ischaemia in swine anaesthetized with medetomidine-ketamine-fentanyl compared to swine anaesthetized with pentobarbital.     

Effect of perezone on arrhythmias and markers of cell injury during reperfusion in the anesthetized rat

In the in vivo rat heart model with transient (5 min) regional ischemia, as induced by left coronary artery ligation, we have demonstrated that perezone reduces dramatically the incidence of reperfusion-induced-arrhythmias. Administered 5 minutes before coronary occlusion, at a dose of 3.1 mg/kg, this drug effectively protects against the high incidence of arrhythmias and the fall of blood pressure. In addition, it inhibits the release of lactic dehydrogenase and creatine-kinase enzymes to the plasma. We propose that the protective effect of perezone might be related to its well documented action of promoting the release of intramitochondrial Ca2+, thus, maintaining ATP production during reperfusion.     

Free radicals in reperfusion-induced arrhythmias: Study with EUK 8, a novel nonprotein catalytic antioxidant

Oxyradicals have been implicated as a possible cause of postischemic reperfusion arrhythmias (RA). However, the ability of enzymatic scavengers such as superoxide dismutase and/or catalase to reduce RA remains controversial. The purpose of the present work was to determine whether a nonprotein catalytic antioxidant, EUK 8, may limit RA in isolated heart preparations. The catalytic dismutation of H₂O₂ by EUK 8 was demonstrated using a Clark electrode. EUK 8's ability to scavenge oxyradicals was studied in vitro by electron spin resonance (ESR) in presence of superoxide-anion generating system. ESR concentration-effect curves obtained led us to use EUK 8 at 50 μmol/l in isolated heart preparations. Isolated rat hearts were submitted to 10 min regional ischemia induced by left coronary artery ligation. Reperfusion was achieved by releasing the coronary ligation, and the incidence and duration of early ventricular arrhythmias were then investigated. In the treated-group, EUK 8 was added to the perfusion fluid (50 μmol/1) 90 s before reperfusion. Our results show that EUK 8 significantly reduced the severity of RA as assessed by the arrhythmia score measurement (control: 3.46 ± 0.21 vs. EUK 8:2.73 ± 0.27, p < .05). In conclusion, EUK 8 is able to limit RA in our experimental model. This effect might be related to the catalytic antioxidant properties of this complex.     

Modification of the size of developing infarcts in the ligated dog heart by betahistine-HCL

The effectiveness of beta-histine-HCL in modifying the size of developing myocardial infarcts was tested in the surgically ligated dog. Branches of the left coronary artery were ligated and a 6-hour continuous intravenous infusion of 0.24 mg/kg/min of beta-histine was administered from 0 to 120 min after ligation. The effect of this treatment was evaluated histologically in studies on acute ischemia by the use of the hematoxylin-basic fuchsin-picric acid stain for early myocardial ischemia. The treatment was also evaluated grossly in a study on chronic ischemia where the dogs were permitted to survive for 30 days before sacrifice. In these experiments the size of infarcts found in the beta-histine-treated animals was compared with those found in the saline controls. Both studies showed that the control ligations produced a large uniform area of ischemia or infarction that was greatly reduced or prevented by immediate treatment with beta-histine. Also, beta-histine was capable of significantly reducing the size of developing infarcts for up to 120 min after ligation.     

Leukotoxin, 9, 10-epoxy-12-octadecenoate, causes cardiac failure in dogs

An epoxy derivative of linoleate, 9, 10-epoxy-12-octadecenoate, was demonstrated to be biosynthesized by leukocytes, thus nominated as leukotoxin. Its chemical structure was determined by gas-chromatography/mass spectrometry and nuclear magnetic resonance measurements. When it was injected intravenously, 15 mg/kg, canine heart showed signs of a typical cardiac failure; viz. Aortic flow started to drop immediately after the injection, and fell to 22% of the original at 40 min after the injection. At that point, systolic aortic pressure dropped to 35%, diastolic aortic pressure to 23%, and electronically differentiated maximal rate of left ventricular pressure rise (LV dp/dt) to 29%. All of experimental dogs died 40 to 50 min after the injection. On the contrary, administration of linoleic acid (15 mg/kg) did not affect these hemodynamical parameters. Therefore, leukotoxin seems to be an important factor to the genesis of heart failure.     

Effects of the lipolysis inhibiting agent beta-pyridylcarbinol (Ronicol) in acute myocardial ischaemia

The antilipolytic, nicotinic acid analogue beta-pyridylcarbinol (Ronicol) has previously been reported to decrease the free fatty acid (FFA) concentration of the arteria-blood, and to moderate the FFA-uptake and O2-consumption of the myocardium; on this basis, the drug may be expected to exert a cardioprotective action. The cardiac effects of Ronicol were therefore studied on a self-control, 'single-vessel' coronary artery ligature dog model. The left anterior descending coronary artery (LAD) was prepared in the in situ heart of anaesthetized, thoracotomized animals. Following the control ligation, a stabilization period and Ronicol infusion (1 mg/kg iv. during 10 minutes), the LAD was repeatedly ligated. The duration of the individual occlusions was 10 minutes. Ronicol significantly decreased the arterial FFA concentration and the epicardial ST segment elevation; its antilipolytic and anti-ischaemic effects were protracted and were still observed 120 minutes after pretreatment. The drug did not decrease the inhomogeneity of ventricular depolarization in the ischaemic myocardium and in the dose applied it had no influence on the heart rate, arterial blood pressure, left ventricular end-diastolic pressure and left ventricular contractility (LV dP/dtmax). In the canine myocardial infarction model employed it was observed that the duration of the anti-ischaemic effect of Ronicol (1 mg/kg iv.) is about 120 minutes. It has the advantage that it does not possess the unwanted cardiovascular side-effects displayed by nicotinic acid observed by us too in this model earlier (Cardiol. Hung. 13, 33-41, 1984).     

Cocaine-induced ventricular fibrillation: protection afforded by the calcium antagonist verapamil

There is increasing evidence that the use of cocaine can trigger lethal cardiac events, including ventricular fibrillation. The mechanism responsible for these lethal cardiac arrhythmias remains to be determined. Therefore, 13 mongrel dogs were instrumented so that heart rate, left ventricular pressure (LVP), and d(LVP)/dt could be measured. After a 3- to 4-wk recovery period, the left circumflex coronary artery was occluded for 2 min, beginning with the last minute of an exercise stress test and continuing for 1 min after the cessation of exercise. None of the dogs developed cardiac arrhythmias during the control exercise plus ischemia test. On a subsequent day, the test was repeated after the injection of cocaine HCl (1.0 mg/kg). Cocaine significantly (P less than 0.01) elevated heart rate, systolic LVP, and d(LVP)/dt, and it elicited cardiac arrhythmias in 12 of the 13 animals during the exercise plus test. In fact, 11 animals developed ventricular fibrillation. Verapamil, a calcium channel antagonist (250 micrograms/kg), attenuated the hemodynamic effects of cocaine and prevented the development of ventricular arrhythmias. These data suggest that cocaine can induce ventricular fibrillation during myocardial ischemia and that these lethal arrhythmias may be prevented by a calcium channel antagonist.     

Left ventricular catecholamines during acute myocardial infarction in the dog

To determine whether changes in left ventricular catecholamine content occur during the first 30 to 90 min of acute myocardial infarction, myocardial catecholamine (radioenzymatic assay) over the interval was studied in the dog. In nine pentobarbital-anesthetized opened-chest dogs without coronary ligation, myocardial catecholamine at 2.5 h after pentobarbital (i) consisted mainly of norepinephrine (87% total catecholamine), (ii) showed a base to apex gradient in norepinephrine (1.44 +/- 0.10 vs. 1.03 +/- 0.10 micrograms/g, p less than 0.05) and dopamine (0.20 +/- 0.03 vs. 0.12 +/- 0.02 micrograms/g, p less than 0.05) but not epinephrine (0.017 vs. 0.016 micrograms/g), and (iii) showed no difference in norepinephrine, dopamine, or epinephrine across basal, mid, and apical left ventricular transverse planes spanning the vascular territories of the two coronary arteries. In 18 pentobarbital-anesthetized dogs with coronary ligation, (i) norepinephrine, measured in 14 regions across the mid left ventricle after 90 min ischemia in four dogs, was less in the ischemic center of the occluded bed than normal myocardium (1.01 +/- 0.04 vs. 1.29 +/- 0.04 micrograms/g, p less than 0.05), and (ii) norepinephrine was unchanged in normal myocardium of 14 dogs at 30, 60, 90 min, and 48 h but decreased in ischemic myocardium by 31% at 60 min (0.89 +/- 0.10 vs. 1.29 +/- 0.08 micrograms/g, p less than 0.025) and 79% at 48 h (0.27 +/- 0.04 vs. 1.26 +/- 0.08 micrograms/g, p less than 0.001). Thus, norepinephrine depletion from ischemic but not normal myocardium is detectable by 60 min during acute myocardial infarction.     

Effects of inspiratory loading on left ventricular myocardial blood flow and metabolism.

With airways obstruction, mean pleural pressure decreases. It has been postulated that associated increases in left ventricular afterload increase myocardial O2 demand (MvO2) and coronary blood flow (CBF). We tested this hypothesis in 12 anesthetized mixed-breed dogs. Through a median sternotomy, dogs were instrumented for the measurement of mean arterial pressure, cardiac output, and left anterior descending CBF. A catheter placed in the coronary sinus allowed sampling of left ventricular venous blood. MvO2 was calculated as CBF x (arteriovenous content difference), and coronary resistance was calculated as (mean arterial pressure)/CBF. After closure of the thoracotomy, animals were studied before and during inspiratory threshold loading (IL) of -20 to -25 cmH2O while breathing 100% O2 before and after bilateral cervical vagotomy. During IL, heart rate fell [approximately 20 beats/min (NS prevagotomy, P less than 0.05 postvagotomy)], arterial PCO2 increased [45 to 66 Torr prevagotomy, 45 to 50 Torr postvagotomy (P less than 0.01)], and arterial O2 content was unchanged. CBF increased with IL:41% prevagotomy (P less than 0.01), 18% postvagotomy (P less than 0.02). However, with IL, MvO2 did not increase significantly either pre- or postvagotomy. Coronary resistance decreased with IL [30% prevagotomy, 24% postvagotomy (P less than 0.01)]. In eight dogs, PCO2 was increased by increasing dead space while the animals were mechanically ventilated and paralyzed. Although there was little change in CBF, heart rate fell by an amount equal to that with IL. We conclude that 1) IL causes coronary vasodilation not related to changes in MvO2, PCO2, or vagal tone; 2) MvO2 does not increase with IL; and 3) decreased heart rate with IL is related to hypercapnia and/or acidosis.